In order to advance discussions related to drug regulations with the aim of eliminating drug lag/drug loss and strengthening drug discovery capabilities in Japan, the “Council on Drug Regulations for Strengthening Drug Discovery Capabilities and Ensuring Stable Supply” was held from May 2023 to March 2024.
One of the issues that was actually addressed based on the discussions of this council was “Clarification of the necessity for Japanese data in pre-market reviews in Japan (necessity of Japanese Phase I trials when participating in international clinical trials),” which we summarize here.
What actions were taken?
The following notices were issued, where the current thinking on the necessity of Japanese Phase I trials has been reorganized and presented.
“Basic principles for conducting phase 1 studies in Japanese prior to initiating multi-regional clinical trials including Japan for drugs in which early clinical development is preceding outside Japan” (Date of December 25, 2023, Notification from the Director of the Pharmaceutical Evaluation Division)
“Q&A for basic principles for conducting phase 1 studies in Japanese prior to initiating multi-regional clinical trials including Japan for drugs in which early clinical development is preceding outside Japan” (Date of December 25, 2023, Pharmaceutical Evaluation Division Administrative Notice)
If you check the relevant sections of the report of this council along with these notices, you will gain a deeper understanding of the intention behind this action.
First of all, this notificaton focus on “assuming that clinical development overseas takes precedence to Japan.” As stated in the report of the council, the council (and MHLW) is of the position that “from the perspective of improving drug discovery capabilities in Japan, it is desirable for Japan to participate in discussions on development plans and clinical trials from the Phase I trial stage.”
With this in mind, the notification indicates, as a basic concept, that “in principle, there is no need to conduct additional Phase I trials in Japanese subjects, unless it is deemed necessary after examining whether the risks to safety and tolerability in Japanese subjects are explainable, tolerable, and manageable based on available data before Japan participates in the global clinical trial.” This is likely a statement that takes into account the opinion of the pharmaceutical industry (also stated in the report).
The notification then presents the approach to making decisions on an individual product basis, ensuring that the final decision on whether or not to conduct Phase I trials in Japanese patients will be made on an individual basis, while emphasizing the importance of “considering domestic and international differences in pharmacokinetics and pharmacodynamics before submitting for pre-market application,” and clearly stating the possibility of “establishing additional safety measures for Japanese patients in global clinical trials.”
Therefore, if clinical development overseas takes precedence to Japan, it may be possible to consider making Phase I trials in Japanese patients unnecessary, but ultimately it should be presented that a decision will be made on an individual product basis, and that even if they are not necessary, additional safety measures in Japan may be necessary in global clinical trials.
(Personal) Outlook for the Future
We think it will take much time for the PMDA decision of whether or not to conduct Japanese Phase I trials to actually change based on the discussions of the review council and the issuance of the notification.
This is because it will take much time for the PMDA’s thinking/action to change. As stated in the report of the council, the PMDA’s position is that it has always been flexible in its decision of whether or not to conduct Japanese Phase I trials (regardless of the discussions at this council). Therefore, it will be difficult for those who think that they have already done so sufficiently to change just because they received this notification.
In fact, the PMDA is indispensable as a gatekeeper for ensuring the safety of Japanese people participating in global clinical trials, and it is likely that they will continue to lean toward cautious judgment.
In addition, even if it is determined that Japanese Phase I trials are unnecessary, it seems necessary to keep a close eye on the trial conduct to see whether the “additional safety measures in Japan” that PMDA instructs/advises will be reasonable.
On the other hand, there will be an increase in cases where developers, regardless of the size of the company, consult with PMDA on the proviso that “clinical development overseas precedes to Japan,” not only for drugs that are currently experiencing drug lag/drug loss, but also for those where “clinical development overseas precedes to Japan” for any reasons, and that Japanese Phase I trials are not necessary.
When developing overseas or globally, including Japan, if there is no/low benefit or need to develop early in Japan (rather than in other countries), clinical development overseas will precede to Japan.
While there is no change in the benefits, this notification at least makes it possible that the need for early development in Japan may decrease, so it will be easier to move the discussion in the direction of “Japan should be able to participate in global clinical trials.” The balance with additional safety measures (the rationality of PMDA’s instructions/advice) will probably be taken into consideration.
This notification is limited to “if clinical development overseas precedes to Japan,” but it is an ambiguous/individual discretion in order to save face for stakeholders including PMDA, but it will accelerate the trend to make Japanese Phase I trials unnecessary, even if it is gradual. Considering Japan’s need to ensure its drug discovery capabilities, develop its industry, and improve its national strength, however, doubts remain as to whether this direction is truly a good one.
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