Marissa Chmiola

In this regular feature on Breakthroughs, we highlight some of the most interesting reads in global health research from the past week. Last week, East Asia Summit members signed a regional commitment to eradicate malaria from the Asia-Pacific region by 2030. This communique, which came out of the 9th East Asia Summit, includes support for the research and development of new drugs and diagnostic tools to fight malaria. As the international community races to develop a vaccine against the Ebola virus, a World Health Organization official said the World Bank may establish a mechanism to help indemnify Ebola vaccine makers in case liabilities arise once a vaccine is widely administered. In some cases, rare adverse reactions to a drug are not always identified through the clinical trial process, so a mechanism that protects manufacturers from liability could reduce the financial risk of bringing an Ebola vaccine to market. The New York Times Magazine took an in-depth look at why there are so few blockbuster drugs invented today. Scientists expected that once the human genome was sequenced, it would usher in a golden era of drug development and profits for the pharmaceutical industry. While there have been breakthroughs, it’s since been discovered that most diseases affecting large numbers of individuals are caused by a handful of interacting mutations, which makes them tougher to treat and prevent. The article looks at this and other factors impacting drug development. A team of Chinese scientists claim to have eradicated malaria in Comoros—a small island nation off the east coast of Africa—by administering a new Chinese-made drug to all 700,000 people on the island as part of a massive medical experiment supported by the Comoran government. The scientists say that by administering repeated doses of medicine to everyone in the country for three months, they removed the malaria parasite from the bloodstream of the entire population, thereby halting the life cycle

In this regular feature on Breakthroughs, we highlight some of the most interesting reads in global health research from the past week. GHTC’s Senior Policy and Advocacy Associate Jenny Howell assesses how tomorrow’s congressional election results could impact global health research and development (R&D). With Republicans expected to gain seats in the House and take control of the Senate, shifts in the makeup and leadership of key committees with oversight over global health R&D are expected. Senators Tom Harkin (D-IA) and Lamar Alexander (R-TN) announced their intention to introduce a new bill to accelerate the development of treatments and vaccines for Ebola. The bill would add Ebola to the list of qualifying tropical diseases for the Food and Drug Administration’s priority review voucher program—which is designed to incentivize the development of drugs, vaccines, and other health tools for neglected tropical diseases. Emily Donaldson, program coordinator at AVAC, and Tom Harmon, senior policy analyst at the International AIDS Vaccine Initiative (IAVI), discussed the state of HIV prevention research funding while the first-ever conference devoted solely to HIV prevention R&D took place last week in Cape Town, South Africa. During his speech at the annual meeting of the American Society of Tropical Medicine and Hygiene, Bill Gates said he believes it is possible to eradicate malaria within a generation. To reach that goal, Gates pledged that the Bill & Melinda Gates Foundation would increase its malaria program budget by 30 percent—to more than $200 million per year. A group of European universities and medical groups plan to give experimental drugs to Ebola patients in West Africa without assigning any trial participants to a placebo group. These groups say it would be unethical to withhold potentially lifesaving treatment, but US officials argue that without a control group, it is impossible to assess whether the drugs are effective. The Wall Street Journal takes a deeper look at this debate.

Photo: © 2011, Charlotte Raymond Photography for International AIDS Vaccine Initiative (IAVI) With the 69th session of the United Nations (UN) General Assembly opening this week in New York and the global community debating how best to refine the post-2015 development agenda, over 150 organizations and individuals signed a petition to UN Secretary General Ban Ki-moon and Member States urging the UN to keep the research, development, and delivery of new and improved health tools at the heart of the post-2015 development agenda. Specifically, the petition—which was circulated by GHTC, the Council on Health Research for Development, and the International AIDS Vaccine Initiative—requests that the “UN fully supports in the post-2015 Sustainable Development Goals [(SDGs)]-Framework the research, development, and delivery of new and improved medicines, vaccines, and other health tools for the diseases and health conditions that predominantly affect low- and middle-income countries as well as marginalized, vulnerable populations globally.” The signing organizations and individuals represent a diverse group of research and academic institutions, private sector entities, and nongovernmental organizations from all regions of the globe: Africa, Asia, Europe, Oceania, and North and South America. GHTC is pleased to see such broad and substantial support for the inclusion of health R&D components in the post-2015 agenda, and hopes that the Member States and officials who are shaping the agenda will take note. Below is the full text of the petition and list of signatories: Excellency, Secretary General Ban Ki-moon, Member States of the UN, We, the below signatory organizations request that the UN fully supports in the post-2015 SDG-Framework the research, development, and delivery of new and improved medicines, vaccines, and other health tools for the diseases and health conditions that predominantly affect low- and middle-income countries as well as marginalized, vulnerable populations globally.  Thanks to the leadership of the UN and investments by Member States, the current Millennium Development Goals have made major contributions to improving the health and lives of millions of people around the world. A sustained focus on some of the greatest global health challenges has led to enormous progress in many areas, including significant improvements in the development and delivery of health tools such as drugs to treat HIV and AIDS, tuberculosis (TB) and malaria. Efforts to tackle diseases have also helped underpin progress in other important areas, such as gender equality, child mortality, and maternal health. Millions of lives have been saved. However, major challenges remain, and the health burden imposed by poverty remains far too high. In this context, it is essential that the post-2015 development agenda retains a strong focus on eliminating poverty-related diseases and conditions. The post-2015 agenda must build on previous achievements to ensure that healthy lives and access to health services can be achieved in an equitable and sustainable way, leaving no one behind. This means ensuring universal access to proven health interventions. But it also means developing and delivering new health technologies which can help address the shortcomings of existing interventions and sustainably reduce morbidity and mortality over the longer term. This will require continued support for the research, development, and delivery of new tools to the combat major epidemics like HIV and AIDS, TB, and malaria, as well as other poverty-related diseases and conditions ranging from neglected tropical diseases to reproductive, maternal, and child health. Continuous investment of human and financial resources in science, technology, and innovation is essential to achieve both economic and social development for all. We are encouraged by the current inclusion of the need to support the development of new medicines and vaccines for diseases particularly affecting developing countries in the Zero Draft document of the SDGs. Concern remains, however, about the omission of medical devices and diagnostics which also contribute to improving health outcomes, the lack of clarity on how this effort will be funded, and how supporting policies, incentives, capacity building, collaboration, and knowledge and technology sharing will be defined and implemented. As organizations working to save lives and improve health, we urge you to commit explicit and full support to health research and related policies and capacity building as a core component of a new, post-2015 agenda for equitable health and sustainable development for all. We ask that you press Member States to offer similar support, and to formally assess how to measure progress towards this goal, and how to fully and sustainably finance and enable the research, development, and delivery of essential new and improved health tools. Sincerely, ACTION Aeras African Services Committee AIDS-Fondet Amsterdam Medical Centre, University of Amsterdam American Society of Tropical Medicine and Hygiene Asociacion Gestion Salud Poblacion Association of Commonwealth Universities AVAC Bishkek Feminist Collective SQ Boston University Canadian Coalition for Global Health Research Canadian HIV and AIDS Legal Network Caribbean Public Health Agency Caribbean Vulnerable Communities Ciflorpan, University of Panamá COHRED Comité Nacional Cubano de Bioética Community Health Evangelism Programme Commonwealth Human Rights Initiative Department of Epidemiology, University Hospital F Hached, Tunisia Department of Psychiatry, Chiang Mai University Dept of Paediatrics, IrruaTeaching Hospital Edo State Nigeria Deutsche Stiftung Weltbevoelkerung Development of People's Foundation Drug Discovery Unit, University of Dundee Drugs for Neglected Diseasesinitiative Duke University ECOM - Eurasian Coalition on Male Health Egerton University Estonian Network PLWHIV European Investment Bank European Public Health Association Euvadis Facultad de Quimica, Universidad de la Republica, Uruguay Faculty of Tropical Medicine Federal Teaching Hospital Abakaliki, Ebonyi State, Nigeria FIND FIOCRUZ Fiocruz Minas Friends Africa (Friends of the Global Fund Africa) GAT George Institute GESPAM GlaxoSmithKline Global Alliance for TB Drug Development Global Health Advocates Global Health Consulting Global Health Council Global Health Technologies Coalition Global HIV Vaccine Enterprise Government of Kenya gTt-VIH (Spain) Hanoi School of Public Health Health Reform Foundation of Nigeria Edo State Chapter, HKMU Hospital Nelson Piccolo Hospital Sionsberg Hubert Kairuki Memorial University icddr,b IHCAI Foundation INDEPTH Network Institute of Human Nutrition and Food Institute of Tropical Medicine Institute Tropical Medicine Antwerp Instituto de Investigaciones Epidemiologicas, Academia Nacional de Medicina, Buenos Aires Instituto de Observação da Terra Instituto de Salud Carlos III Instituut voor Tropische Geneeskunde Interagency Coalition on AIDS and Development International AIDS Vaccine Initiative International Consortium on Anti-Virals International Organization for Chemical Sciences in Development International Partnership for Microbicides International Vaccine Institute Johns Hopkins Bloomberg School of Public Health Kairuki Memorial University Kapkatet medical training Centre Kenya National Bureau of Statistics Koningklijk Instituut voor de Tropen Kyrgyz Indigo La Gazette Law Office of Laurel G. Yancey, P.C. Medical Research Council of Zimbabwe Medicines for Malaria Venture menZDRAV Foundation Micro Insurance Academy Ministry of Education and Sports, Philippines Ministry of Health and Social Welfare, Tanzania Ministry of Health, Barbados National AIDS Research Institute National Institute of Health Research & Development NEPAD Science, Technology and Innovation Hub Netherlands Health Research Organization Nige Academy of Science North Eastern Council, Health Adviser One child-one world One Family Health Oswaldo Cruz Institute Parviflora Research Organization PATH People’s Health Movement Philippine Council for Health Research and Development Philippine Department of Health Policy Cures Population Council Public Health Institute Public Private Partnership Health Society RALSA Foundation Research Department, National Hospital Rosales Research into Cultura and Reproductive Health For Sustainable Human Development (RECARDEV) RESULTS UK Royal Tropical Institute, Netherlands Rural Community Health Research SA Medical Research Council Sabin Vaccine Institute School of Population Health, University of Queensland Section of Infectious Diseases, Dept of Medicine, St Luke's Medical Center, QC, Philippines Sensoa South Africa-Department of Health South African Research Ethics Training Initiative STOP AIDS Swiss Tropical & Public Health Institute The Africa Centre for Health and Population Studies The Environment Ameliorators The University of Western Australia Tools To Work Treatment Action Group Uhamka University Unidad de Investigacion Cientifica, Facultad de Ciencias Medicas, UNAH Universidad del Valle Universidad Nacional Autonoma de Mexico Universidade de Sao Paulo University of Bergen University of Birmingham University of Brasilia University of Cagliari University of California, Irvine University of Cape Coast University of Edinburgh University of Health and Allied Sciences, Ho. Ghana University of KwaZulu-Natal University of Melbourne University of Nigeria, Nsukka University of Oslo University of the Witwatersrand Washington Global Health Alliance Y+ Network Individuals: Alix Beith Francesca Coloni Franko Family Wanjiku Kabiru Malcolm McNeil Ophelia Mendoza Ellene Mocria  

Earlier this month, advocates from the Community Research Advisors Group (CRAG)—an international, community-based advisory body working to ensure the engagement of affected communities in tuberculosis (TB) research conducted by the Centers for Disease Control and Prevention (CDC) —published an article in The Lancet offering a community perspective on the use of the drug bedaquiline to treat drug-resistant and drug-susceptible TB. The US Food and Drug Administration (FDA) approved bedquiline for the treatment of drug-resistant tuberculosis—via an accelerated approval process—in December 2012, making it the first new drug from a novel class approved to treat TB in more than 40 years. Laia Ruiz Mingote and Dorothy Namutamba—co-chairs of CRAG— and Mike Watson Frick—TB/HIV Program Officer at GHTC member organization, Treatment Action Group—are among the article’s co-authors, and join us to answer questions about the article and discuss the benefits and risks of using bedaquiline to treat TB. Bedaquiline is the first new drug from a novel class approved to treat TB in more than 40 years. PATH/Katrina Peach Q: Bedaquiline has been shown to be effective in treating drug-resistant TB in combination with other drugs, but it also has some serious side-effects and risks. Explain what those are. In Phase II studies, bedaquiline showed promising activity against multidrug-resistant TB (MDR-TB). The drug reduced the average time to a negative TB culture from 18 to 12 weeks and increased the proportion of participants with a negative culture at 6 months from 58 percent to 79 percent. However, bedaquiline posed several safety concerns that should be addressed before testing the drug in people with drug-susceptible TB. Most attention has focused on bedaquiline’s association with QT prolongation—a potentially serious disturbance in the heart’s electrical rhythm. Other TB drugs also cause QT prolongation, including moxifloxacin and the other new MDR-TB drug, delamanid (developed by the company Ostuka). Other side effects of bedaquiline include liver toxicity, accumulation of phospholipids in cells, and even death. In one Phase II trial, a significantly higher number of participants receiving bedaquiline died than those receiving placebo. While these deaths did not have a common cause and occurred months after the trial, the FDA could not rule out the possibility that bedaquiline played a role. Since bedaquiline has a long half-life, meaning that it remains in the body for a long time, the drug may continue to pose a side effect risk to patients even after they stop taking it. Q: Given its side effects and risks, do you still believe bedaquiline merited accelerated approval by the FDA? Do you believe other countries should also approve bedaquiline’s use for drug-resistant TB? The accelerated approval was necessary. There are few effective treatment options for patients with MDR-TB and extensively drug-resistant TB (XDR-TB), and many of these patients are unable to tolerate existing options, as they also have strong side effects and risks of their own including hearing loss, neurological disturbances, and skin discoloration. However, there is a need for more information and clinical data to know how to manage the risks tied to bedaquiline. We have to make it clear that bedaquiline is not for all TB patients, but rather only for those people who are unable to tolerate other MDR-TB drugs to which their TB is susceptible or who might not survive without access to bedaquiline, as there are no other treatment options. In countries and regions with high incidence of drug-resistant TB, bedaquiline is a necessary and important addition to second- and third-line therapies. Yet most countries have been slow to approve bedaquiline, meaning that most patients can only access it through unreliable compassionate use mechanisms. Other countries, particularly those of the former Soviet Union, lack the legal frameworks that enable compassionate use. In countries with high incidence of drug-resistant TB, bedaquiline is an important addition to second- and third-line therapies. PATH/Nguyen Ba Quang Additionally, the high price of bedaquiline may discourage its use among patients who need it most. Janssen—the company that developed bedaquiline—has announced a tiered pricing scheme in which the price of bedaquiline varies depending on a country’s Gross National Income: high-income countries will pay about $30,000, middle-income countries will pay $3,600 and low-income countries will pay $900. Countries with the most severe MDR-TB epidemics are usually middle-income countries including South Africa, India, Russia, and China. While South Africa may be able to access the lowest price of bedaquiline, it’s unclear whether Janssen will extend the lower $900 price to other middle-income countries like China, where second-line TB drugs are not provided for free by the government. Can Chinese TB patients really afford bedaquiline at a price of $3,600? Even in high-income countries, the steep price of the drug can drain the general budget of TB programs, especially considering the high cost of other second-line drugs used to treat MDR-TB. Finally, in ensuring access to the treatment, Janssen must also make every effort to track safety and patient outcomes in people who receive bedaquiline. In the United States, a patient registry exists in theory, but many doctors do not know about the registry, and those who do have had difficulty enrolling patients into it. In the absence of a Phase III clinical trial of bedaquiline, patient registries may offer the best way to obtain additional safety data. Q: Clinical trial data on bedaquiline’s use for drug-resistant TB suggests it could also be effective in shortening treatment time for drug-susceptible TB as part of a first-line therapy combination. What are your concerns about the inclusion of bedaquiline in trials exploring its use for drug-susceptible TB? As mentioned, bedaquiline is a game changer in cases of MDR- and XDR-TB. However, for drug-susceptible TB, we have a well-established standard of care and other options for shortening treatment using existing drugs—such as rifapentine which is manufactured by Sanofi—or investigational drugs— such as PA-824 which was developed by the TB Alliance—that so far lack the safety signals observed in the Phase II trials of bedaquiline. The CDC’s Tuberculosis Trials Consortium will soon begin a Phase III study to see if replacing rifampicin with rifapentine can shorten drug-susceptible TB treatment from 6 to 4 months. The TB Alliance is also testing a 4-month drug-susceptible TB treatment regimen that uses a combination of PA-824, moxifloxacin, and pyrazinamide. Patients with drug-susceptible TB face a very different risk-benefit trade-off than people with drug-resistant TB. Currently, drug-susceptible TB has a safe and effective standard of care, although we agree that at six months, it is too long and there is the necessity to make it shorter. It is because of the safety of the regular regimen that, together with the current data, bedaquiline may not offer the best way forward for shortening drug-susceptible TB treatment. We believe that before studying bedaquiline for drug-susceptible TB, we need much more information about this new drug, its long-lasting presence in the body and common side effects. In addition, the use of bedaquiline in first line treatment could, in fact, risk an increase in resistance, leaving patients with fewer treatment options.

  Breastfeeding has served as the primary method for a mother to feed her infant since the dawn of humanity, but could it also be a way for her to administer life-saving medicines to her baby? The answer is yes—if a group of researchers from the United States and United Kingdom have their way. The JustMilk nipple shield contains a rapidly dispersible tablet containing drugs or nutrients that are delivered to the infant during breastfeeding. Photo: JustMilk The researchers—who have formed the nonprofit JustMilk—are developing a nipple shield device that allows a breastfeeding mother to administer drugs or nutrients to her infant through her breast milk. The device is easy to use—a mother would simply place the shield—which contains a rapidly dispersible tablet potentially containing antimalarials, antiretrovirals, antibiotics, or micronutrients—on her breast while feeding her child. As the milk passes through the device, it breaks down the tablet and delivers the medicines or nutrients to the infant. The “eureka moment” According to JustMilk’s cofounder Dr. Stephen Gerrard, PhD, the idea for the device emerged out of a design challenge—how to prevent HIV transmission during breastfeeding in developing countries—that his team was issued at the 2008 International Development Design Summit. The team had an idea to create a wearable device that deposits HIV-inactivating compounds into breast milk. After discovering the existence of both potential compounds and a wearable device—a nipple shield—the team realized it was on to something. “The eureka moment was that we could combine the two, and then you have a way of depositing antimicrobial compounds into milk,” said Gerrard. “The second point straight after that was—hang on—this could be a general drug and nutrient delivery device for infants.” Since then, the JustMilk team has focused on the broader potential of the device as a drug or nutrient delivery system. “Over 4.8 million infants under the age of one die each year from conditions like pneumonia, malaria, diarrhea, and HIV,” said Gerrard. “And an overwhelming majority of those conditions can be treated, and the deaths can be avoided by appropriate administration of agents to the infant….We’re trying to tackle those big issues, and we’re looking to make a major impact.” Overcoming the challenges of drug delivery in low-resource settings Gerrard believes JustMilk’s device offers advantages over conventional methods for administering drugs to infants, which often create challenges in low-resource settings. Liquid drug formulations can have a limited shelf life and require refrigeration; while powdered or dry formulations require reconstitution with potable water and can create accurate dosing issues. Gerrard believes a prefilled, disposable version of the JustMilk nipple shield could address many of these challenges, as well as empower a mother by allowing her to personally administrator medicine to her baby in a natural context. A work in progress: Putting users first JustMilk co-founders Geoff Galgon (left) and Dr. Stephen Gerrard, PhD (right) at the Saving Lives at Birth Challenge. Photo: JustMilk JustMilk, which received a grant last year from the Saving Lives at Birth Challenge, is still in the early stages of product development and is currently conducting research to inform the design, marketing, and eventual delivery of the device. In the next two months, JustMilk will begin user acceptability studies with mothers at the University of Venda in South Africa to answer questions like: should the device be disposable or prefilled with medicines, how should it be packaged, and would its use generate stigma for users—and if so—how can that be prevented? JustMilk also plans to conduct a study examining how infants react to intermittent use of the nipple shield to determine if the breastfeeding process is impacted by the infant using the shield once or twice a day. Gerrard sees that these studies are vital to the development process. “You have to have your end user right there from the beginning of the design process,” he said. “You have to get all these things right in the first place; otherwise, if you’re going through the clinical trial approval process and you’ve got something wrong, you’re going to have to go back again.” Gerrard acknowledges that the next six months will be a critical time period for the organization as it seeks to establish the viability of the product, mitigate any risks during its development, and potentially attract the involvement of medical device manufacturers. He explained, “Our goal with this device is to establish feasibility, demonstrate that it can confer a health benefit to infants, and hope the market reacts.” Marissa Chmiola is GHTC’s communications officer. JustMilk received a funding grant in 2013 from the Saving Lives at Birth Challenge—which is supported by the US Agency for International Development, the Bill & Melinda Gates Foundation, the Norwegian Ministry of Foreign Affairs, Grand Challenges Canada, and the UK Department for International Development. JustMilk has also received support from the Clinton Global Initiative, public health charity FHI 360, the University of Cambridge, and the National Collegiate Inventors and Innovators Alliance.

  Senate supports global health R&D in defense appropriations bill and report. Photo: Ken Kistler Earlier this month, we reported that both the House and Senate Appropriations Committees included language supporting global health research and development (R&D) in their reports concerning funding for the Department of State, foreign operations and related programs. Last week, we heard even more good news for global health R&D out of the Senate Appropriations Committee—this time related to the Department of Defense (DoD). The fiscal year (FY) 2015 defense appropriations bill—which was approved by the Committee last Thursday—includes a $7 million increase for peer-reviewed medical research—from $200 million in FY 2014 to $207 million this year—despite reducing overall DoD funding from FY 2014 levels. In addition, in the accompanying report, the Appropriations Committee includes very strong language recognizing DoD’s substantial contributions to global health R&D and the need to support sustained US investments in this area. The committee report includes language submitted by GHTC recognizing “the critical contribution that the department’s [R&D] portfolio makes in protecting our troops from infectious and neglected diseases they may encounter on missions around the world” and noting “the need to sustain and support US investment in this area by fully funding those R&D programs that carry out this work.” Committee recognizes role of infectious disease research in improving US security The committee report also recognizes the threat that neglected infectious diseases—such as malaria, dengue fever, and Chikungunya—pose to the effectiveness of US forces deployed overseas and expresses concern over reductions in research funding for these disease areas. In the report, the committee notes that it is “concerned with the department’s decisions over recent years to precipitously decrease funding for malaria research” and that it “encourages the department to address diseases of military importance and invest in research for chemoprophylaxis, surveillance, and other countermeasures.” Photo: PATH/Gabe Bienczycki Report calls for DoD to improve coordination across R&D programming The committee report also includes language—submitted by GHTC—which directs each DoD program involved in infectious disease research to submit a report of its R&D activities to the House and Senate Defense Committees outlining the program’s funding and accomplishments from FY 2011 through 2014. As well, the committee urges DoD to partner with other organizations involved in infectious diseases research—including other federal agencies—to mitigate the duplication of research efforts and maximize the use of DoD resources. It is GHTC’s hope that these reports and activities will lead to improved coordination across DoD global health R&D programs, as well as improved coordination across all US agencies involved in global health R&D, which will in turn help fill current gaps in research programming and assure US investments are used most effectively. GHTC is glad to see the Senate recognizing DoD’s critical role in global health R&D, as well as advocating for sustained funding and improved coordination for global health R&D programming at DoD. We are hopeful that the language included in the Senate defense appropriations report will be included in whatever final legislation is passed.