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Pyramax® Granules (Photo: MMV) After four successful Phase 3 clinical trials enrolling more than 3,500 patients in 18 countries, the European Medicines Agency (EMA) has granted Pyramax® Granules, a pediatric malaria medicine, a positive opinion under Article 58—a mechanism through which the EMA reviews and issues a scientific opinion on products that are not intended for use in Europe. Pyramax® Granules is a combination of two antimalarials and was developed by Medicines for Malaria Venture (MMV), a member of the GHTC, in partnership with Shin Poong Pharmaceutical Co. Ltd. The treatment is designed to be easy for children to consume: its bitter taste is masked and it is taken in liquid form, as children often struggle to swallow pills. Next, MMV and Shin Poong will work to introduce Pyramax® Granules as well as Pyramax®, the tablet version which is suitable for adults, in malaria-endemic countries. A recent article in NPR: Goats & Soda examines Zika virus, a disease transmitted by the same mosquito vector of dengue fever and chikungunya, that has been rapidly spreading throughout South America and the Pacific Islands in recent years. One in five individuals infected with the virus experience Zika fever, which in addition to fever involves rashes, joint pain, conjunctivitis, headaches, vomiting, and muscle pain. Cases of Zika fever are likely underdiagnosed, as awareness of the disease is limited and its symptoms are similar to infections associated with other members of the Flaviviridae virus family, including dengue fever, yellow fever, West Nile, and Japanese encephalitis. There are no reported deaths to date, but there is growing evidence that the virus can be transmitted sexually or from mother to infant during pregnancy. As there are no vaccines or drugs for Zika fever, treatment involves addressing the symptoms, using fever reducers and painkillers. A group of global health advocacy organizations—including GHTC members the Drugs for Neglected Diseases initiative, TB Alliance, Infectious Diseases Society of America Center for Global Health Policy, Sabin Vaccine Institute, and Treatment Action Group—sent an open letter to the US Senate Health, Education, Labor and Pensions (HELP) committee, calling for amendments to the priority review voucher (PRV) program at the US Food and Drug Administration (FDA) to ensure it adequately incentivizes research and development (R&D) for neglected diseases, as intended. Under the program, companies that receive FDA approval for a drug for a neglected disease (see list of eligible diseases) are awarded a voucher for expedited FDA review (six months rather than ten) of a future product. The vouchers are transferable and have been sold at increasing rates, the most recent going for US$350 million. The letter calls for PRVs to only be awarded for products that are "truly new" as two of the six vouchers that have been awarded were for products that had long been in use outside of the United States.[1] The organizations are also calling for recipients of the voucher to be required to develop a strategy to ensure the product is made affordable and accessible to patients in the countries in which the eligible disease is endemic. The United Kingdom (UK) announced last week the creation of the Ross Fund which will provide £1 billion ($1.5 billion) over five years to fight malaria and other infectious diseases. The funding, which will come from the UK overseas aid budget, includes £90 million for malaria eradication; £100 million for infectious disease R&D; £115 million for the development of drugs, diagnostic, and insecticides for malaria, tuberculosis, and other infectious disease resistance; and £188 million for biodefense and rapid response systems for epidemic preparedness. Global Good has developed a cooler that can store and transport vaccines at freezing temperatures for over a month using just ice and no electricity. The Arktek cooler uses vacuum thermal insulation, an approach used to preserve spacecraft entering extreme temperatures. The cooler has been tested in Senegal (with support from GHTC member PATH) and Ethiopia, and last year, the Arktek was modified for use in Ebola vaccine clinical trials, during which the cooler kept the vaccines between -76 and -112 degrees Fahrenheit for three days. [1] There are two separate PRV programs at the FDA, one for neglected tropical diseases and one for rare pediatric diseases. Of the six PRVs that have been awarded, three each have been for neglected tropical diseases and rare pediatric diseases. Since the beginning of the PRV program, six PRVs have been awarded—three for neglected tropical diseases and three for rare pediatric diseases.  

It’s that time of year when Americans chow down on turkey with family and friends and express gratitude for the many things in life for which they are most thankful. In the spirit of Thanksgiving, GHTC asked our members and staff to share what they are most thankful for when it comes to research, development, and delivery of lifesaving global health technologies. Here’s what they had to say:  

Snakebites, which Médecins Sans Frontières describes as “one of the world's most neglected public health emergencies,” kill 200,000 people each year. This makes snakes the second deadliest animal after mosquitoes. However, not only has research and development for snakebite antivenoms received little investment, but production of existing treatments is also declining due to their low profitability for pharmaceutical companies. Antivenoms are traditionally developed using antibodies produced by animals that have been bitten by snakes, but a number of small biotech companies and even individuals are testing innovative ways to create new, multipurpose antivenoms. Dr. Claire Komives, a professor of Chemical Engineering at San Jose State University, is working to enlist the E. coli bacteria to produce a promising antivenom, as the use of bacteria could make production significantly cheaper and easier to scale up. Meanwhile, a team of researchers across Europe and Central America are developing a treatment for a myriad of common venoms, starting with an antivenom that is effective against three different venoms. Their plan is to identify deadly venoms against which their product is not effective and then develop and incorporate a treatment for that venom into their product. Finally, a team at the California Academy of Sciences is screening chemical compounds in existing, approved drugs to develop a product that could stabilize a bitten patient, giving them more time to seek treatment. The World Health Organization estimates that one-third of the world’s population has latent tuberculosis (TB), only 10 percent of whom will actually contract the disease. However, co-infection with a helminth, a parasitic worm, increases one’s chance of developing TB and exacerbates the symptoms, particularly lung damage. Scientists have long suspected that the parasitic infection impeded the immune system’s ability to fight TB, inhibiting immune cells that provide protection against TB. However, new research out of Washington University in St. Louis suggests that a specific molecule produced by helminths’ eggs prompts an inflammatory immune response that increases one’s susceptibility to TB and its symptoms. The team was able to engineer immune cells that do not produce the molecule, and mice co-infected with TB and the parasite who were given the engineered immune cells did not have the damaging, inflammatory immune response. Analyses of blood samples from TB patients also demonstrated a correlation between the presence of the molecule and the severity of TB symptoms. Photo: PATH/Wendy Stone Researchers at The Scripps Research Institute (TSRI) are developing an HIV and AIDS vaccine candidate that targets a region found on 90 percent of known strains of the HIV virus. The team at TSRI has been conducting experiments to prompt the immune system to generate broadly neutralizing antibodies—proteins which fight multiple strains of the HIV virus—and discovered that four of these antibodies all targeted the same part of the virus, the V2 apex. Further, two of the antibodies have an unusual advantage. While most antibodies mutate from their original form to become more effective at fighting a virus, two of the antibodies were able to bind to the V2 apex in their initial form, consequently speeding up the immune response. However, the body doesn’t naturally make a large number of these antibodies, instead focusing on the further developed antibodies. To address this, the team at TSRI engineered a version of an HIV protein to which those basic antibodies bind with the anticipation that it will lead to their increased production. The engineered protein is being used in a vaccine candidate that will next be tested in animal studies.

TPP countries. Photo: CBCAfter ten years of debate, on November 5, 2015, international negotiators released the final text of the largest regional trade agreement in history—the Trans Pacific Partnership (TPP). This trade deal between the United States and 11 other Pacific Rim countries (Australia, Brunei, Canada, Chile, Japan, Malaysia, Mexico, New Zealand, Peru, Singapore, and Vietnam) links 40 percent of the world’s economy, dramatically reduces tariffs, and establishes high standards for labor, environmental, and intellectual property (IP) protections—including enhanced protections on pharmaceutical products.Why does TPP matter for global health?IP protections for health products can be a double-edged sword. They help to encourage innovation and spur the development of new drugs, tools, and other health technologies by temporarily providing exclusive rights to sell or market a product—allowing developers to recover expensive upfront investments in research and development (R&D). Without this promise of protection, companies might be skeptical to invest in new R&D for fear a competitor could steal their trade secret and sell a similar product, undercutting their profit. At the same time, many public health advocates believe that when IP protections are too strong, they impede access to affordable medicine. In this case, the health care costs of delaying introduction of affordable generic medication could outweigh the benefits of incentivizing innovation.When the 1994 World Trade Organization agreement on Trade-Related Aspects of Intellectual Property Rights (TRIPS) was negotiated, parties sought to strike a balance between promoting public health and encouraging health-related innovation. TRIPS set a global minimum of 20-year patent protection for pharmaceutical products, while at the same time affirming the rights of countries to take measures to protect public health and promote access to medicines for all. This included designating public health crises as national emergencies, in which countries can override IP protections, and allowing least-developed countries a 10-year on-ramp period to introduce patent protections.As TPP’s provisions were negotiated behind the scenes, many public health advocates feared that the agreement would go far beyond TRIPS standards and establish a new high-water mark for pharmaceutical patent and data protections that would become the minimum standard for future trade deals. Now that the official text has been released publicly, we can see the results of the negotiations.What’s in TPP?Below I break down IP protections in TPP, describe their potential impact on health technologies, and discuss how these provisions compare to the changes speculated.Patents for new uses of an existing productPhoto: PATH/Eric BeckerWhat would TPP do?“confirms that patents are available for inventions claimed as at least one of the following: new uses of a known product, new methods of using a known product, or new processes of using a known product.”This provision allows “evergreening” of existing pharmaceuticals, or the ability to re-patent an existing or slightly revised product for a new application.Why is this concerning? How did negotiations shake out?Under TRIPS, countries can choose to exclude new uses of existing products from patentability. TPP (and other trade deals negotiated after the 1994 TRIPS agreement) allows “evergreening” across all technologies and does not single out pharmaceuticals. While public health advocates feared TPP would include a new provision explicitly prohibiting countries from implementing an enhanced efficacy requirement for “evergreen”-type patents, it is not included in the final text and therefore efficacy requirements remain the individual decision of each party country.Patent term extensionsWhat would TPP do? “provide the means to…adjust the term of [a] patent to compensate for delays” in patent approval. This provision allows companies to petition for a patent extension if there has been “unreasonable delay” in processing an application for a patent. “Unreasonable delay” is defined to mean a delay of more than five years from initial filing or a delay of more than three years after a formal request for examination on patent delay. “with respect to a pharmaceutical product that is subject to a patent…make available an adjustment of the patent term to compensate the patent owner for unreasonable curtailment of the effective patent term as a result of the marketing approval process.” This provision allows companies to petition for an extended patent term if a country unreasonably delays the marketing approval process. Why is this concerning? How did negotiations shake out?TRIPS does not specify what constitutes “unreasonable delay.” Advocates feared TPP would go beyond standards set by other trade agreements and lessen the time companies could claim an ureasonable delay for patent approval to four years from filing and two years from request for examination. Instead, TPP maintains the status quo at five years and three years respectively, with no definition of unreasonable delay in granting marketing access.Data exclusivity Photo: PATH/Patrick McKernWhat would TPP do?Provide five years data exclusivity for pharmaceutical products if “the submission of undisclosed test or other data concerning the safety and efficacy of the product” is required “as a condition for granting marketing approval.” This provision prevents generic manufacturers from using test or clinical trial data from a branded product to demonstrate safety or efficacy of the generic (and therefore be awarded marketing rights) for five year after a patent expires. Provide three years data protection “with respect to new clinical information submitted as required in support of a marketing approval of a previously approved pharmaceutical product covering a new indication, new formulation or new method of administration.”Why is this concerning? How did negotiations shake out? Data exclusivity, in effect, extends the life of a patent because, most often, generic manufacturers cannot afford to conduct their own duplicate clinical trials and tests. This means that generic manufacturers must wait until data exclusivity has expired before they can use branded data to justify the safety or efficacy of their product and introduce it into the market. Data exclusivity is not discussed in TRIPS, and while previous trade agreements have included data exclusivity for new pharmaceutical products, TPP is the first agreement to extend data exclusivity to new uses of existing products.Biologics What would TPP do? “provide effective market protection through…protection of undisclosed test or other data…for a period of at least eight years from the date of first marketing approval of that product.OR “provide effective market protection through… protection of undisclosed test or other data…for a period of at least five years” and “through other measures.” These provisions prevent generic manufacturers from using test or clinical trial data from a branded biologic to demonstrate safety or efficacy of the generic biosimilar for a defined period of time. Countries can choose whether to require a minimum of eight years data exclusivity or minimum of five years data exclusivity combined with additional, unspecified measures that acknowledge the upfront cost of investing in R&D for biologics. Why is this concerning? How did negotiations shake out? Biologics are a new class of pharmaceutical product that hold tremendous promise for hard-to-treat diseases and conditions. Since the technology is so new, it is uncertain how patent terms and data exclusivity will impact the scale-up and roll-out of this new class of drugs. Because this technology was unknown in 1994, biologics were not included in TRIPS. Each country party to TPP has established different IP protections on biologics—ranging from twelve years data exclusivity in the United States, to eight years in Japan, to five years in Australia, to no protection at all in Vietnam.Public health advocates were concerned that US pharmaceutical companies were behind the United States’ push for 12-year data exclusivity for biologics in TPP, mirroring provisions in the Affordable Care Act. Other nations, led by Australia, Chile, and Peru, strongly opposed a twelve-year term because  delaying the introduction of biosimilars could increase the cost of medicine and strain public health systems. After contentious negotiations that threatened to derail the entire trade deal, a compromise was reached: TPP countries can chose to provide a minimum of eight years of data protection for biologics or a minimum five years of protection combined with “other measures” of protection.  What’s next?While some IP elements in TPP remain concerning for public health advocates, negotiations did not expand IP protections for pharmaceuticals as much as many had feared. In addition, TPP includes language reaffirming commitment to the Declaration on TRIPS and Public Health stating: “The obligations of [the IP] Chapter do not and should not prevent a Party from taking measures to protect public health.” IP provisions “should be interpreted and implemented in a manner supportive of each Party’s right to protect public health and, in particular, to promote access to medicines for all.” “Each Party has the right to determine what constitutes a national emergency or other circumstances of extreme urgency, it being understood that public health crises, including those relating to HIV/AIDS, tuberculosis, malaria and other epidemics, can represent a national emergency or other circumstances  of extreme urgency.”Still, there is reason to closely monitor this trade agreement as it is considered for ratification in each of the twelve member states. High-level officials from the World Health Organization worry that TPP represents corporations influencing decision-making in health policy, and groups like Médecins Sans Frontières state that, “Although the text has improved over the initial demands, the TPP will still go down in history as the worst trade agreement for access to medicines in developing countries.”On the other end of the spectrum, Senator Orrin Hatch (R-UT) who leads the Senate Finance Committee—key to passing TPP through Congress—is “concerned that, particularly with regard to intellectual property, the administration may not have gotten the best deal possible” and should return to the negotiating table. While TPP doesn’t change US law on biologics, he remains concerned unequal treatment abroad may prohibit US companies from recouping the costs of investment.President Obama signaled his intent to sign TPP when the Administration released the agreement’s text on November 5th. Per statute, there must be at least 60 days for public review and comment before the President can sign, and the Administration has pledged to extend the comment period to 90 days. Next the President will send legislation authorizing implementation of TPP to Congress, where members will have a maximum of 90 days to approve or disapprove of the trade deal, without amendment.Even if TPP is ratified, there will be a significant transition period before all regulations go into effect—it could take decades to implement some provisions in developing country signatories like Vietnam. In this way, the full impact of TPP on access to medicine will not be realized for years to come. It is important that the global health community continue to monitor this deal and push for trade agreements that appropriately balance protections for IP with protections to public health and access to medicine.IPCourtney Carson is GHTC’s senior policy and advocacy associate.