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Almost a year since Pfizer Inc.’s COVID-19 vaccine was authorized for emergency use in the U.S., Japan is still without an approved vaccine developed by domestic pharmaceutical companies.

Now, with daily new cases hovering around 100 nationwide and with nearly 80% of the population having received at least one dose of a vaccine, making it difficult for developers to recruit unvaccinated volunteers for clinical trials at home, the odds of getting a successful vaccine to market appears increasingly difficult.

To give the industry a strong shot in the arm, Japan’s drug regulator has eased requirements for clinical trials, and the government is setting the groundwork for giving a prompt approval of new drugs in times of emergency as long as efficacy is inferred based on similar shots, though rigorous safety checks will remain in place.

Change already afoot

Previously, the health ministry usually required a randomized, double-blind, placebo-controlled clinical trial of around 30,000 volunteers to gather the most reliable data on the efficacy of new vaccines. But the coronavirus pandemic prompted the government to allocate several hundreds of billion yen in subsidies to accelerate the development and production of vaccines developed by domestic firms.

Japan is not alone in trying to speed up the development of new drugs amid the global health crisis. Faced with a large disparity in vaccine access between rich and developing nations, a global consensus has been building that it’s important to approve the next generation of COVID-19 vaccines as fast as possible. The Group of Seven industrialized countries in June discussed the 100 Days Mission: a plan to have safe and effective vaccines and drugs that are ready to be produced at a global scale within 100 days of the start of a future pandemic.

More than 130 COVID-19 vaccine candidates are in clinical studies worldwide, but firms are finding it difficult to follow in the footsteps of the highly efficacious vaccines made by Pfizer Inc. and Moderna Inc., which were developed at unprecedented speeds. The International Coalition of Medicines Regulatory Authorities (ICMRA) discussed the difficulty of securing enough volunteers for final-phase clinical trials of second-generation vaccines and explored ways to harmonize the design and approval of international vaccine trials.

Following the discussions by the ICMRA, Japan’s drug regulator, the Pharmaceuticals and Medical Devices Agency (PMDA), in late October announced a simplified process for the clinical trials of COVID-19 drugs. Among the key changes is a focus on relative efficacy studies.

A nurse receives a booster shot of the Pfizer-BioNTech COVID-19 vaccine at Chiba University Hospital on Wednesday. | BLOOMBERG
A nurse receives a booster shot of the Pfizer-BioNTech COVID-19 vaccine at Chiba University Hospital on Wednesday. | BLOOMBERG

Blind, placebo-controlled trials involving 30,000 volunteers are considered preferable to evaluate vaccines, but the creation of highly efficacious vaccines has raised ethical questions on conducting such trials as trial participants would be passing up opportunities to get vaccinated with another shot. Another challenge is the significant decline in new cases across the country in recent months, which makes it nearly impossible to conduct effective clinical trials to gauge vaccine efficacy, says Dr. Hiroyuki Moriuchi, professor of pediatrics at Nagasaki University.

As an alternative, the PMDA has embraced the idea of using the neutralizing antibody responses as immune system biomarkers to predict the protection given by a vaccine. For example, the vaccine under development by Daiichi Sankyo Co. can be compared with the same messenger RNA vaccines made by Pfizer and Moderna. The regulator also approved the use of a platform design under which different COVID-19 vaccines are compared against an effective vaccine, such as Pfizer’s, to predict efficacy.

“When a completely new vaccine makes a global debut, a clinical trial would be insufficient if it did not enroll several tens of thousands of trial volunteers,” Moriuchi said. “But given the difficulty of evaluating efficacy in Japan where there are few patients, there’s no choice but to evaluate the effectiveness of subsequent vaccines using the so-called surrogate markers.”

Another pillar of the changes to evaluate a vaccine’s safety is a reduction in the number of minimum volunteers needed for final phase clinical trials from the previous requirement of around 30,000 to at least 3,000 — enough to detect harmful side effects that occur once in every 1,000 shots. Shionogi & Co., which is set to begin its final phase clinical trials globally by the end of December, has said it will use the new evaluation method for its recombinant protein-based vaccine candidate, which it aims to commercialize by the end of March.

Ministry’s next steps

A health ministry panel launched discussions on Nov. 18 with an eye toward setting up a framework that would allow for the prompt approval of drugs and vaccines once efficacy is inferred without compromising safety. The move came after the Cabinet in June decided to consider a special drug approval system for emergency situations by the end of the year.

Pfizer's experimental COVID-19 antiviral pills are produced at a laboratory in Freiburg, Germany. | PFIZER / VIA AFP-JIJI
Pfizer’s experimental COVID-19 antiviral pills are produced at a laboratory in Freiburg, Germany. | PFIZER / VIA AFP-JIJI

At the top of the ministry’s list of concerns is the country’s protracted approval for new vaccines and drugs compared with Western nations. When it comes to emerging life-threatening illnesses, Japan does not have a framework comparable to the United States’ emergency use authorization system or the conditional marketing authorization in the European Union. For example, Moderna’s vaccine received Japan’s special approval on May 21, four and five months after it was authorized in the EU and the U.S., respectively, as it took time to confirm both the efficacy and safety of the shot.

By taking into account overseas examples, the health ministry panel is considering giving authorization to new drugs with fixed expiration dates in case of emergencies by relaxing requirements on efficacy. Authorization expiration dates could be extended after the effectiveness and safety are confirmed following commercialization. After the details of the new framework are finalized, the health ministry will submit a revised bill pertaining to the Pharmaceutical and Medical Device Act to parliament next year.

Moriuchi, who also works as a pediatrician at Nagasaki University Hospital, supports the new framework under consideration, noting that potentially severe side effects like anaphylaxis or myocarditis were not discovered during the final clinical trials conducted by Pfizer and Moderna. The government should weigh both the advantages and disadvantages before authorizing potentially life-saving medicine, he says, adding that that is exactly the issue he faces every day when it comes to child cancer patients, whose best hope of recovery is the use of medicine that has only been approved in adults.

“It’s difficult to conduct clinical trials for children as these illnesses are still rare,” he said. “It’s not rare that some children who take those drugs would die in some cases due to strong side effects, but not using those unapproved drugs would result in the loss of all those children. So I think it’s desirable that experts would judge whether to authorize the drug or not after weighing the side effects that could occur and the lives that could be lost by not introducing it indefinitely.”

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