Akuugo injection for intracerebral implantation is a Japan origin ATMP with intended use for improvement of chronic motor paralysis following traumatic brain injury. The Marketing Authorization Holder (MAH) is SanBio.
The pre-market review of Akuugo and its discussion for approval in ATMP Committee were unprecedented, so I put a brief review of them here.
Status (as of the end of June 2024)
Firstly, the March 2024 ATMP Committee meeting had an unusual agenda for discussing the “direction of pre-market review” for this product. The MHLW provided a document with overview of its pre-market review results prepared by the PMDA.
The document titled “Summary of the deliberation on Akuugo at ATMP Committee” was published on March 25, 2024 by the MHLW. (here in Japanese only)
As shown in this document, Akuugo is expected to have a certain level of efficacy based on the results of clinical trials, and considering the safety profile, the benefit-risk balance seems to be suitable for approval.
However, due to quality issues, the investigational ATMP used in clinical trials and the ATMP for commercial use cannot be of the same quality.
Taking this situation into consideration, the ATMP Committee discussed the possibility of its approval on June 20, 2024, and conditional (and time-limited) approval was recommended.
As stated in SanBio’s press release (in Japanese), the approval conditions include the confirmation and reporting of the equivalence/homogenity of quality, the submission of a new partial change review application to the PMDA, and the product not being shipped until the approval of the partial change review application.
Therefore, although Akuugo has been approved, it will remain unavailable for marketing and use. According to SanBio’s explanation above, they will manufacture it for commercial use about twice to collect quality data, confirm equivalence/homogenity, and aim to launch it in February to April 2025.
Akuugo was designated as a SAKIGAKE product, aiming for pre-market review within six months, and the pre-market review application was submitted in June 2022 (related article in Japanese). However, in the end, the pre-market review period took more than two years.
Comments
In Japan, if it seems difficult to obtain approval for a drug/medical device/ATMP, the MHLW and the PMDA almost never decide to deny the approval. Instead, they strongly urge the company (MAH) to withdraw the pre-market review application.
In the case of Akuugo, its clinical significance was suggested, and it was a designated SAKIGAKE product, so the MHLW and the PMDA seemed to have a hard time dealing with the situation.
In addition, considering the reasons for refusal of approval for ATMPs under the Pharmaceuticals and Medical Devices Act, its conditional approval was inevitable (instead of deny of approval). The following are the reasons for refusal of approval for ATMPs as stipulated in the Pharmaceuticals and Medical Devices Act.
Article 23-25
(2) In cases that fall under any of the following items, the approval prescribed in the preceding paragraph will not be granted:
(i) when an applicant does not receive license prescribed in Article 23-20, paragraph (1);
(ii) when a manufacturing facility that manufactures regenerative medicine products pertaining to the application does not receive license prescribed in Article 23-22, paragraph (1) (limited to the criteria relating to the items for the application and to those available for production) or accreditation prescribed in paragraph (1) of the preceding Article (limited to the criteria relating to the item for the application that is available for production);
(iii) when the item falls under any of the following (a) to (c), as a result of an examination of the matters related to qualities, efficacy and safety of the regenerative medicine products pertaining to the application, such as the name, constitutive cells, transgenes, components, quantity, dosage administration, methods of usage, efficacy or effects, performance, and side effects:
(a) when the regenerative medicine products pertaining to the application are not found to have the efficacy or effects indicated in the application;
(b) when the regenerative medicine products pertaining to the application are found to have no value as a regenerative medicine product as they have harmful effects which outweigh their efficacy or effects;
(c) beyond the cases set forth in (a) or (b), when the regenerative medicine products fall under the cases specified by Order of the Ministry of Health, Labour and Welfare as not being appropriate as regenerative medicine products;
(iv) when the methods to control manufacturing or the quality of the items at that manufacturing facility of the regenerative medicine products pertaining to the application are not found to comply with the standards specified by Order of the Ministry of Health, Labour and Welfare.
Of these, the issue of quality at this time is whether they fall under Article 23-25, (2), (iii), (c). And for this item (c), it is necessary to further confirm the following provision of the Regulation for Enforcement of the Pharmaceuticals and Medical Devices Act.
Article 137-22
Cases where regenerative medicine products are specified by Order of the Ministry of Health, Labour and Welfare as not being appropriate as regenerative medicine products prescribed in Article 23-25, paragraph (2), item (iii), (c) of the Act (including as applied mutatis mutandis pursuant to paragraph (9) of the same Article; the same applies in the following paragraph) are the cases where the properties or qualities of regenerative medicine products related to the application are remarkably inappropriate with regard to health and hygiene.
The question is whether Akuugo falls under the category of a product whose “properties or quality of ATMPs are remarkably inappropriate with regard to health and hygiene,” but I believe the MHLW and the PMDA were unable to go that far.
While it depend on future quality data, it is very unclear whether things will proceed as SanBio predicts.
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