Firm's struggle with COVID drug development highlights clinical trial hurdles in Japan

TOKYO -- A Japanese pharmaceutical firm has been dogged by problems as it enters the final phase of clinical trials for an oral medication to treat mild to moderate COVID-19, one of several such potential game-changing drugs under development worldwide.

Shionogi & Co. aims to apply within the year for government approval of the new drug. However, at a Nov. 1 press conference, Shionogi President Isao Teshirogi said that the oral medication's development was "admittedly behind our original schedule."

Shionogi began the final clinical trial phase at the end of September. The firm originally aimed to secure about 2,100 patients in Japan for the trial. But Teshirogi determined that the recent drastic drop in domestic COVID-19 cases would make it difficult to get that many subjects. The company hastily decided to expand its clinical trials to South Korea, Singapore, Vietnam and the United Kingdom.

"We'd like to take all possible measures in preparation for applying for pharmaceutical approval within the year," said President Teshirogi.

The development of Shionogi's new medication has seen a string of extraordinary issues.

Drug development requires a series of clinical trials, or experiments where the medication is given to patients to examine its safety and efficacy. Tests aimed at gaining government approval are normally conducted in hospitals.

The first obstacle that Shionogi faced during its preparations for clinical trials was that there were no COVID-19 patients with the target symptom severity in Japan's hospitals. The drug is meant to treat coronavirus patients with mild or no symptoms, but in Japan, patients with severe symptoms are given hospitalization priority, and most patients with mild symptoms recuperate at home or in accommodation facilities.

"Normally, patients examined at a specific hospital can participate in a clinical trial there, but coronavirus patients with mild symptoms are not linked with hospitals. Patients also can't just sign up (for the trial); they're managed by public health centers. Not being able to collect clinical trial cases unless we gained the understanding of administrative bodies was a major issue," said Takahiro Fukuhara, associate deputy manager of Shionogi's Clinical Research Department.

It was around July this year that the company began to approach local governments -- a first for both the company and the administrative bodies, resulting in a series of challenges for the pharmaceutical firm.

"There were various points of concern, including to what extent we should cooperate in a company's clinical trial as a government body," said a Kanagawa Prefectural Government official responsible for negotiations with Shionogi.

The parties ran into trouble during discussions on the handling of patients' personal information. The prefectural government cannot unilaterally hand this information out to a company, meaning Shionogi would have to reach out to each potential trial participant individually. It was then decided that Shionogi leaflets with information on the clinical trial and contact information would be included in the document bundle the local government gave to patients when they arrived at their recuperation site.

In this way, Kanagawa Prefecture became the first local government to cooperate with Shionogi. More local governments subsequently joined the effort, including Osaka and Gifu prefectures, where the company managed to begin clinical trials at the end of October.

The recuperation facilities hosting clinical trials are "satellite facilities" of medical institutions that have clinical trial contracts with Shionogi. Besides nurses assigned by the prefecture, the company also dispatches nurses involved in clinical trials to the facilities, and they regularly examine the amount of virus in the participants and take blood samples. Participants are lent smartphones so they can be remotely examined by doctors almost daily. The recuperation facilities cooperating in the trial consequently have more thorough medical measures in place than other sites.

The clinical trial faces yet another obstacle. The number of patients admitted to these accommodations fell below expectations due to the sudden decrease in daily coronavirus infections. This is great news for society, but a setback for the drug trial.

Shionogi built a system enabling not only patients at recuperation sites but also those at home to participate in the trial. Though securing enough nurses to visit homes and assigning them to different places is a serious burden, Fukuhara stressed the importance of "creating a state where we can include patients in clinical trials under any circumstances." He said, "We have no choice but to act flexibly."

As for patient reactions, Fukuhara said that many people readily agree to join the trial, saying they would like to be of help, or that being examined so closely is personally beneficial. But, he added, there are also people working remotely from the recuperation facilities who say they have "no time to spare," as well as young people who refuse as they believe that they will get better without treatment.

"Japan is said to have some of the world's worst difficulties doing clinical trials," said Hiroshi Mukae, professor at the Nagasaki University Hospital's department of respiratory medicine. Though Shionogi is having trouble due to a decrease in infections, the professor pointed out that, in Japan, their progress will also be impeded if coronavirus cases rise. What does this mean?

Nagasaki University has been conducting a clinical trial of the HIV drug nelfinavir since July 2020 as a potential treatment for mild or asymptomatic coronavirus infections. The Nagasaki Prefectural Government and the Nagasaki University Hospital's Infection Control and Education Center have cooperated in the trials, and a system was arranged so that patients who seemed to fit the trial's parameters were given examination priority at the university hospital.

However, Takahiro Takazono, associate professor at the hospital's respiratory medicine department and the head of the trial's patient recruitment, said, "Although 20 to 30 people visited the hospital per day when patient numbers were increasing, we were only able to explain the clinical trial to two to three of them."

Professor Mukae said, "The more daily infections there are, the busier we get. Doctors are occupied with treatment and can't afford the time for clinical trials. Ideally, progress would be made on the trials as patient numbers grew, but we don't have nearly enough staff for that."

According to professor Mukae, the university reached its target of 120 trial participants in August this year, through the cooperation of multiple medical institutions in the country, and is currently analyzing the results.

Clinical trials in Japan have traditionally been difficult. Large, 1,000-bed-plus hospitals are common in the United States, but most medical institutions here are small or medium-size, meaning companies must ask many hospitals for cooperation to get enough trial participants. A pharmaceutical industry source pointed out, "It's a slow-moving, high-cost endeavor requiring a lot of labor." The individual said that these structural problems became glaring amid coronavirus medication and vaccine development.

One such example is the delayed implementation of decentralized clinical trials (DCTs), which are increasingly common in the U.S. and other countries. Utilizing digital technology, they allow people to participate in clinical trials at home, without having to visit hospitals.

In a guidebook created in July to pave the way for DCTs in Japan, the Japan Pharmaceutical Manufacturers Association (JPMA) cited "disruptions in executing (regular) clinical trials" including participants being unable to go to hospitals due to the pandemic, and the inability to provide test drugs. The guidebook states, "From the standpoint of crisis management, it is hoped that the implementation of DCTs will also move forward in Japan."

Hirotaka Nagashima is director of the Clinical Research Center at Tokyo Center Clinic, which conducts DCTs. Nagashima told an Oct. 6 web seminar held by the Japanese subsidiary of U.S. health care consulting firm IQVIA, "Countries that can't present high-standard results are not chosen for international joint clinical trials (by overseas pharmaceutical giants). If DCTs are not pushed forward in Japan, Japanese companies may be passed over."

For inquiries on trials for Shionogi's oral coronavirus medication, please phone the clinical trial information desk at 0120-559-807 (in Japanese).

(Japanese original by Ai Yokota, Lifestyle and Medical News Department)