As the nation races to find a vaccine, authorities and experts are working to ensure probity and safety. Zhang Zhihao reports.

A worker checks tablets on a chloroquine phosphate production line in Nantong, Jiangsu province, last month. (XU CONGJUN / FOR CHINA DAILY)

At a news briefing on Feb 24, Bruce Aylward, an epidemiologist with the World Health Organization, described a major obstacle to research on the novel coronavirus.

He said too many clinical trials are being conducted simultaneously and there are not enough patients to provide samples, which may lead to unreliable results.

"We have got to start prioritizing enrollment into projects that may save lives, and save them faster," he said, adding that the issue is not unique to China, but is global because coronavirus research is moving at breakneck speed.

The government, scientists and officials are fully aware of the problem.

Wu Yuanbin, head of the Bureau for Social Development at the Ministry of Science and Technology, said conducting such trials requires great expertise and oversight. Therefore, last month, the ministry and related central government bodies published a guideline to screen applications and regulate ongoing trials.

The guideline states that the drugs cited in applications for clinical trials should be commercially available and have demonstrated clear efficacy against the virus in lab cells or animal tests.

In addition, the dose for patients receiving the test medication may not exceed the amount recommended in the instructions included in the drug's packaging.

Meanwhile, in an open letter in the Chinese Journal of Epidemiology last month, 12 scientists urged their peers to conduct coronavirus-related clinical research more ethically and rigorously.

They argued that the rapid growth in the number of poorly designed experiments could be a waste of valuable research assets and yield inaccurate results, and may even be irresponsible and pose a risk to patients.

Practitioners prepare traditional Chinese medicine for infected patients in Shaanxi province last month. (TAO MING / XINHUA)

On Monday, the Chinese Clinical Trial Registry, an online public database for applications and approval of clinical trials, noted that about 280 studies were being conducted on the virus, including more than 100 clinical drug trials. The number was a significant rise from the 40 recorded on Feb 10.

The trials include the use of anti-HIV or anti-flu drugs to treat the virus, which had infected more than 80,200 people and killed over 2,980 on the Chinese mainland as of midnight on Tuesday.

Tests were also being conducted to assess the efficacy of interferon and hormone therapies, biological agents such as umbilical cord blood cells, traditional Chinese medicine and even tai chi exercises.

At a media briefing last month, Wu said the large number of simultaneous experiments has resulted in some projects competing for patients and resources.

"So, as we are researching, we are also working on improving management, which will hopefully identify effective drugs in a scientific, efficient and orderly manner," he said.

Challenges

According to the scientists' letter, some coronavirus-related studies on the registry suffered from poor design, including insufficient sample sizes, inefficient control-group planning, poor randomization, unclear evaluation standards, incomplete data and other issues.

One notable example was a study on the benefits of soybean extract for severely infected patients that had just two people in each of its control and treatment groups.

Other observational studies have investigated the therapeutic effects of physical exercise, such as shadowboxing or taking six-minute walks every day, which experts said are hard to quantify and analyze scientifically.

Zhang Lan, director of the School of Pharmacology of Xuanwu Hospital at Capital Medical University in Beijing, said low sample sizes in some experiments are due to a gradual decline in the number of newly confirmed cases, as well as difficulties in finding patients who haven't received other treatments. All of these factors may affect the results.

"A big sample size can eliminate many biases and outliers that may otherwise interfere with the experiment," she said. "It is unscientific to say a drug is truly effective without proof from clinical trials. Without that, all the drugs used to treat COVID-19 (the coronavirus) are only considered potential candidates."

According to the open letter, an experiment would theoretically need around 1,000 subjects to prove a treatment's effectiveness on patients with mild symptoms. For severely infected patients, the sample size would need to be at least 800.

Coronavirus-related lab samples are demonstrated in Shanghai in January. (DING TING / XINHUA)

"It is impossible for the current number of patients to meet the sample demands of all the registered experiments," the scientists wrote. "But if the experiments are not well-designed, they are less likely to produce quality results that are effective and safe."

The letter rebuffed the view that clinical experiments can cut corners in design or ethical oversight during an ongoing epidemic in the hope of generating a larger number of insights more quickly.

"This notion is irresponsible for patients and can lead to unreliable results. Drugs and treatments that have been shown to be ineffectual can still have side effects; we cannot transfer the risks of ineffective drugs to patients," it said.

The signatories urged China's scientists to strictly uphold ethical and quality design for clinical trials, and called for stronger regulations and supervision from government bodies.

A biology professor from Beijing, who spoke on condition of anonymity, said research on new epidemics typically follows a "boom-bust "cycle in which there is high academic interest and support during an outbreak, but enthusiasm quickly wanes when it ends, leaving many projects unfinished.

"At times, it feels like the whole scientific community is grasping at straws and trying everything it can to curb the epidemic," he said.

"Despite the current emphasis on open science and generating findings, they are not excuses for poor experiment designs, and non-peer-reviewed results shouldn't be taken by the public as established fact."

Stricter rules

Last month, a woman from Wuhan, Hubei province, who had an irregular heartbeat and psychosis, was rushed to the intensive care unit at Wuhan Puren Hospital. Local media reported she had overdosed on a variant of chloroquine phosphate, a commercially available antimalarial drug currently being tested for efficacy against the coronavirus.

The woman took hydroxychloroquine sulfate, which is also being tested for use against the virus.

Neither she nor her family members had been infected, but she bought the drug on the internet and took it as a preventive measure. She has recovered, but requires constant monitoring.

Infected patients are given Remdesivir, a drug undergoing trials, at a hospital in Wuhan, Hubei province, last month. (CHEN ZHUO / FOR CHINA DAILY)

Huang Haidong, director of emergency care at the hospital, told local media that the epidemic has put people on edge. That means some will try medications that have been reported to have an inhibitory effect on the virus in lab or animal tests, but have not received confirmation of efficacy in clinical trials.

Wu, from the ministry, said most of the drugs currently under trial are commercially available, so their safety is generally guaranteed. Testing such drugs to treat new epidemics allows scientists to skip several time-consuming stages in clinical trials, meaning patients can receive effective treatments sooner.

He stressed that only hospitals designated to treat the disease are allowed to conduct clinical trials, including makeshift hospitals in Wuhan. Moreover, a senior expert, who can formulate detailed experiments and risk-management plans, must be in charge of such trials.

All trials are also subject to ethical inspections, and the findings of the tests will be announced via official government channels, he added.

Yan Jiangying, deputy director of the National Medical Products Administration, told a media briefing last month that the government has accelerated the approval procedures for drugs and clinical tests with dedicated expert teams, and also streamlined the application process. However, safety and efficacy remain paramount prerequisites.

The administration has dispatched 13 inspection teams to work with local authorities to monitor drug production and clinical trials, and to report developments to the authorities, she said.

Rules in action

Last month, the Hubei Health Commission ordered all medical professionals to strictly monitor patients taking chloroquine phosphate, because an overdose could result in sudden death.

While the commission noted that there have been no reported cases of deaths related to overdoses of the drug, the statement reminded medical professionals to be careful when administering it, as the country plans to roll out more clinical trials of chloroquine phosphate.

Following the Hubei statement, the National Health Commission issued a more detailed guideline for the drug, listing suitable patient demographics and dosage, plus contraindications and precautions.

Experts hope the guidelines will discourage people from taking chloroquine phosphate without proper supervision, especially as some domestic pharmaceutical companies have announced that they are ramping up production to make the drug more easily available.

In his "clinical diaries", a regular bulletin for medics, Tong Chaohui, vice-president of Beijing Chaoyang Hospital, said chloroquine phosphate was developed in the 1950s, but the low number of malaria cases in recent decades mean Chinese people and medical professionals may not be familiar with it.

"Every time there is an epidemic, people always want to find a wonder drug to control it－unfortunately, there has never been a wonder antiviral drug," he wrote.

"Researchers must be self-disciplined, conduct clinical trials rigorously and avoid conflicts of interest. The more difficult the situation, the more adamantly scientists should safeguard the bottom line of science and medicine."

Contact the writer at zhangzhihao@chinadaily.com.cn