(Bloomberg) -- Early on a snowy, winter morning in January 2012, Wu Xiaoliang, a 37-year-old farmer, stopped by his local doctor to remedy a headache. At a small clinic near his village he received two injections made from traditional Chinese herbs. Hours later, villagers saw him struggling to prop himself up on his moped as he drove home. By noon, he was dead.
What killed Wu was later described in an autopsy report as a "drug allergy." But doctors couldn’t pinpoint what he was allergic to because the shots he was given contained dozens, if not hundreds, of different compounds extracted from two herbs.
For centuries, Chinese have bought plant and animal parts from traditional clinics, and boiled them into bitter soups to treat colds, strokes and even cancer. But the Chinese medicine sector has modernized along with the rest of the country, with local manufacturers turning age-old recipes into fast-acting injectable drugs.
Chinese medicine injections generated sales of $13 billion last year, according to the research firm Forward Industries Institute. Listed companies worth billions of dollars have thrived, benefiting major global funds like those managed by Schroders Plc., UBS Group AG and Skagen AS that hold their stocks.
Yet, the industry’s ascent has also raised public health concerns. Over a hundred injections based on traditional recipes are sold in China these days, some without stringent human trials. Doctors often prescribe them in an array of untested combinations. Adverse reactions, from skin rashes to fatalities like Wu’s, doubled to about 133,000 last year from 2011, according to government data.
Having struggled for decades to rein in the sector, regulators have recently begun pushing for an overhaul of Chinese medicine injections, seeking to weed out unsafe and ineffective products. But the process could take up to a decade, given the complexity of these intravenous pharmaceuticals.
"For the majority of these chemicals, their properties and their safety to the human body are not properly evaluated and some of them are not even discovered yet," said Justin Wu, associate dean at the department of medicine at the Chinese University of Hong Kong. "If you just focus on this point, I don’t think traditional Chinese medicine injections can pass through any regulatory authority outside China."
Drugmakers such as China Shineway Pharmaceutical Group, Guangxi Wuzhou Zhongheng Group, Tianjin Chase Sun Pharmaceutical Co. and Livzon Pharmaceutical Group are now among the biggest public companies with substantial revenue from traditional injectable remedies. Manufacturers maintain their injections are safe and that the problems arise from incorrect use by doctors.
Still, due to the history of lax regulation, many injectables based on Chinese medicine haven’t been evaluated in strict scientific clinical trials. That means the reactions they set off in the body aren’t fully known. Chinese medicine is based on centuries of practical experience. But it is traditionally taken orally, which gives the digestive system a chance to shield patients from harmful chemicals. Injecting the concoctions into the bloodstream can heighten side effects.
When Shineway first registered its traditional medicine injections in the 1990s, no clinical studies were needed, according to Chen Zhong, a vice president for R&D and quality at the company, which describes itself as the nation’s largest maker of these types of shots.
In recent years, Shineway has invested in post-market monitoring to track allergic reactions and has found its treatments highly safe, he said. But the drugs approved decades ago are still sold and haven’t had to undergo full-fledged testing in subsequent regulatory reforms, according to Chen. Three stages of human trials were only required of therapies approved after 2008, he added.
Chen reckons less than 10 percent of the shots being sold by the traditional medicine industry have undergone this kind of stringent review. He compared the shortfall of scientific studies to skipped classes: “The lessons we missed before, we can make up from now on step by step."
In developed countries like the U.S., drugs must undergo several stages of review, often involving thousands of patients. China has instituted similar requirements for chemical medicines. But corrupt Chinese regulators in the early 2000s allowed thousands of therapies based on questionable data to be sold across the country, leaving a legacy of poorly tested treatments, the government has acknowledged.
"The safety problem of traditional Chinese medicine injections has always been rather serious," Ke Sufang, an analyst at Shenzhen-based Forward Industries, said in an email.
These are signs the sector is now drawing more scrutiny in Beijing. On Aug. 29, the head of the China Food and Drug Administration, Bi Jingquan, declared that when traditional therapies are prepared with contemporary methods, the "results should be reported, reviewed and regulated as modern medicine." They must also show greater benefits than risks in clinical trials, he said.
In May, the agency pledged to reassess the quality of all marketed injections within the next decade, a push to advance a 2009 review of the Chinese industry that had made little headway. The China FDA didn’t respond to interview requests.
Shineway’s ascent offers a window into the industry’s journey. The company, which started as a chemical drugmaker, developed 11 traditional injections between 1993 and 1995 to boost growth. They were seen as symbols of the modernization of the ancient science. “Clinical trials were needed for new drugs, but the requirements were very simple,” Chen said. And Shineway was copying existing products, so it didn’t have to do even the easier tests under the regulatory requirements of that time.
Drugmakers can charge more for injections because they require added production, according to Forward Industries. That’s made them a vital business for many firms.
Nowadays Shineway boasts $160 million in sales each year from injectables, and a market value of about $770 million. Its annual report states "evidence-based medical research is also being carried out." Its top foreign investors as of midyear included funds run by London-based Schroders and Norway’s Skagen. Skagen and Schroders didn’t comment.
Its competitor Livzon, which has a market value of $5.1 billion, says injectable versions of traditional therapies act faster and help patients who can’t take drugs orally. The company said its main injectable, used by cancer patients, was registered in 1999 after three phases of clinical trials and was found safe with adverse reactions of less than 0.2 percent in a study. Livzon’s international investors this year included funds managed by UBS, which didn’t comment.
Among other large players in the market are Wuzhou Zhongheng and Tianjin Chase Sun, each of which has a market valuation of about $2 billion. Neither responded to requests for comment.
Chinese medicine has inspired life-saving discoveries like artemisinin for malaria, which won a researcher from the country a Nobel Prize. The industry’s proponents argue Western drugs also have adverse effects, and traditional ones shouldn’t be discounted. The ancient formulas have been shown to be safe through their long history, said Wang Meng, a researcher at Tianjin University of Traditional Chinese Medicine.
Yet, the injectables business has introduced more complexity. Take a popular injection called Qingkailing, which Shineway and several other companies have approval to sell. Qingkailing logged the highest number of adverse reactions from 2011 to 2015, according to the China FDA, which didn’t list the manufacturers of the batches involved.
Shineway’s website says its version "relieves internal heat, reduces phlegm and promotes the restoration of consciousness." The drugmaker also touts it as a remedy for an astoundingly wide array of conditions: fever, stroke-induced paralysis, acute hepatitis, pneumonia and brain hemorrhage.
The product is safe and a monitoring program found just 118 adverse events in 30,840 cases when it was used over five years, Chen said. The company says it’s the largest seller of the injection and borrowed the usage instructions directly from an ancient recipe. That, however, was intended for oral use.
Even though it wasn’t studied in late-stage trials, doctors prescribe Qingkailing for fevers, colds, comas and strokes "based on their own experiences,” Chen said. At the same time, he said that physicians who don’t follow the labeling are a major cause of adverse reactions.
Indeed, off-label use can be lethal. In February 2016, 24-year-old Yu Fu was given a mixture of Qingkailing and an antiviral for a fever and died from an allergic reaction, according to a lawsuit filed by his family. A Chinese court ruled the clinic was "80 percent liable," for mixing the drugs, blaming the rest on Yu’s own condition. Court documents didn’t list the manufacturer of either drug and the doctor running the clinic testified that he had followed standard practices.
"I hope speaking out can stop more people from being given drugs the way Yu Fu was," Wang Xiaona, his widow said.
In recent years, dozens of families have filed similar lawsuits in Chinese courts against hospitals and received compensation from them. Usually, the suits are against physicians and hospitals because it’s easier to sue a local entity instead of a faraway drug corporation, according to Huang Dongtao, a lawyer in northern China.
In February, the Chinese government restricted insurance reimbursements for 26 types of traditional medicine injections to larger hospitals, a bid to discourage use in small clinics where emergency treatment for allergies isn’t available.
Shineway’s production of traditional Chinese medicine injections fell by about one third this year as those changes reduced usage, said Chen. Such pressures will remain on the industry over the next 5-10 years, he predicted.
Back in 2012, Wu Xiaoliang was given two kinds of herbal injections, neither of which required allergy tests or had warnings that they not be used in combination. In his lush hilly village, family members say that when he returned home after the injection he was nauseous and shivered although they piled blankets on him. By the time the ambulance arrived, his heart had stopped.
"I already didn’t have a mother," said his daughter, who is now 18. "I even lost my father."
Wu’s family received 157,000 yuan ($24,000) from the doctor who treated him after a medical review said the drugs weren’t used in violation of any rules but noted that the physician didn’t rinse the intravenous injection tube when switching medicines. The doctor "didn’t fully realize the risks of using Chinese medicine injections" the review said.
For his part, the physician maintained that he committed no error, and Wu’s death was an "unpredictable medical event."
©2017 Bloomberg L.P.
With assistance from Li Hui