The U.S. Army’s plan to grant exclusive rights to a promising Zika vaccine to a major pharmaceutical company has raised questions about whether that threatens its future affordability and availability to people in developing countries.
The purified, inactivated Zika virus vaccine — called ZP IV — has been developed by the U.S. Army and is currently in its first phase of testing at the Walter Reed Army Institute of Research in Maryland and the National Institutes of Health.
If it successfully passes clinical trials, the vaccine would have the potential to halt the spread of the virus, transmitted by mosquitoes and sexual intercourse, which has been reported in 69 countries since 2015, including the United States, and is linked to serious birth defects in children.
The deal was posted by the Army on the public Federal Register in December and will give Sanofi Pasteur, the vaccine unit of French multinational pharmaceutical company Sanofi, exclusive access to the new vaccine technology, which has been developed and paid for by the U.S. government. In return, Sanofi will take on the role of conducting clinical trials, getting regulatory approval, manufacturing and distributing the vaccine.
The humanitarian aid organization Médecins Sans Frontières has criticized the Army’s decision to grant Sanofi the patent license, which will give the company an exclusive right to make, use and sell the vaccine for 20 years, as well as 12 years of marketing and data exclusivity even after the patent has expired. MSF is saying this will give the company a monopoly on the drug and thus no incentive to make it affordable. Sanofi could also choose to stop developing the vaccine if it decides it is commercially unattractive.
The Zika virus was first discovered in Uganda in 1947 in monkeys, with the first human cases detected five years later in Tanzania and Uganda. The first large Zika outbreak in humans occurred in 2007 in the Pacific Island of Yap in the Federated States of Micronesia. Between 2013-14, outbreaks in the Pacific Islands pointed to a link between Zika and congenital malformations and neurological and autoimmune complications in babies.
In May 2015, Brazil confirmed Zika was spreading throughout the country, and soon reported neurological disorders in newborns and an increase in microcephaly — abnormally small heads — among infants.
Between Nov. 2015 and Jan. 2016, cases were reported in 18 countries in Latin America and the Caribbean. In Feb. 206, the WHO declared Zika a public health emergency of international concern and the U.S. reported the first case of Zika transmission in Texas. As of Nov. 2016, 69 countries and territories have reported Zika virus transmission since 2015. More than 2,100 cases of nervous-system malformations have been reported in Brazil alone and a further 300 cases reported worldwide, according to the World Health Organization.
In August, the WHO downgraded Zika from its public health emergency status after nine months, but health officials say the virus is “not going away” and they expect further outbreaks to occur. WRAIR is focused on Zika due to concerns about infection among U.S. army service men and women during deployment and travel and in bases where Zika could spread — as of November, there were 149 cases of Zika infection among military staff and their family members.
MSF wants the U.S. Army to consider granting an “open nonexclusive” patent license instead, opening up the technology to other pharmaceutical companies for testing and development. MSF argues this will increase competition and thus bring down the price and ensure the vaccine reaches those who need it in middle-income and developing countries.
“Ministries of Health and people around the world will only be able to benefit from the U.S. government investment if the resulting vaccine is effective, safe, available, affordable and suitably adapted to the resource-limited settings where most people affected by Zika virus live,” MSF said in a statement.
“The next step in the Zika vaccine development process, including its licensing and technology transfer strategy, needs to ensure that U.S. government funding and leadership in vaccine R&D results in a vaccine that is effective and accessible for all patients in need in the U.S. and globally, including the most neglected,” the group added.
The United Nations High Level Panel on Access to Medicines, formed in 2015 to address the lack of access to medicines in many developing countries, appears to agree with MSF’s recommendations. In its 2016 report, the panel said: “Universities and research institutions that receive public funding must prioritize public health objectives over financial returns in their patenting and licensing practices,” and listed the use of nonexclusive licenses, the donation of IP rights, and taking part in public sector patent pools as potential mechanisms by which to do this.
Sanofi has responded by saying it’s assuming “financial and opportunity risks” by partnering with the government on Zika as there is no guarantee of a commercial market for the vaccine.
“...we’re still assuming financial and opportunity risks because there is no clear path to commercialization at this time, as the epidemiology of this infectious disease is still a moving target,” according to Sanofi’s research and development project lead, Jon Heinrichs.
The U.S. Army told Devex in an email statement: “We believe granting an exclusive license in this case is reasonable and necessary to most quickly and most safely provide this potential vaccine for public use to combat the growing international threat of the Zika virus.”
Unusually, the U.S. Army has extended the time period for comments on the announcement in the Federal Register by an additional 45 days until March 10, the second time the comment period has been extended, to allow time to compose written responses to the submissions.
Experts have predicted the Zika market could be worth more than $1 billion a year, driven by U.S. and European travelers willing to pay high prices for such vaccines, Reuters reported in October.
Sanofi is part of a race to develop a Zika vaccine
The ZP IV vaccine — which is thought to be the furthest along in terms of development in the Zika vaccine field — is developed from the inactivated Zika virus. The vaccine was shown to give 100 percent protection against the Zika virus in mice, according to a study published in science journal Nature last August.
Sanofi is not alone in working on the Zika virus vaccine. It is not even the only drug company to receive U.S. government funding to work on the issue; GlaxoSmithKline has partnered with the NIH to evaluate a new vaccine technology for Zika known as SAM (self-amplifying mRNA), and Japanese company Takeda has also entered the vaccine hunt with $312 million funding from BARDA.
Another group of concerned organizations — including Knowledge Ecology International, a nonprofit that lobbies to increase access to medicines — have also written to the Army to complain about the Sanofi deal.
KEI says Sanofi does not need to be incentivized to develop the vaccine and take it to the market — the standard justification for granting such exclusive licenses — since the candidate vaccine has already received “extensive government subsidies” and is extremely likely to get additional funds.
“The grant of the exclusive rights in the patent is an unnecessary incentive to bring the invention to practical application because of the significant federal funding in the clinical trials and the grant of additional exclusivities and subsidies,” KEI said.
In September, BARDA — the U.S. Biomedical Advanced Research and Development Authority, a unit within the U.S. Department of Health and Human Services — gave Sanofi $43.2 million “for phase II development and manufacturing” of the Zika vaccine, according to a Sanofi press release.
KEI communications and research associate Zack Struver explained that if approved, Sanofi will also earn a priority review voucher from the U.S. Food and Drug Administration, which it could “sell on for millions of dollars,” and so already has “sufficient incentive” to develop the vaccine with or without the exclusive license, he said.
Priority review vouchers are designed to speed up the review process for new drug products and thus incentivize drug companies to work to develop treatments for rare diseases or those without a robust market. Vouchers are transferable and have been sold to other companies for upwards of $300 million.
However, the statement from the U.S. Army said there was a strong case for granting Sanofi exclusive rights to the technology, due to competition from the “many” groups working on a Zika vaccine. Sanofi is taking on “risk” by accruing the license since there is a “long way to go in terms of time and money” before a Zika vaccine can be approved, they said. Furthermore, the army is also yet to receive the patent from the U.S. Patent and Trademark Office, and there is a chance it “may never issue,” adding more “risk” for Sanofi.
“The federal government needs a non-federal partner with the research and production capabilities and the willingness to invest their own substantial funding to most quickly get this product to the market and available for public use,” the spokesperson added.
The KEI letter to the army also asks for four conditions to be imposed on the licensing agreement. These include requiring Sanofi to limit the price of the vaccine to “no more than the median price being charged in other high income countries;” limiting the length of time that Sanofi has exclusive rights to the technology, requiring the vaccine be made “available and affordable” in developing countries; and requiring Sanofi to be transparent about the costs of research and development.
The U.S. Army responded by saying the license agreement has stipulations in place to “protect the public interest,” including the option to terminate if Sanofi fails to “bring the invention to practical application within a reasonable time,” or “make the benefits of the invention reasonably accessible to the public.”
Sanofi says no “clear path to commercialization” for Zika at this time
The pharmaceutical company says that even with the public funding from BARDA, taking ZP IV through the many stages of testing, approval and manufacturing requires Sanofi to take on “financial and opportunity risks” due to the fact Zika is “still a moving target” and there is “no clear path to commercialization at this time,” according to Heinrichs, Sanofi’s research and development project lead.
“We have modeled various commercial scenarios including current endemic areas, spread to other geographies and the travel market, among others. The nature of the epidemiology and spread of the virus will impact the degree of profitability,” Heinrichs said.
Sanofi may have a point, according to Paul Wilson, assistant professor of clinical population and family health at Columbia University’s Mailman School of Public Health, who says there is “genuine uncertainty” surrounding how big the Zika problem will be and how widely a vaccine would be used. This is compounded, he said, by the fact that the virus could ultimately become widespread but “without causing harm,” or even die out as people become immune.
If this turns out to be the case, however, MSF’s and KEI’s concerns may be valid since Sanofi would likely lose interest in the project and fail to drive the vaccine all the way through development, WIlson said.
“I’m sympathetic to MSF’s position — when you have a vaccine being developed with public funding and you give the rights to one firm, you have every right to put in place conditions to make sure vaccine will be available to all who need it,” he said.
“The U.S. government has to at least justify why an exclusive license is necessary,” WIlson added.
Sanofi could be the best company for the job
The company has experience with vaccines against viruses in the same family as Zika, known as flaviviruses, having developed vaccines for Japanese encephalitis and dengue fever.
This could explain why the U.S. Army is keen to entrust the Zika virus vaccine to Sanofi, which is an established player and one with a track record of supplying vaccines to developing countries, according to Wilson.
“It is still more or less true that only the big multinational pharmaceutical companies have ever been able to successfully bring a truly new vaccine to market. Even when you have a vaccine candidate that’s at the stage of this Zika one is now, there are still many challenges involved in the later stages of development,” he said.
However, the capacity of pharmaceutical firms in India, Brazil and China to develop vaccines is “growing rapidly” and some of these firms could probably bring the vaccine to market, although perhaps not as rapidly as a multinational, WIlson said.
The vaccine industry has long been dominated by four major multinational pharmaceutical companies — GlaxoSmithKline, Merck, Sanofi-Pasteur, and Pfizer, which accounted for approximately 86 percent of global vaccine revenue in 2015. Their monopoly is attributed to entry barriers such as high start-up costs and long lead times; vaccines can take anywhere from 10 to 16 years to reach the market, preventing other companies from competing.
Phase III trials are technically difficult to conduct and many drugs and vaccines fail them, and developing a robust manufacturing process is “very technical” and is subject to “stringent regulatory requirements,” which can be hard to navigate, Wilson explained.
“The U.S. Army may want a MNC partner because they believe that is the surest way to ensure that the vaccine gets developed quickly. There are only a few companies out there that have the relevant experience and have shown an active interest in developing country markets, which Sanofi has demonstrated,” he said.
Access will not be an issue in the poorest countries if GAVI steps in
In relation to MSF’s and KEI’s concerns about access to the vaccine, if approved, GAVI, the Vaccine Alliance — a partnership of major donors and pharmaceutical companies designed to ensure access to vaccines for children in developing countries — could support low-income countries in purchasing the vaccine, Wilson said.
Sanofi confirmed in an email to Devex that it has worked with GAVI on distribution of vaccines in the past, and so working with the alliance on the Zika vaccine was “certainly a possibility,” but that a strategy for “pricing and distribution” would be developed later in the process.
However, the real problem of access will be in middle-income countries, such as Brazil, which are ineligible for GAVI funding but where the vaccine is urgently needed.
“Sanofi doesn’t see a market in the poorest countries and so they’re happy to provide vaccines at a reasonable price there through GAVI, since it would be seen as bad PR not to. But they are not necessarily prepared to make those concessions in places like Brazil and India, where the greatest access concerns would be,” Wilson said.
Sanofi has bad track record when it comes to serving developing countries, MSF says
MSF spoke out against Sanofi in 2015 after the company decided to stop manufacturing a pan-African snakebite antivenom because it was no longer lucrative, leaving a gap in supplies that MSF said would be likely to lead to unnecessary deaths.
The NGO is worried that if given the exclusive license for the Zika vaccine, the pharmaceutical company will follow the same path and neglect countries with great need but less opportunities for profit, according to Judit Rius Sanjuan, MSF’s U.S. access campaign manager.
Instead, Sanjuan wants the U.S. Army to offer Sanofi a nonexclusive license, which she argued would be “better public policy,” ensure the Zika virus has broader geographical scope, and protects the U.S. government from “having all its apples in one basket.”
There are other ways to get medicines through development and into markets
There have been successful examples of the U.S. government offering nonexclusive licenses for patented technologies through the United Nations backed Medicines Patent Pool, a global health financing mechanism set up in 2010 to share drug technology and research to speed up development, lower costs and increase access to newer HIV/AIDS, viral hepatitis C, and tuberculosis treatments in developing countries.
MPP works by signing agreements with patent holders — such as the NIH and the U.S. Army but also nonprofits, pharmaceutical companies and individuals — to create a pool of relevant patents. The partners are then licensed to generic drug manufacturers who can then produce generic versions of the medicines, often utilizing more than one patented technology in the process of development.
For example, in 2010, the NIH licensed a patent on Darunavir to the MPP, which spurred the development of a new combination drug. Furthermore, Johns Hopkins University announced on Jan. 25 that it is licensing its patent for the drug candidate sutezolid, which could be used to treat tuberculosis, exclusively to the MPP.
While the MPP does not currently work on vaccines, and so licensing to the MPP was not an option for the U.S. Army, these examples set a “good precedent” for “innovative” nonexclusive licensing agreements and how effectively sharing research can expedite research and development, increase collaboration, and diversify the medicine development process, MSF’s Sanjuan said.
Furthermore, there have been other notable examples of the U.S. granting nonexclusive licenses for the development of vaccines. For example, the human-bovine rotavirus vaccine technology was licensed by the NIH to eight organizations, one in the United States and seven in the developing countries, to manufacture and distribute the rotavirus vaccine.
Updated Jan. 27, 2017: This article was updated to include the new deadline for comments on the Federal Register.
Sophie Edwards is a reporter for Devex based out of Washington D.C. and London where she covers global development news, careers and lifestyle issues. She has previously worked for NGOs, the World Bank and spent a number of years as a journalist for a regional newspaper in the U.K. She has an MA from the Institute of Development Studies and a BA from Cambridge University.
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