China is poised to become a major global vaccine maker, but first it must overcome serious problems with quality control.
In 2007, Zheng Xiaoyu, head of China's State Food and Drug Administration (SFDA), was found guilty of corruption and swiftly executed. To the rest of the world, Zheng's punishment might seem extraordinarily severe given that his crime was taking bribes of 6.5 million yuan (US$1 million) in exchange for approving substandard medicines. For China, however, this move was a clear sign of its determination to build its reputation as a key player in global health.
Now, the country may be seeing this brutally enforced determination bear fruit. In October 2013, a Chinese-made vaccine for Japanese encephalitis — a viral brain infection spread by mosquitoes that is similar to West Nile fever and prevalent in South-East Asia — became the first Chinese drug to have its safety and quality endorsed by the World Health Organization (WHO). Every year the Japanese encephalitis virus infects as many as 50,000 children under 15 years old, killing up to 15,000, yet there are no antiviral treatments. The SFDA — renamed in April 2013 as the China Food and Drug Administration (CFDA) — was instrumental in securing the vaccine's approval, which allows United Nations (UN) agencies to use it in vaccine programmes. Buoyed by this success, China is already lining up more vaccines for WHO approval, including vaccines against flu, polio and rotavirus, according to a spokesperson from the CFDA.
This landmark event has been welcomed by many who believe that China's capacity to produce large numbers of vaccines cheaply means that millions more people can be immunized. The WHO's director-general, Margaret Chan, said: “There is a huge potential for vaccine manufacture in China and we hope to see more and more Chinese vaccines become WHO prequalified. The whole world will benefit.”
China has more than 30 domestic vaccine manufacturers that together produce 49 vaccines against 27 diseases. The country's annual manufacturing capacity is nearly a billion doses — about a fifth of Europe's vaccine production. But question marks remain over China's future as a world vaccine supplier. Zheng's story, while extremely high profile, is just one of many scandals surrounding China's research reputation. In the past few decades, the country has seen countless cases of unethical trials, corruption in hospitals and pharmaceutical companies, and counterfeit, substandard or tainted medicines. Despite a renewed commitment to high-quality research and increased funding, China is still failing to tackle these inadequacies.
Chinese spending on research and development (R&D) has grown by 20% per year since 1999 and now exceeds US$100 billion per year. China is likely to have more research papers published this year than the United States, according to the Royal Society in London1. It is already home to 25% of the world's R&D workforce, according to the UK innovation charity Nesta. However, in a report published in October 2013, Nesta warned2 that the rise in the quantity of Chinese research “has not yet been matched by similar leaps in quality.”
This general trend certainly applies to pharmaceutical R&D. Indeed, China has a poor track record in drug production and clinical trials. For example, in clinical trials conducted in China in 2006 for the blood-thinning drug apixaban (Eliquis), the US Food and Drug Administration found that some patients were given the wrong drug, the trial was run poorly and in violation of good-practice guidelines, and serious side effects were not reported. There have also been cases of clinical trials in which participants have either been coerced into the trial or not told of potential drug risks, and have had to pay for medical treatment for side effects3.
The growing presence of multinational pharmaceutical companies has helped to increase China's capacity to produce drugs, but those companies have had a rough ride. In 2013, for example, GlaxoSmithKline's China office was embroiled in scandal amid accusations of bribing Chinese doctors and government officials4, and it later emerged that Sanofi's China branch is also being investigated for bribing Chinese doctors. Several other global pharmaceutical companies with a Chinese presence are also under scrutiny for similar alleged wrong-doing.
China is also notorious for producing low-quality or counterfeit medicines, including antimalarial drugs5. And in 2008, powdered baby milk products contaminated with melamine left 296,000 children sick, causing a major scandal6. “For a country as big as China, if it cannot even manufacture infant formulas that all its citizens can trust, the chance that it can become an international supplier of drugs and vaccines is very slim,” says Sun-Wei Guo, a professor of obstetrics and gynaecology at Fudan University in Shanghai.
All these concerns raise red flags over China's ability to become a major vaccine producer. Quality is “a critical issue”, says Seth Berkley, chief executive of the GAVI Alliance, based in Geneva, Switzerland, which works to ensure broader worldwide access to vaccines. “You are giving the vaccine to healthy children and you've got to believe that what is in that vial is what's advertised, and that it's completely safe.”
Long march to quality
The introduction of China's vaccine against Japanese encephalitis required international funding7. Researchers at the Chengdu Institute of Biological Products (CDIBP), a subsidiary of the China National Biotec Group (CNBG), discovered the vaccine in 1988. But development of the vaccine for the global market began only in 2003 when PATH joined forces with the CDIBP — funded by US$35 million from the Bill & Melinda Gates Foundation.
The collaboration “established reliable methods of diagnosing and tracking the disease to help countries understand it, prioritize it, and focus on prevention efforts in regions where children are most at risk,” says Kathy Neuzil, director of the Vaccine Access and Delivery Program at PATH. Improved disease surveillance and clinical trials were introduced to establish the vaccine's immunogenicity and safety. The culmination of this effort, says Neuzil, was the design of a new manufacturing facility to ensure “high-quality, adequate, stable and affordable vaccine supply.” Only then, in 2011, did the WHO deem China's SFDA to be a functional regulatory authority for vaccines. This was a crucial step because to receive WHO approval for a vaccine, the manufacturing country must have a national agency seen to be able to monitor production and provide regulatory oversight.
Even so, China's vaccine manufacturing sector is by no means ready to go global. Xiaoming Yang, chief executive of the CNBG, acknowledges that China's familiarity with international practices is hazy. “Chinese manufacturers will face lots of challenges,” he says, including “a lack of knowledge of international market regulation and lack of experience in conducting overseas clinical trials.”
To improve international relations, China must attract overseas talent back to China “to play a critical role in bridging local and international practices,” says Jack Zhang, head of the China programme at PATH, a non-governmental organization based in Seattle, Washington. Its capacity to undertake robust clinical trials is still poor, he says, and he urges researchers to follow good clinical-practice guidelines “to foster more rigorous ethical standards for clinical study.”
These barriers make it unlikely that China will become a significant international supplier of drugs and vaccines “in the foreseeable future,” says Guo. A key challenge, adds Guo, is that “in a country where there is a lack of free flow of information, talent and capital, where accountability exists only on paper, and where all major decisions are made by officials who have little incentive to be innovative other than to keep their jobs, the quality of any mass-produced product is predictably inferior.”
It is on this issue of quality control that China's reputation as a vaccine supplier ultimately rests, as failure to maintain standards could result in WHO approval being rescinded. Approval “is a stringent process so the WHO can be confident that the product meets international standards,” says David Wood, who heads vaccine regulation coordination in the WHO's Health Systems and Innovation Cluster.
The WHO takes this matter seriously, and some Indian vaccine suppliers to GAVI have lost their prequalification status because quality control had fallen short of previous levels. In 2012, the WHO revoked its approval of an oral polio vaccine made by Panacea Biotec, one of India's largest makers of generic drugs8.
Yang contends that the Chinese drug-making industry is trustworthy, however, and that the widely reported scandals are anomalous. Those events, he says, “do not represent the mainstream of China's pharmaceutical industry. We have established a complete regulatory system from clinical development to market launch.”
Berkley, who has developed strong working relationships with senior public-health officials in China through numerous visits, says that “these scandals haven't only been external, they have also been internal, and there's a lot of anger about that in the country. China's leadership is aware of the problems they have had on quality and will take this seriously.” Zheng's execution seems as bold a sign as any of China's determination to succeed.
China's high performance in some sectors of manufacturing, such as microelectronics, shows that it can achieve quality. “We're long past the days when a 'Made in China' sticker would be a sign of instant alarm,” says James Wilsdon, professor of science policy at the University of Sussex, UK.
But electronics don't trigger the same societal concerns as food products or vaccines, Wilsdon says. Bribery and corruption scandals such as those that hit China's pharmaceutical industry are an “international manifestation of domestic dynamics,” he adds. “If this is happening in global players like GlaxoSmithKline, how much are they happening in large state-owned enterprises? Clearly, far more.”
Since 2005, researchers conducting clinical trials in China have been strongly advised to register them in the Chinese Clinical Trial Registry (ChiCTR), which was set up to improve transparency and feeds into the WHO's International Clinical Trials Registry Platform. However, such a system can only function if it has the full support of the research community and regulatory industry. By December 2013, only 3,927 trials had been registered, which researchers at the ChiCTR say falls far short of the several thousand trials per year estimated to take place, based on the number of published studies. One positive sign is that the CFDA made the registration of clinical trials mandatory in September 2013.
But until there is concrete action and clear signs of improvement, sceptics such as Guo will remain unconvinced. “There are a lot of talks, and even a lot of meetings, but not a lot of actions, let alone outcomes,” he says. “The decision-makers should understand that when it comes to supplying quality drugs and vaccines, political mumbo-jumbo won't work.”
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Bound, K. et al. China's Absorptive State: Research, Innovation and the Prospects for China–UK Collaboration (Nesta, 2013).
Cyranoski, D. Nature 435, 138 (2005).
Case Studies for Global Health (Alliance for Case Studies for Global Health, 2009).
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Shetty, P. Production: Vaccines from the East. Nature 507, S12–S13 (2014). https://doi.org/10.1038/507S12a