TOKYO -- The development of domestic COVID-19 vaccines is about to enter a crucial stage in Japan, amid the adoption of new rules for evaluating efficacy and difficulties in gathering participants for clinical trials.
While the method of conducting the final phase of clinical trials, which are required for putting vaccines into practical use, had been the focal point, international regulatory authorities announced a new set of rules in late June. In response to this, three of four pharmaceutical companies that have begun first-stage clinical trials in Japan are poised to enter into their final phase of testing by the end of the year. Although the rollout of foreign-made vaccines has moved forward in the country, there has been discussion on a possible third round of inoculations, and high hopes remain surrounding domestic vaccines.
As coronavirus vaccinations progress worldwide, companies that have joined late in the game to develop shots, including Japanese makers, are placed in a difficult situation. In Japan, the four companies of Shionogi & Co., Daiichi Sankyo Co., KM Biologics Co., and AnGes Inc. have been carrying out their initial stage of clinical trials, testing on a small group of subjects. However, the vaccine developers had not been able to get a clear picture on how to go about the final phase of trials, which are said to be the greatest obstacle.
Foreign firms including U.S. pharmaceuticals giant Pfizer proved their vaccines' efficacy in final phase clinical trials last year by dividing the tens of thousands of participants in numerous countries into two groups. One was given authentic vaccine shots, the other placebos. They then compared how COVID-19 developed -- or didn't -- in each group. However, as vaccinations have accelerated in many countries from the beginning of this year, and given the existing supply of effective vaccines that have been put to practical use, administering placebos to clinical trial subjects has become an ethical issue. Thus, it has become difficult for later companies to conduct clinical trials using the same methods taken by their precursory counterparts.
In March, the International Coalition of Medicines Regulatory Authorities (ICMRA) -- which comprises pharma watchdogs of 28 countries and regions, including Japan, the United States, and those in Europe -- began discussing alternative approaches for vaccine clinical trials. In a new set of guidelines issued in late June, the ICMRA indicated that it will approve tests using vaccines already in use, instead of placebos to compare efficacy.
Following this change, it also became possible to reduce the scale of trial participants from the original size of tens of thousands to several thousand to prove efficacy. The three firms of Shionogi, Daiichi Sankyo, and KM Biologics have revealed they aim to start their final stage of clinical trials within this year.
Meanwhile, new challenges have emerged, one of which is gathering participants for the clinical studies.
Daiichi Sankyo began its first-phase clinical trials targeting adults and senior citizens from March, while setting its target number of subjects at 152. The company said that it "greatly struggled" to gather elderly participants who had not yet been vaccinated, as the trials were held at around the time many started receiving vaccination vouchers from local governments. Although the ICMRA's new guidelines have allowed firms to scale down the number of trial participants, a company representative said, "Even if it's down to several thousand people, it's hard to gather participants who have not yet received shots."
Another issue is securing supplies of authorized vaccines that are necessary to compare efficacy with newly developed ones. In Japan, the vaccines of Pfizer, U.S.-based Moderna, and Britain's AstraZeneca have been authorized for use, but all supplies have been purchased from the respective firms by the government, and there are no existing stocks designated for clinical trials. Amid a global shortage of vaccines, there is little room for companies developing their own vaccines to directly buy already authorized ones.
Masayuki Yabuta, head of Daiichi Sankyo's biologics unit, insisted that authorized vaccines cannot be secured without the national government's support. While the Ministry of Health, Labor and Welfare expressed its desire to consider what support they could provide, Shionogi President Isao Teshirogi commented, "We'd also like to follow the new guidelines, but the more we consider whether it will really speed things up, the more difficult it becomes."
There is another issue regarding which companies' vaccine to use for efficacy comparison. There are numerous types of vaccines, such as messenger RNA vaccines, and while choosing the same type of vaccine is recommended, among Japan's four companies carrying out clinical trials, only Daiichi Sankyo is developing a type of COVID-19 vaccine that has been authorized for use in the country.
Furthermore, Pfizer and Moderna vaccines have been found to have an efficacy rate of over 90%, and if chosen as comparators, "this raises the bar to an incredible level," said a senior health ministry official. How regulatory authorities will draw the passing line for vaccines will also become a focal point.
The Japanese government has agreed with Moderna and Takeda Pharmaceutical Co., which handles domestic supplies of Moderna's vaccines, for an additional 50 million doses, as part of next year's vaccine supplies. It also plans to procure 150 million doses of U.S. firm Novavax's vaccines via Takeda Pharmaceutical. Novavax vaccines have not yet been put to use in the United States, but if they are authorized in Japan, the 150 million doses will cover a great majority of the Japanese public.
From this spring, Japan has dealt with the bitter experience of the country's vaccine rollout being delayed due to a dependence on foreign products. Shionogi and KM Biologics have announced that they will be able to carry out large-scale production of vaccines next year, which has elicited strong anticipation, in terms of stable supply supposing additional rounds of inoculations will be carried out.
Meanwhile, another point at issue besides safety and efficacy is whether domestic vaccines will be superior to existing ones, and if they can be distinguished from other vaccines.
For Pfizer and Moderna vaccines, which are currently the most commonly used in Japan, many side effects, such as fevers and pain, have been reported. They're also tricky to handle due to the need to store them at freezing temperatures and their nature of each vial containing multiple doses. In consideration of these points, Japanese companies that are currently developing vaccines have been taking great pains to bring out good qualities. A Shionogi official says the firm is working on a product which will be able to be stored in a fridge, with one vial used per person.
A source close to the national government emphasized, "Coronavirus vaccines still have much room for improvement, and it is possible there could be domestic ones with better qualities." Japan is likely to remain, for the time being, in a phase in which companies' development capabilities and governmental support surrounding coronavirus vaccines are tested.
(Japanese original by Ai Yokota, Lifestyle and Medical News Department)