Drug Development Global Program

Tweet to Defeat: Twitter relay to help stop diarrheal disease

Join experts on Wednesday, October 11, for #overtakeDD, a global, 24-hour sprint of research and innovation.

Worldwide, health experts and communities are gaining on diarrheal disease. Yet even as impressive strides have been made to reduce deaths from diarrhea, the number of overall cases has seen only a modest decline. That means persistent gut infections still damage the health and potential of children, families, and communities.

It’s time to widen our lead.

On Wednesday, October 11, PATH and the Diarrhea Innovations Group (DIG) invite you to join diarrheal disease researchers, scholars, and advocates to help accelerate the pace of innovation.

For 24 hours, our #overtakeDD Twitter relay will put diarrheal disease on the spot, with dozens of experts discussing their research, highlighting tough questions and new ideas, and answering your questions.

We expect candid discussion on the future of research and development on our most stubborn challenges—and on what it will take to sideline diarrheal disease for good.

Visit us once, a few times, or all day at #overtakeDD to follow along, ask questions, and contribute to the conversation.

Why relay now?

Although safe, effective, and affordable treatment and prevention methods are available for diarrhea, they have not always been widely adopted or available, and may not offer comprehensive protection against diarrhea’s long-term effects. This leaves millions of children waiting for lifesaving solutions.

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Creating excellence for all

By Eric Nelson, MD, PhD, University of Florida College of Medicine and College of Public Health and Health Professions and Adam C. Levine, MD, MPH, Brown University Alpert Medical School

Dr. Nelson and Dr. Levine are members of the Diarrhea Innovations Group, housed at PATH.

Apple computer company was founded on three principles:

  • Empathy: “We will truly understand [the customers’] needs better than any other company”
  • Focus: “In order to do a good job of those things that we decide to do, we must eliminate all of the unimportant opportunities”
  • Impute: “People judge a book by its cover. People form an opinion about a company or product based on the signals it conveys. It must convey excellence.”

These principles are rarely extended to global health—where “field appropriate” approaches often become what Paul Farmer characterizes as “crap for poor people.”

Our team has embraced Apple’s principles to explore how we might impute excellence when it comes to last-mile delivery of care for the poor in remote regions. Our mission is to combine medical, technological, and scientific skill sets to discover new approaches to combat infectious disease outbreaks. We do this by listening to both patients and their health care providers in the hope that conversation uncovers unanticipated problems and reveals solutions inspired by the end-user.

Inspired solutions through dialogue

Three care providers at icddr,b huddle around a mother and child. One of the care providers holds a mobile phone, which he's using on app on to assess the child's level of dehydration.

A health care provider at icddr,b tests the Rehydration Calculator developed by our team to assess a child’s level of dehydration. Photo: Brown University Alpert Medical School/Adam Levine.

As a model system for intervention, we chose cholera outbreaks in Bangladesh and Haiti for several reasons: (i) proof of principle against a pathogen like Vibrio cholerae that kills swiftly and inflicts disproportionate harm on the extreme poor can have broad impact; (ii) cholera can be clinically diagnosed and prompt administration of low-cost oral rehydration solution or intravenous fluids as appropriate can drop deaths from 20 percent to less than 1 percent; and (iii) despite limited historical success, new tools and opportunities are coming together that inspire optimism for effective and rapid outbreak control in the future.

With these principles and strategy, we began building a dynamic and comprehensive team that included the Bangladesh Ministry of Health, rural government doctors and patients in Bangladesh, Silicon Valley and Hyderabad technology developers, mapping experts, and academic clinicians and scientists.

After a period of conversation with stakeholders in Bangladesh and Haiti, we identified two main problems with outbreak response. The first was that clinicians were not equipped with decision-support tools to make the right diagnosis and, therefore, treatment plans and clinical reports for epidemiologists were unreliable. The second was that paper-based data collection was unstructured and delayed. With so many data points, it was difficult to determine the most important data and make appropriate clinical decisions. In addition, smartphone survey tools required connectivity that did not exist in outbreak areas, and commercial survey products did not readily allow for team-based data entry.

Learning from failure

Over three years, we have systematically been addressing these challenges while having copious, but instructive, failures.

These failures have all stemmed from an under-appreciation of the fact that the ultimate sophistication is simplicity, another Apple priority. We began by making a decision-support tool that integrated with a data-collection tool and worked like an electronic medical record system for both doctors and epidemiologists. Although the tool failed pre-tests and live-tests, it took a year to acknowledge and stop the project. We pivoted to make a very simple two-page, decision-support calculator (known as Rehydration Calculator) for clinicians and then a separate lean data-collection platform for epidemiologists (the Outbreak Responder platform).

Screenshots of the mobile phone app.

Smartphone decision-support tool: (A) Home page with the Rehydration Calculator for decision support (upper) and the data-collection platform (lower). (B) Data input page. (C) WHO-derived recommendations for medication and fluid administration; units can be changed by side-swiping. “i” represents a link to educational summaries and primary publications. (D) Outbreak Responder data-collection and aggregation platform for the research team (also known as ‘Response Team’). ‘QI’ is a portal for customized quality improvement questions intended to be used by researchers only. Source: PLOS Neglected Tropical Diseases.

We tried to incorporate advanced Google maps techniques to map the dyad of treatment and residence locations. But we failed to appreciate that many communities do not conceive of their space in the two dimensions of a flat map. This led to a simpler solution that seems to work broadly; communities know their geographic hierarchy, such as United States/ California/ Santa Clara County/ Palo Alto. This discovery helped us to shift complexity (e.g., Google maps) away from the users on devices to the back end by providing a simple drop-down menu that queries their geographical hierarchy.

We began to learn what was beyond the scope of our core team’s mission. It became clear that we were developing a vehicle for information and that we were not the ones to populate the vehicle. There was a gap in high-quality research into the performance of diagnostic models and management strategies. Even the World Health Organization (WHO) guidelines for assessing dehydration in patients with diarrheal disease lacked sufficient evidence in accuracy and reliability.

While we may be able to improve adherence to guidelines with our calculator, the improvement is useless if the guidelines have not been rigorously evaluated and shown to work effectively in clinical practice. In response, the ‘we’ in the core team was expanded by establishing a partnership with Dr. Levine at the Brown University Alpert Medical School. Partnering with researchers at icddr,b in Bangladesh, Dr. Levine has begun developing new evidence-based assessment guidelines that may have greater accuracy for assessing dehydration in children with acute diarrhea than current standards.

Eye on customer, focus, and excellence

To impute excellence also requires validation. We view health technologies at times like medications. They may have indications, contra-indications, and unintended consequences. Dr. Nelson conducted a pre-intervention and intervention clinical study on the impact of the Rehydration Calculator at two hospitals in northern Bangladesh during the fall cholera outbreak season. The calculator led to the normalization of dehydration assessment, the correct antibiotic usage, and a decrease in IV fluid usage by approximately half.

These results were promising but the study lacked generalizability and independent control. A large cluster randomized control trial (RCT) is being started to address these limitations. Outbreak Responder was deployed in the pilot and will now be used in the cluster RCT to collect and aggregate nearly one million data points. In parallel, Dr. Levine has begun comparing the utility of paper versus smartphone adaptation of WHO and newer methods for assessing dehydration in children and adults; one goal of this project is to populate the Rehydration Calculator with these newer evidence-based methods.

This journey has had unexpected turns, challenges, and successes. We hope it shows that a mindful eye on customer, focus, and imputing excellence yields important gains. We are still mid-journey and plan to deploy both the Rehydration Calculator with updated assessment algorithms and the Outbreak Responder in Haiti. We view these technologies as additional tools in a larger toolkit that we hope will prove useful in the fight to eliminate cholera from Haiti. We also hope that this story has ripple effects beyond the infectious disease space.

Please contact us with ideas and questions.

PATH in San Francisco, Debbie Naguwa

PATH’s team in San Francisco works to advance transformative global health innovations to improve the lives of women and children, primarily through our work in drug development. In this post, we learn more about Debbie Naguwa, project administrator for PATH’s Drug Development program.

Photo: Debbie Naguwa.

How would you describe your role? Primarily, I manage financial data and budgets for our projects. I also assist with the initiation of new contracts and act as a liaison with Seattle headquarters to ensure compliance with PATH policies and procedures.

Where are you from? I am originally from Hilo, Hawaii. The picture featured here is Akaka Falls on the Big Island of Hawaii. A previous employer moved me from Honolulu to San Francisco. I love that people ask me questions about Hawaii before they go on vacation there!

At the Drug Development program retreat earlier this year, you became the first recipient (and namesake!) of a new award, recognizing “generosity of spirit, a bringing in of those who may otherwise be on the outside, and compassion.” Can you tell us about this special recognition? I’m a bit embarrassed about this, but I was honored and flattered to receive the inaugural “Deb Naguwa Aloha Award.” I was blown away to have an award named after me and look forward to recognizing another team member next year!

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WHA Roundup: a new WHO head, the demise of an R&D pooled fund, and the access debate rages on

This post originally appeared on the Global Health Technologies Coalition (GHTC) Breakthroughs blog.

By Matthew Robinson, MA, policy and advocacy officer, GHTC

Photo: World Health Organization/L. Cipriani.

As the 70th session of the World Health Assembly (WHA) winds to a close, memberstate delegates and civil society advocates are collectively taking a moment to catch their breath and reflect on an extremely eventful WHA. In a single week, the World Health Organization (WHO) gained a new Director-General—Dr. Tedros Gehbreyesus of Ethiopia—increased mandatory contributions from member states, and passed a landmark cancer resolution, just to name a few key decisions. In addition to these seismic shifts in the landscape of WHO, health research and development (R&D) was also featured prominently across a number of WHA agenda items, some of which saw highly consequential developments.

Consultative Expert Working Group on Research and Development: Financing and Coordination (CEWG)

The long-running CEWG process finally appears to have reached its end. After more than a decade of exploring approaches to support R&D for neglected diseases and actions to stand up a voluntary R&D-pooled fund at WHO, Assistant Director-General (ADG) Marie-Paule Kieny notified the Assembly that no further work would be done on either the pooled fund or the initial round of demonstration projects associated with it.

Her comments came at the close of a lengthy session in which both member states and civil society organizations universally echoed the call for more resources to enable the fund and demonstration projects to operate effectively, as well as bemoaning the lack of contributions to date. In justifying the decision to cease work on these projects, ADG Kieny noted that no additional funding has been raised for the fund beyond the US$11 million pledged over three years ago. With that level of funding, the programs were simply not sustainable, she explained.

On a positive note, the WHO Global Observatory on Health R&D—which was created to facilitate R&D coordination and guide prioritization—was spared the ax. While resources are not available to expand its database of R&D projects and data immediately, it is now operational and can be expanded at any time, as additional data and funding become available.

Access to medicines

As expected, the debate around access to medicines continued to rage at this year’s WHA. Although there was not a dedicated agenda item on follow-up to the United Nations Secretary General’s High-Level Panel on Access to Medicines (HLP) report, a number of countries, including Brazil, India, and Argentina, took every opportunity to raise the report in their remarks on other agenda items. In particular, agenda item 13.3 Addressing the Global Shortage of, and Access to, Medicines and Vaccines—which has historically focused more on supply chain issues—saw particularly heated debate, as well as intricate parliamentary maneuvering.

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Member Q&A: Robert Choy, PhD

This post originally appeared on Inside American Society of Tropical Medicine and Hygiene (ASTMH).

“The ASTMH Annual Meeting is one of the only times we can reliably expect that most, if not all, of our partners will gather in the same place.” –Robert Choy, PhD

Robert Choy, PhD, was randomly selected for a Q&A from among five members who correctly answered our trivia question in March during TropMed History Month. (The question: Besides Hurricane Georges in 1998, what other time was the Annual Meeting canceled? The answer: 1918, due to an influenza pandemic.) Dr. Choy is Associate Director, Research and Preclinical Development, with PATH’s Drug Development program, based in San Francisco. He received his PhD from the University of Washington in Molecular and Cellular Biology and is the world’s foremost authority on the effects of Prozac on C. elegans. In more than six years at PATH, he has worked with various industry, academic and government collaborators to advance drug development projects for enteric and diarrheal diseases. He recently contributed to a range of projects in the PATH portfolio, including a CFTR chloride channel inhibitor for cholera, novel inhibitors against various targets in Cryptosporidium, tribendimidine for soil-transmitted helminths, and nutritional interventions for environmental enteric dysfunction. In his spare time, Dr. Choy enjoys speaking to students and post-docs at local universities such as UC Berkeley, UC Santa Cruz and Santa Clara University about what it is really like to work on drug development for neglected diseases.

How did you know the answer to the TropMed History Week trivia question?
I found a copy of Dr. Stephanie James’s Presidential Address from 1998, the year that the Annual Meeting planned to be in Puerto Rico but was canceled by Hurricane Georges. In her address, she mentioned the cancelation of the 1918 meeting due to the influenza pandemic.

What are the global health R&D innovations that you are most excited about right now? 
I’m most excited about the FDA’s Priority Review Voucher (PRV) program, an innovative approach to incentivize global health R&D by offering a reward (the PRV) for registering a new treatment for a neglected tropical disease. The vouchers enable Priority Review (typically six months, as compared with the usual 10 or more months) for another drug application and are transferable. Since the program was initiated in 2007, at least six vouchers have been sold, with the most expensive going for $350 million. The potential payoff has attracted the attention of venture capital firms that have historically not been interested in tropical disease treatments because of the lack of commercial value. PATH recently was able to leverage the potential value of a PRV to secure a $25 million investment from Clarus Ventures and the Global Health Investment Fund to support the development of tribendimidine, a new treatment option for soil-transmitted helminths. In collaboration with Swiss Tropical Public Health Institute, the Chinese Center for Disease Control and Prevention, and Shandong Xinhua Pharmaceutical Company, we are working to advance tribendimidine for use in global deworming campaigns, and we are optimistic that this innovative funding model will provide a new source of support for other global health R&D innovations as well.

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How we measure the true impact of diarrheal diseases

By Ibrahim Khalil and Puja Rao, Institute for Health Metrics and Evaluation, University of Washington

The problem: One-time illness or lifelong impairment?

When a child experiences a single episode of diarrhea, they typically feel uncomfortable for a short period of time, but with appropriate care, they recover and continue to live a life free from disability. But when access to safe water and sanitation is limited—and children are constantly exposed to an assortment of bacteria and viruses—what happens when a child experiences frequent bouts of diarrhea without proper remedy? To answer this question, we need to better understand the cyclical relationship of diarrheal diseases and enteric infections during the crucial period of early childhood development and related poor health outcomes that can result over a lifetime.

Close-up of infant

Repeated enteric infections, such as diarrheal diseases, can impair a child’s growth and development and negatively impact long-term well-being. Photo: PATH/Gabe Bienczycki.

We know that repeated and persistent exposure to enteric infections like diarrhea may lead to intestinal inflammation and damage in the gut. Compromised gut health inhibits nutrient absorption in the body and can lead to malnutrition and eventually long-term health consequences, such as stunted physical growth, impaired cognitive development, and/or increased susceptibility to opportunistic infections, including pneumonia, the leading killer disease of children younger than five years. The more we understand about this vicious cycle, the better we are able to make meaningful policy decisions to break the cycle of poor health using primary and secondary prevention strategies.

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Meet the amazing cast behind a life-changing drug

This post originally appeared on the PATH blog

How one consortium is expanding drug options to fight parasitic worms worldwide.

Eugenio de Hostos, seated, holds a mug and talks to a colleague off camera.

Eugenio de Hostos leads PATH’s work in drug research and preclinical development. Photo: PATH/Erika Amaya.

It was well after midnight in San Francisco when Eugenio (“Geno”) de Hostos picked up the phone—but when his colleagues in China answered, he felt the familiar jolt of excitement.

He’d felt the same thrill at dawn, talking to his colleagues in Switzerland. At five, in a call to Maryland with the US Food and Drug Administration (FDA). And the previous week, chugging a cup of coffee while furiously scratching notes in a 6:00 a.m. conference call with project partners.

Geno leads PATH’s work in drug research and preclinical development, and for the last two years, he and his team—with pivotal support from colleagues at Swiss Tropical and Public Health Institute (Swiss TPH), the National Institute of Parasitic Diseases (NIPD) at the Chinese Center for Disease Control and Prevention, and Shandong Xinhua Pharmaceutical Company (XPC)—have been building a cast of global experts, partners, and funders to do something remarkable: get an underutilized, life-changing drug into the hands of communities affected by a debilitating neglected tropical disease.

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Breathing life into medical oxygen ahead of WHO committee decision

By Adam Lewis

This post originally appeared on The Huffington Post.

Mount Kilimanjaro stands nearly 20,000 feet above sea level, its snow-capped peaks providing a stark contrast against northern Tanzania’s otherwise equatorial backdrop. As Africa’s tallest mountain, it draws tens of thousands of climbers a year: some of whom reach the summit successfully, many of whom must stop short because of low levels of oxygen in their blood (the peak’s atmospheric pressure offers about half the breathable air as at sea level). The irony, however, is that in Tanzania – and nearly every country in sub-Saharan Africa – you don’t need to climb a mountain to reach an environment with too little oxygen; you just have to walk into a hospital.

Oxygen is one of the most frequently-required medical interventions in the world, yet it remains in critically short supply in low-resource hospitals. The World Health Organization (WHO) estimates that less than half of health facilities in Africa have reliable access to medical-grade oxygen – let alone the trained staff, supplies and infrastructure to deliver it.

Without medical oxygen, health providers are unable to treat critically ill patients with low levels of oxygen in their blood – an effect of conditions such as trauma, obstetric complications, heart failure and respiratory diseases like pneumonia, a leading cause of death for children globally. As one Tanzanian doctor recently explained to me, oxygen is essential throughout the entire hospital because low blood-oxygen levels – known as hypoxemia – can be both ubiquitous and, in many cases, fatal.

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Time to “decrypt” a wily parasite

By Robert ChoyAssociate Director of Research and Preclinical Development for Drug Development, PATH

Cryptosporidium harms children—we need research and development to stop it.

A still from the video, “DefeatDD: Superheroes vs. Villains.” Cryptosporidium is one of the featured bad guys. Image: PATH.

A lot of ugly things in nature are relatively harmless (Exhibit A: the star-nosed mole)—but Cryptosporidium isn’t one of them.

Unsettling under a microscope and dangerous in the human body, this tiny parasite is one of the most common causes of diarrheal disease (DD) worldwide. Yet for years, attention and research for “Crypto,” as it’s often called, has lagged.

Here’s the story of this “hidden spore”—and why research and development for effective tools should be a global priority, now.

The long-term consequences of diarrheal diseases

Worldwide, DD is a leading cause of death among children under five. Even when children survive the disease itself, repeated rounds put them at risk for long-term health and developmental consequences, including malnutrition, stunting, and deficits in cognitive development. Over time, persistent DD can also cause a kind of gut damage known as environmental enteric dysfunction, which contributes to malnutrition and can prevent some vaccines from working properly.

Together, these factors make children more vulnerable to opportunistic infections. In impoverished areas with limited sanitation, hygiene, and clean water, that can kick off a vicious cycle of illness, malnutrition, and reinfection.

Bringing the “hidden spore” to light

It turns out that Cryptosporidium (from the Latin for “concealed spore”) is the culprit behind many cases of DD worldwide—but we didn’t always know that. In 2013, a landmark study, the Global Enteric Multicenter Study, or “GEMS,” identified the viruses, bacteria, and parasites that most often cause DD.

Many of the usual suspects turned up. But so did Crypto—and that was a surprise. Continue reading »

PATH in San Francisco, Eugenio de Hostos

PATH’s team in San Francisco works to advance transformative global health innovations to improve lives of women and children, primarily through our work in drug development. In this post, we learn more about Eugenio de Hostos, director for research and preclinical development for PATH’s Drug Development program.

Eugenio de Hostos stands on a snowy mountain with a bright sky behind him.

On a ski trip in Switzerland. Photo: Eugenio de Hostos.

How would you describe your role? I lead our work on early-stage research and development (R&D) projects and build a pipeline of R&D opportunities.

Do you have any pets? My daughter has five fish in an aquarium. She outsources taking care of them to me.

What is one of your favorite sayings? The more you try to do, the more you actually do.

Who is one of your heroes? Albert Schweitzer, a French-German philosopher and physician. I am inspired by his selfless dedication to helping the sick and neglected, far away from his own home and in a time when few others cared about these things.

What was the last book you read? Lost City of Z by David Grann.

What do you like most about your job? The mission, the variety of things I get to do, and the opportunity to interact with a lot of interesting people.

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