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Expedited Programs for Regenerative Medicine Explained | iPS Cells & Regenerative Medicine

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TECHNOLOGY EXPLAINER

Expedited Programs for Regenerative Medicine
— review may get faster, but "manufacturing readiness" does not

Japan, the United States and Europe each have programs meant to speed the development and review of cell and gene therapies. Yet the FDA states plainly that, even with a designation, the CMC (chemistry, manufacturing and controls) information required for approval does not change. Japan's "conditional and time-limited approval" gets a product to market sooner, but on the premise that the sponsor re-applies within the term to verify efficacy. Once the differences between the programs are clear, the preparation asked of materials and manufacturing comes into view.

Built from primary sources: published material from the FDA, the Ministry of Health, Labour and Welfare (MHLW), the PMDA and the EMA / Last updated October 2026

Conceptual scene with development and review documents on the left and closed-system cell-product manufacturing and quality-control equipment on the right
Expedited: development dialogue and review processStill required: manufacturing and quality (CMC) evidence
AI-generated concept image. An expedited program does not remove the need to prepare manufacturing and quality evidence for approval. US RMAT and EU PRIME are development-support designations or frameworks; Japan's conditional and time-limited approval is an approval pathway, not the same type of program. The people, site, equipment and documents are fictional and show no real review procedure or duration.
What this article covers
  1. What expedited programs for regenerative medicine are (the short version)
  2. Why cell and gene therapies need programs of their own
  3. United States — RMAT, Fast Track, priority review, accelerated approval
  4. Our calculation: the numbers for RMAT requests and grants
  5. Japan — conditional and time-limited approval, and SAKIGAKE-designated regenerative medicine products
  6. Europe — ATMPs, PRIME, accelerated assessment
  7. The three regions side by side
  8. A materials engineer's view (1): expediting moves materials and manufacturing readiness earlier
  9. A materials engineer's view (2): a time-limited approval is a promise to supply "small quantities, at the same quality, for several years"
  10. Open issues, and what is still undecided
  11. Glossary / References / Claim-to-source audit
How claims are labelled in this article

Sourced = content stated in laws, notifications, guidance or published material (link given)
Our calculation = a figure this article derived from stated assumptions
Not yet confirmed = drafts, items under revision, plans and other matters not settled
Our arrangement of the programs and readings from the materials and manufacturing side are marked separately as Commentary.

A note on medical matters

This article explains approval programs for regenerative medicine and cell and gene therapy and where they meet materials and manufacturing. It does not evaluate or compare the efficacy or safety of individual products, and is not medical advice. Product names that appear are cited only from information published by regulators as examples of how the programs operate. For any decision about treatment, consult a healthcare professional. The general basics of approval systems (Breakthrough Therapy, priority review, accelerated approval, real-world data and so on) are covered in our explainer on regulatory submissions and real-world data; this article is confined to the parts specific to regenerative medicine and cell and gene therapy.

1. What expedited programs for regenerative medicine are (the short version)

  • United States: for regenerative medicine therapies there is the RMAT (Regenerative Medicine Advanced Therapy) designation. It was created by the 21st Century Cures Act on 13 December 2016 and combines the benefits of Fast Track and Breakthrough TherapySourced [Sources 1 and 5].
  • Japan: for "regenerative medicine products", a category created by the amendment enacted in 2013 (which renamed the Pharmaceutical Affairs Act the Act on Securing Quality, Efficacy and Safety of Products Including Pharmaceuticals and Medical Devices, the PMD Act), Article 23-26 of the PMD Act provides conditional and time-limited approval. A product is approved with a term of no more than 7 years and conditions, and the sponsor applies again within the term so that efficacy can be verifiedSourced [Sources 9 and 10].
  • Europe: all ATMPs (advanced therapy medicinal products) fall under the centralised procedure, and under the EMA's PRIME scheme a rapporteur of the committee for advanced therapies (CAT) is assigned earlySourced [Sources 22 and 26].
The single most important line in this article

The FDA's draft guidance on RMAT and related matters (September 2025) says in effect that no expedited-program designation changes the CMC information required for approval to ensure quality, including CGMP compliance of the manufacturing facilities, and that what matters for approval is a demonstration of process control showing a consistent product with predefined critical quality attributes (CQAs) for strength, potency, identity and purity Sourced [Source 6].

The faster review and clinical work go, the earlier the readiness of materials, process and analytics is asked for. That is the core of this for a materials engineer (commentary).

2. Why cell and gene therapies need programs of their own

The FDA's CMC guidance of May 2026 lists the following as challenges when cell and gene therapy (CGT) products proceed by ordinary development methodsSourced [Source 7].

  • Product complexity and patient-specific manufacture
  • Advanced processes and cutting-edge technology
  • Small patient numbers and few manufacturing runs
  • Product characterisation and analytical testing
  • Short shelf life, leaving a narrow time window from manufacture to administration

The Japanese notification describes the background of conditional and time-limited approval in terms closer to the material. It says that regenerative medicine products made of cells, viruses and the like are often heterogeneous, and that while proving efficacy calls for clinical trials with enough subjects, in many cases, such as rare diseases, evaluation has to rest on trials with few casesSourced [Source 9]. The text of the law itself puts, as the first requirement for conditional and time-limited approval, that the regenerative medicine product in the application is not homogeneous (Article 23-26, paragraph 1, item 1)Sourced [Source 9].

RegionCategory of its ownScope (summary)
United StatesRegenerative medicine therapy (FD&C Act section 506(g))Cell therapies, therapeutic tissue-engineered products, human cell and tissue products, or combination products using them. Excludes those regulated solely under section 361 of the Public Health Service Act and 21 CFR Part 1271. In the FDA's interpretation some human gene therapies and xenogeneic cell products can also be included [Source 1]
JapanRegenerative medicine product (PMD Act Article 2, paragraph 9)Processed human cell products used in regenerative medicine (including gene-transduced cells for ex vivo gene therapy) and products for in vivo gene therapy, placed in a new category separate from drugs and medical devices. Created by the amendment enacted in 2013 [Source 9]
EUATMP (advanced therapy medicinal product)The EMA says all ATMPs are subject to the mandatory centralised procedure, with scientific evaluation by the EMA. A prior classification consultation on whether a product is an ATMP is also available [Source 26]

All Sourced (FDA [Source 1], MHLW notification [Source 9], EMA [Source 26]). The scope is a summary, not the full text of the provisions.

3. United States — RMAT, Fast Track, priority review, accelerated approval

Map of expedited programs for regenerative medicine and cell / gene therapy (our arrangement) Note: program names are the official ones. Placing them in three columns is this article's own, not an official classification. Advice during development Faster review Form of approval, after approval US Japan Europe RMAT / Fast Track / BT Apply with or after the IND FDA replies within 60 days Early interaction, rolling review Priority Review Decision within 60 days of filing Review goal 6 months if priority (for BLAs once submitted) Accelerated Approval Approval on a surrogate or intermediate endpoint, confirmed afterwards. RMAT can meet this via patient registries or RWE SAKIGAKE designation Priority consultation, concierge, enhanced pre-assessment, priority review. Orphan designation separate Priority review (SAKIGAKE) Explained as a 6-month target (usual new drugs: 12 months) Orphan drugs get priority review Conditional and time-limited approval Heterogeneous product, efficacy presumed, safety shown. Term up to 7 years; re-apply within it to verify efficacy PRIME Early appointment of a CAT rapporteur, kick-off meeting, repeated scientific advice Can get accelerated review PRIME products can have Accelerated Assessment confirmed at the time of filing Conditional MA, etc. A good number of PRIME products are ATMPs, approved through conditional marketing authorisation (EMA report)
Fig. 1 Conceptual diagram (vector drawing). The US follows the FDA [Sources 1, 5 and 6], Japan the MHLW and PMDA [Sources 9, 11, 12 and 27], and Europe the EMA [Sources 22 and 23]. Arranging them in the three vertical columns is this article's own, and a given program can have several characters at once. The figures are those published for each program and are not for direct comparison between countries.

The RMAT designation — what must be met, and what is gained

According to the FDA's RMAT page, a drug qualifies if it meets all three of the followingSourced [Source 1].

  • It is a regenerative medicine therapy (a cell therapy, a therapeutic tissue-engineered product, a human cell or tissue product, or a combination product using them)
  • It is intended to treat, modify, reverse or cure a serious or life-threatening disease or condition
  • Preliminary clinical evidence shows the potential to address an unmet medical need in that disease

The request is made together with the IND or as an amendment to the IND (the investigational new drug application), and is not granted while the IND is on clinical hold. The FDA notifies its decision within 60 calendar days of receiptSourced [Source 1]. The final guidance of 2019 describes the benefit of RMAT designation as all the benefits of Fast Track and Breakthrough Therapy (rolling review, intensive guidance from phase I, involvement of senior management and so on), and says it can be used for early discussion of surrogate or intermediate endpointsSourced [Source 5].

DesignationLevel of evidence required (FDA 2019 guidance)Main benefits
Fast TrackNonclinical or clinical data show the potential to address an unmet medical need. Early in development, an effect in in vitro or animal models can be enoughMeasures to speed development and review. If the FDA judges from a preliminary evaluation of submitted clinical data that efficacy is possible, rolling review may be possible. Priority review is also possible if the data at filing support it
Breakthrough TherapyPreliminary clinical evidence indicates a substantial improvement over available therapy on one or more clinically significant endpoints (a higher bar than Fast Track)All the benefits of Fast Track, plus intensive guidance on efficient development and involvement of senior management
RMATPreliminary clinical evidence shows the potential to address an unmet medical need. Evidence of "substantial improvement" is not required. Historical controls, retrospective studies, case series and studies outside the US are acceptable in some circumstancesAll the benefits of Fast Track and Breakthrough Therapy. Early discussion of surrogate or intermediate endpoints that would support accelerated approval. Provisions on how post-approval requirements can be met

All Sourced (FDA, "Expedited Programs for Regenerative Medicine Therapies for Serious Conditions", February 2019 [Source 5]). The table is a summary, not the full text of the document. A designation is not approval and does not change the statistical standard for approval.

Forms of approval — accelerated approval, and ways to confirm after approval

Under FD&C Act 506(g)(7), a product given accelerated approval after RMAT designation may in some cases meet its post-approval requirements with clinical evidence other than a conventional confirmatory trial. The FDA guidance lists these meansSourced [Source 5].

  • Submission of clinical evidence, clinical trials, patient registries and real-world evidence such as electronic health records
  • Collection of a larger confirmatory dataset agreed in advance
  • Post-approval follow-up of all patients treated before approval

The revised draft of September 2025 adds that there are "limited cases" in which observational studies where real-world data serve as the treatment and control arms, or externally controlled trials using natural history data, can fill gaps in confirmatory evidence, and lists as conditions for acceptance data reliability and relevance, comparability of populations, missing data and selection biasNot yet confirmed [Source 6]. For the basics, see our explainer on regulatory submissions and real-world data.

The 2019 final version and the 2025 revised draft

The RMAT guidance has a final version of February 2019 [Source 5], and a revised draft was published in September 2025. The draft says that, once finalised, it will replace the 2019 version, and that it rests on the commitments of PDUFA VII (the 2022 reauthorisation of the FDA user fee act)Sourced [Sources 6 and 8]. The FDA's CMC guidance of May 2026 still describes this document as a draftSourced [Source 7]. So the content of the revised draft was not settled as of this survey (October 2026)Not yet confirmed. The points that the revised draft states plainly, unlike the 2019 version, matter to materials engineers (taken up in chapter 8).

Products approved after RMAT designation (as published by the FDA)

The FDA publishes a list of products approved after RMAT designation. As of 30 September 2025 there were 14 productsSourced [Source 3].

Approval dateBrand name (nonproprietary name)Use as the FDA describes it (summary)
2021-02-05BREYANZI (lisocabtagene maraleucel)Large B-cell lymphoma (after two or more prior therapies)
2021-06-15StrataGraftWound closure of thermal burns with intact epidermal elements (adults)
2021-10-08RETHYMIC (allogeneic processed thymus tissue)Immune reconstitution in children with congenital athymia
2023-05-19VYJUVEK (beremagene geperpavec)Wounds of dystrophic epidermolysis bullosa (from 6 months of age)
2023-06-29ROCTAVIAN (valoctocogene roxaparvovec)Severe hemophilia A (adults)
2023-12-08CASGEVY (exagamglogene autotemcel)Sickle cell disease (12 years and older)
2023-12-08LYFGENIA (lovotibeglogene autotemcel)Sickle cell disease (12 years and older)
2024-02-16AMTAGVI (lifileucel)Unresectable or metastatic melanoma
2024-03-18LENMELDY (atridarsagene autotemcel)Metachromatic leukodystrophy (certain forms in children)
2024-04-25BEQVEZ (fidanacogene elaparvovec)Moderate to severe hemophilia B (adults)
2024-08-01TECELRA (afamitresgene autoleucel)Unresectable or metastatic synovial sarcoma (adults)
2024-11-08AUCATZYL (obecabtagene autoleucel)B-cell precursor acute lymphoblastic leukemia (adults)
2024-12-19SYMVESS (acellular tissue engineered vessel)Vascular conduit for extremity arterial injury (adults)
2025-04-28ZEVASKYN (prademagene zamikeracel)Wounds of recessive dystrophic epidermolysis bullosa

All Sourced (FDA, "CBER RMAT Approvals", as of 30 September 2025 [Source 3]). The uses are a summary of the FDA's wording and are not an evaluation of any product's efficacy or safety. Products approved after RMAT designation include not only cell therapies but also gene therapies and tissue-engineered products. The list does not say whether a product was approved under accelerated approval.

4. Our calculation: the numbers for RMAT requests and grants

The FDA (CBER) publishes the outcomes of RMAT designation requests by fiscal year. The tally from 13 December 2016 to 30 September 2025 is as followsSourced [Source 2].

Fiscal yearRequestsGrantedDeniedWithdrawn
20173111182
20184718272
20193717182
20203413210
2021249132
20223014151
20233518170
20245943142
20259150223

All Sourced (FDA, "Cumulative CBER RMAT Designation Requests Received by Fiscal Year" [Source 2]). The FDA notes that requests awaiting an outcome are included in the number of requests. The page was updated on 4 November 2025.

Our calculation

From the table above we work out a few figuresOur calculation.

  • Totals: 388 requests, 193 granted, 165 denied, 14 withdrawn. By difference 16 are awaiting an outcome (388 − 193 − 165 − 14), all from fiscal 2025 (91 − 50 − 22 − 3 = 16)
  • Grant rate (among those with an outcome): 193 ÷ (193 + 165) = about 54%. By year: fiscal 2017 38%, fiscal 2020 38%, fiscal 2023 51%, fiscal 2024 75%, fiscal 2025 69% (outcomes only)
  • Growth in requests: from 34 in fiscal 2020 to 91 in fiscal 2025, about 2.7-fold (91 ÷ 34)
  • Relation to approvals: 14 products approved (FDA list, as of 30 September 2025). Against 193 grants, 14 ÷ 193 = about 7%. But there is a lag of years between designation and approval, so this is not a success rate

Premises and limits: the grant rate excludes withdrawals and requests awaiting an outcome. The FDA's year is the fiscal year (October of the previous year to September), a different unit from the calendar year of the approval date in the approvals list. The FDA also tabulates by year the number of designations withdrawn or revoked after being granted, and in that table, as of 30 June 2025, the figure was 0 for every year [Source 4].

Outcomes of RMAT designation requests, and products approved after RMAT Left: FDA (CBER) requests and outcomes by fiscal year, Dec 2016 to Sep 2025. Right: approved after RMAT, by approval year. 31 2017 38% 47 2018 40% 37 2019 49% 34 2020 38% 24 2021 41% 30 2022 48% 35 2023 51% 59 2024 75% 91 2025 69% 3 2021 0 2022 4 2023 6 2024 1 2025 Grant % Requests (number above bar) Products approved (by year) Granted Denied Withdrawn Awaiting outcome (our subtraction) Note: grant % = granted / (granted + denied), our calculation excluding withdrawn and awaiting; years follow the FDA (fiscal years). Note: counts on the right are tallied from the approval dates in the FDA list (30 September 2025). 2022 has no product.
Fig. 2 Drawing that includes our calculation (vector drawing). Requests, grants, denials and withdrawals follow the FDA (CBER) table [Source 2], and approved products the FDA list [Source 3]. The grant rate, the number awaiting an outcome (by subtraction from requests) and the approvals by year are values derived by this article, not published values. There is a lag of years between designation and approval, and the bars on the right do not mean the "successful share" of the bars on the left.

What can be said from these numbers (commentary): requests rose in fiscal 2024 and 2025, and the share granted also rose. Meanwhile, the number of approved products stays far smaller than the number of designations. A designation is only one entrance on the road to approval. The FDA states that RMAT designation is not the same as approval and does not change the safety and efficacy standards required for approval [Sources 5 and 6].

5. Japan — conditional and time-limited approval, and SAKIGAKE-designated regenerative medicine products

How conditional and time-limited approval works (PMD Act Article 23-26)

An MHLW notification (29 March 2024) sets out the requirements by quoting the lawSourced [Source 9].

  • When a regenerative medicine product meets all three of the following, the Minister of Health, Labour and Welfare may approve it with conditions and a term of no more than 7 years:
    (1) the product in the application is not homogeneous; (2) it is presumed to have the efficacy, effect or performance claimed; (3) it is not presumed to have such harmful effects that it has no value in use
  • The term may, where particularly necessary for proper review, be extended by up to 3 years after hearing the opinion of the Pharmaceutical Affairs Council (paragraph 2 of the same Article) [Source 10]
  • The person who received approval must apply for approval again within the term (paragraph 5). If a re-application has been made but no disposition has been made within the term, the approval remains in effect until the disposition is made (paragraph 6) [Source 10]

The notification is also firm on the purpose of the system. It says that a development plan should not take conditional and time-limited approval as its final aim and should from the start include verification of efficacy, and that if, as a result of re-applying within the term and evaluating after marketing, efficacy is not confirmed, continuation of approval will not be allowedSourced [Source 9].

Flow of conditional and time-limited approval, and the 8 products so approved Top: flow of the system (per the notice). Bottom: approval dates of 8 products in PMDA lists (our arrangement). Clinical trial Efficacy presumed, safety confirmed Conditional / time-limited Term up to 7 years (extension up to 3 years) Post-marketing evaluation All treated cases are in principle evaluated Re-apply in time: regular approval Refused / withdrawn: approval lapses Note: on approval of the re-application (category 1-2), the conditional approval lapses and a regular approval is given [Source 10]. 2015 2017 2019 2021 2023 2025 2027 HeartSheet Sep 2015 (approval withdrawn Jul 2024) STEMIRAC Dec 2018 Collategene Mar 2019 (lapsed Jun 2024) Delytact Jun 2021 Akuugo Jul 2024 Elevidys May 2025 ReHeart / Amchepry Mar 2026 (2 products) Note: dates from the PMDA list [Sources 13 to 18]; the HeartSheet withdrawal and Collategene lapse from MHLW notices [Sources 20 and 21]. Note: dots are placed by approval month, roughly; the timeline is not strictly to scale. Other outcomes are not shown. Note: the count of 8 is this article's: the 4 products in the MHLW notice (March 2024) plus 4 more given conditional and time-limited approval in the PMDA lists for fiscal 2024 to 2026.
Fig. 3 Conceptual diagram (vector drawing). The flow of the system follows the MHLW notices [Sources 9 and 10], and the approval dates the PMDA lists of approved products [Sources 13 to 18]. The count of 8 products and the placement of the dots are this article's arrangement. It does not evaluate the efficacy or safety of any product.

The course of the 8 products (published facts only)

Brand name (company)Date of conditional and time-limited approvalTerm and what followed (as published)
HeartSheet (Terumo)2015-09-18Term of 5 years plus a 3-year extension (to 17 September 2023). Re-applied on 7 September 2023. Notice of withdrawal of the approval on 25 July 2024 [Source 20]
STEMIRAC injection (Nipro)2018-12-28Term of 7 years [Source 21]
Collategene intramuscular injection 4 mg (AnGes)2019-03-26Term of 5 years (to 25 March 2024). Re-applied on 31 May 2023. Application withdrawn on 27 June 2024, and the approval lapsed. Product in circulation to be recovered promptly [Source 21]
Delytact injection (Daiichi Sankyo)2021-06-11Term of 7 years [Source 21]
Akuugo, for intracerebral implantation (SanBio)2024-07-31Term of 7 years, SAKIGAKE designation, orphan [Source 19]. In a partial-change approval on 8 December 2025, the approval condition on evaluating equivalence / comparability of quality, set in view of limited manufacturing experience, was deleted as having been addressed [Source 17]
Elevidys intravenous infusion (Chugai Pharmaceutical)2025-05-13Conditional and time-limited approval (viral vector product, orphan) [Source 17]
ReHeart (Cuorips)2026-03-06Term of 7 years, application of 4 April 2025, orphan [Sources 19 and 17]
Amchepry (Sumitomo Pharma)2026-03-06Term of 7 years, application of 5 August 2025, SAKIGAKE designation, orphan [Sources 19 and 17]

All Sourced (PMDA lists of approved products [Sources 13 to 18], MHLW notices and meeting materials [Sources 9, 19, 20 and 21]). The terms for STEMIRAC and Delytact are the "7-year approval term" stated in the material attached to the notice of 27 June 2024 (the notice on the lapse of Collategene). Indications and clinical results are not included.

What can be read from this (commentary): of the 8 products, the published materials confirm "withdrawal of approval" and "lapse" for 2 (HeartSheet and Collategene); the others are within their term, or the outcome could not be confirmed in published materials. The published facts show that a time-limited approval is not a one-way road of "approval, then regular approval", but a system in which the arrival of the deadline can lead to the end of supply.

How quality is handled at approval and after — the notification of October 2025

In a notification dated 6 October 2025 (Iyaku-kishin-hatsu 1006 No. 1), the MHLW sorted out how conditional and time-limited approval is handledSourced [Source 10]. Its chapter 5, on quality, matters to those in materials and manufacturing.

  • Regenerative medicine products too, like drugs, need to build a quality control strategy that includes critical quality attributes, critical process parameters and how they are controlled. What matters is not "ensuring quality merely by specifications" but how control from raw materials to product can consistently give the expected quality
  • At the time of conditional and time-limited approval, a study of repeated runs alone may not have fully identified the sources of variation in process parameters and raw materials, so it cannot be said that a product meeting the intended quality can be made consistently; verification may therefore be needed to confirm that products of the expected quality are obtained
  • The quality control strategy at approval may be provisional. At the manufacturing site, control using quality risk management is carried out, and in light of manufacturing experience accumulated through product quality review and additional knowledge of quality attributes obtained after approval, control items and process parameters that may become critical quality attributes are continually improved

On the application procedure, the notification also asks that a draft basic plan for evaluating post-marketing approval conditions be attached to the application, and that, in principle, all cases treated be included in the post-marketing evaluation [Source 10]. It adds that even if the application is withdrawn or the approval withdrawn after re-application, the study results collected within the term will be reviewed by the PMDA and published as a review report [Source 10].

SAKIGAKE designation for regenerative medicine products, and orphan designation

Apart from conditional and time-limited approval, Japan has designations that promote developmentSourced.

  • The SAKIGAKE review designation system: created on 1 April 2015 for early practical use of innovative drugs, medical devices and regenerative medicine products. Where the target for an ordinary new drug is 12 months, the MHLW explained that designated products would be reviewed with a target of 6 months, using the PMDA's pre-assessment (announcement of 5 October 2017) [Source 12]
  • It was then put into law by the 2019 amendment, and designation as a SAKIGAKE-designated regenerative medicine product rests on Article 77-2, paragraph 2 of the PMD Act. There are four requirements; for regenerative medicine products they are (1) a novel mechanism of action, (2) a serious disease with a major effect on life, (3) markedly high efficacy or safety for the target disease, and (4) intent and a system to develop and file early in Japan ahead of the world (or within 3 months of the first country's filing) [Source 11]
  • A designation brings priority consultation, fuller pre-assessment, priority review and a concierge [Source 11]
  • Designation as an orphan regenerative medicine product requires, among other things, fewer than 50,000 target patients in Japan, and the product is reviewed with priority (PMDA) [Source 27]

Among the 8 products above, the published materials record Akuugo and Amchepry as SAKIGAKE-designated and Akuugo, Elevidys, ReHeart and Amchepry as orphan regenerative medicine products [Sources 16, 17 and 19]. We have not confirmed whether the other 4 products have such designations.

6. Europe — ATMPs, PRIME, accelerated assessment

The EMA says all ATMPs are subject to the mandatory centralised procedure, with scientific evaluation by the EMASourced [Source 26]. The centre of expediting is PRIME (PRIority MEdicines), a scheme that supports development of drugs addressing unmet medical needs through early dialogueSourced [Source 22].

PRIME benefit (EMA)TimingContent (summary)
Early appointment of a rapporteur of the CHMP or CAT1 month after PRIME eligibility is grantedDiscussion of technical and scientific preparation for filing. For advanced therapies, a rapporteur of the CAT
Kick-off meeting3 to 4 months after grantingAdvice from the rapporteur and a team of experts on the overall development plan, future scientific advice and regulatory strategy
Repeated scientific adviceAt any time / at key milestonesHTA bodies, patients, the FDA and others can take part. Additional advice on shortened timelines under some conditions
Pre-filing meetingAbout 1 year before the marketing authorisation applicationState of development and maturity of the dossier, type of application (such as conditional marketing authorisation), generation of evidence after approval
Confirmation of accelerated assessmentAt the marketing authorisation applicationRaises certainty about the review timeline

All Sourced (EMA, "PRIME: priority medicines" [Source 22]). For small and medium-sized enterprises and academia there is Early Entry PRIME, granted at an early stage on the basis of, for example, nonclinical proof of concept.

PRIME in numbers — ATMPs are about 27% of requests and 46% of grants

The EMA's five-year report on PRIME (data from March 2016 to June 2021) says the following about ATMPsSourced [Source 23].

  • ATMPs were about 27% of requests for PRIME eligibility but had the highest success rate and made up 46% of all PRIME products. The report gives as the reason that their requests generally combined a high potential to address unmet medical need, a very specific mechanism of action and strong proof-of-concept evidence
  • Of 16 PRIME products that started under accelerated assessment, 7 (44%) were ATMPs. For non-PRIME products, by contrast, only 1 ATMP (4%) started under accelerated assessment
  • Among the reasons for reverting from accelerated assessment to standard review, ATMPs had many major quality concerns (specifications, manufacturing problems, process control). Switching to standard review was frequent in the PRIME analysis as well (56%)

A later EMA page gives cumulative figures as of July 2026: of requests for PRIME eligibility, 26% were granted and 67% denied (the rest out of scope, withdrawn or transferred) [Source 22]. We could not confirm figures for ATMPs alone on this updated page.

A "toolbox" for quality data — the EMA's Toolbox guidance

In April 2022 the EMA published Toolbox guidance to make it easier for PRIME and similar products to assemble quality (Module 3) data. ATMPs are coveredSourced [Source 24]. We pick out the points that bear on materials and manufacturing.

  • Stability: where standard stability data are not available, an application may be possible, on scientific grounds, with data for a shorter period (for example 6 months) and in some cases from fewer than 3 batches
  • Process validation: it gives as examples where a protocol may be submitted before approval instead of the final report: introduction of a new cell bank, introduction of a new reference standard, hold-time studies and transport validation. Case by case, under risk assessment, it can also be deferred to after approval
  • GMP level of starting materials: the establishment of a new cell bank should follow GMP, but in exceptional cases an MCB made at an academic institution may be regarded as manufactured at an appropriate level of GMP, subject to traceability, contamination prevention, extensive characterisation, risk assessment and so on (see our explainer on cell manufacturing and cell banking)
  • Comparability: ATMPs vary greatly in starting material and fall outside ICH Q5E. The principles of comparability apply, but should be read together with the separate Q&A for ATMPs (EMA/CAT/499821/2019)

A joint EMA and FDA Q&A (December 2023) sets out quality and GMP points (control strategy, process validation, stability, GMP) for PRIME and Breakthrough, but states plainly that on the FDA side it covers only products under CDER and not ATMPs under CBER [Source 25].

7. The three regions side by side

AspectUnited States (FDA / CBER)Japan (MHLW / PMDA)Europe (EMA)
Designation specific to regenerative medicineRMAT designation (created by the Cures Act of 13 December 2016)SAKIGAKE designation for regenerative medicine products; orphan regenerative medicine product designationNot limited to ATMPs; PRIME, open to all fields, is central. ATMPs make up a large share within PRIME (46% of grants, 2016 to 2021)
When to applyWith the IND or as an IND amendment. Reply within 60 calendar daysConsult the MHLW beforehand. For now designations are made about twice a year (roughly April and October) (notice of January 2024)At the exploratory clinical trial stage (Early Entry rests mainly on nonclinical data)
Support during developmentCombines the benefits of Fast Track and Breakthrough. Rolling review possiblePriority consultation, fuller pre-assessment, conciergeEarly appointment of a CAT rapporteur, kick-off meeting, repeated scientific advice, pre-filing meeting
Shortening reviewPriority review (6-month review goal for a BLA)6-month target for SAKIGAKE designation (as explained when the system was created; 12 months for ordinary new drugs)Accelerated assessment can be confirmed at filing
Form of approvalRegular approval / accelerated approval. For RMAT, confirmation can sometimes be met with patient registries or RWEConditional and time-limited approval (term up to 7 years, extension up to 3 years, re-application within the term)Conditional marketing authorisation (common for ATMPs among PRIME products)
After approvalCollection of confirmatory evidence. Withdrawal is possible (for accelerated approval)In principle all treated cases are in the evaluation of approval conditions. If the re-application is withdrawn, or refused after the term arrives, the approval lapsesConditional authorisation is renewed every year (see our explainer on regulatory submissions and real-world data)
Documents on flexibility in quality (CMC)CMC guidance of May 2026 (CBER). The 2025 revised draft on RMATChapter 5 of the notification of 6 October 2025 (quality control strategy)Toolbox guidance of April 2022 (ATMPs also covered)
StatusThe September 2025 revised draft of the RMAT guidance is not finalNotifications in forceGuidance in force

The table is an arrangement of what is Sourced (FDA [Sources 1, 5, 6 and 7], MHLW and PMDA [Sources 9 to 12], EMA [Sources 22 to 24]). "Status" is as of this article's survey (October 2026). The renewal of European conditional authorisation is a summary based on another article in this series.

8. A materials engineer's view (1): expediting moves materials and manufacturing readiness earlier

We now re-read the primary sources so far from the side of materials and process. The FDA's revised draft of September 2025, its CMC guidance of May 2026, the EMA's Toolbox and Japan's notification of October 2025 all point the same way.

What a materials engineer should read here (1): the product used in the clinic and the product to be made must be the same

An RMAT request needs preliminary clinical evidence, and the FDA guidance says that evidence must have been generated with the product that is to be developedSourced [Source 5]. The 2025 revised draft is more specific. Where a manufacturing change makes the product that generated the evidence differ from the product being developed, it recommends including comparability data, and says that if comparability cannot be shown the evidence generally does not support RMAT designation. It also writes that if a manufacturing change is made after designation and comparability with the pre-change product cannot be shown, the post-change product may no longer meet the RMAT requirements. A footnote adds, however, that a manufacturing change does not necessarily preclude an initial designation or lead to its withdrawal, and that each case is judged individuallySourced [Source 6].

From the materials side, any change of raw material or supply, such as culture medium, serum replacement, enzyme, beads, vector, container or cryopreservation solution, can become a "manufacturing change" (commentary). The more a development aims at an expedited designation, the more it is worth choosing, from the earliest clinical lots, materials that will not be changed later. A wish to switch later to a cheaper alternative, or to add suppliers, brings the burden of comparability with it.

What a materials engineer should read here (2): the phrase "characterise early" calls for materials property data

As examples of CMC preparation, the 2025 revised draft lists designing a quality control strategy based on critical quality attributes (CQAs), planning analytical method validation and commercial process validation, and a risk-based strategy for manufacturing changes including scale-up and scale-out, and says that, to avoid later delays from failing to identify critical quality attributes and so failing to ensure quality, characterisation of the product is encouraged from early on and throughout developmentSourced [Source 6].

The CQAs of a cell product can include some derived from raw materials (activity of a growth factor, residual enzyme, residual beads, leachables from containers and so on). So what is asked of a materials maker can be read as, beyond the figures on the delivery specification, information and samples that let a customer examine early which property of the material affects which quality attribute of the product (commentary).

Item in the FDA CMC guidance of May 2026What it says (summary)Points bearing on materials and containers (commentary)
CGMP during clinical developmentManufacture of phase 1 investigational drugs is generally exempt from compliance with 21 CFR Part 211, though process characterisation throughout development is recommendedSourcedThe exemption does not mean "no GMP paperwork is needed"; it leaves homework for when the product moves to commercial scale
Acceptance criteria for release testsRelatively loose criteria may be accepted early, but acceptance criteria must be set before phase 2 and 3 start. The timing for establishing numerical criteria before confirmatory studies is to be discussedSourcedAcceptance criteria for raw materials become the basis of the product's release criteria
ComparabilityA risk assessment for every manufacturing change. For minor, low-risk changes, limited data may be accepted (submitted before administering the post-change product)SourcedA change of material is the first input to the risk assessment
Process validation (PPQ)There is no set minimum number of PPQ batches; the number is decided with justification. Completing PPQ after approval, or commercial concurrent release of PPQ batches that meet criteria, may be consideredSourcedTo show consistency of quality with few lots, the lot-to-lot variation of materials must be small
Commercial specificationsWith few product lots, statistically robust commercial criteria may not be settable. A commitment to re-evaluate criteria after approval can also be considered. Changes go by prior-approval supplementSourcedManufacturing data accumulated after approval (including material lots) become the basis of specifications
StabilityReal-time data from 3 lots over 6 months or more at the commercial facility are generally recommended. A different number of lots is possible by risk assessment. Clinical lot data can also be used if made with the commercial process, formulation and containerSourcedIf the container and closure specification is not fixed early, stability data cannot be reused
Retention samples and analytical methodsExceptions to retention samples are considered for small lots and patient-specific lots. Alternatives to pharmacopoeial methods, such as rapid microbial testing, are also considered if validatedSourcedAnalytics that can judge quality from a small sample, and the design of container-integrity evaluation, are what count

The first two columns are Sourced (FDA, "CMC Flexibilities for Developing Human Cellular and Gene Therapy Products for a BLA", May 2026 [Source 7]). The right-hand column is commentary from this article. This guidance explains flexibility, and assumes prior discussion with the FDA for each product.

Materials and manufacturing readiness asked for at each stage of an expedited development Each box summarises published statements. The ordering into stages is this article's, not a formal schedule of any program. Early clinic (IND) Apply CGMP suited to the phase (phase 1 is generally exempt from Part 211) Characterise the process in parallel FDA [Source 7] Designation request Product behind the clinical evidence must be the one developed If it changes, add comparability data FDA [Sources 5, 6] Confirmatory trials Set release-test acceptance criteria before phase 2 / 3 Identify CQAs and critical process parameters early FDA [Sources 6, 7] Application Justify the number of PPQ batches Stability: 3 lots and 6 months or more at the commercial site is generally recommended (alternatives possible) FDA, EMA [Sources 7, 24] After approval If approved on few lots, re-evaluate specifications In Japan, re-apply within the term and keep improving the control strategy FDA, MHLW [Sources 7, 10] Note: the FDA's May 2026 CMC guidance describes flexibility the FDA may consider, and assumes prior discussion per product [Source 7]. Note: a designation does not change the CMC data needed for approval [Source 6]; flexibility is in their order, amount and timing. Note: stability lots and period are the FDA's general recommendation; the EMA also mentions under 6 months or 3 lots [Source 24].
Fig. 4 Conceptual diagram (vector drawing). The content of each box summarises statements by the FDA [Sources 5, 6 and 7], the EMA [Source 24] and the MHLW [Source 10]. Arranging them into stages is this article's own and does not show any actual development plan or review procedure.
What a materials engineer should read here (3): Japan's notification says repeated runs alone are not enough

On quality control at the time of conditional and time-limited approval, Japan's notification of 6 October 2025 says that a study of repeated runs alone may not have fully identified sources of variation such as raw materials in process parameters, and that consistent manufacture cannot then be claimedSourced [Source 10]. For Akuugo (conditional and time-limited approval on 31 July 2024), the approval conditions required that, in view of limited manufacturing experience, quality information be collected promptly under a predefined plan, equivalence / comparability of quality between the trial product and this product be evaluated and reported, and that the necessary partial-change application be filed and the product not be shipped until it is approved. This condition was deleted as addressed in the partial-change approval of 8 December 2025Sourced [Source 17].

What can be read from this (commentary): the system is designed on the premise that at the time of approval the sources of variation in materials and process are not yet well understood, and that after approval, factors will be identified from actual manufacturing experience and the approved matters changed if necessary. For a materials maker, even after approval, lot-by-lot property data and change-control records become the material supporting the customer's "evaluation of equivalence".

9. A materials engineer's view (2): a time-limited approval is a promise to supply "small quantities, at the same quality, for several years"

Conceptual scene showing small-volume closed-system cell-product manufacturing, testing and recording of samples, then placement into a transport container
1. Manufacture small batches2. Test and document each lot3. Supply under controlled conditions
Fig. 5 AI-generated supply-workflow concept image. After a time-limited approval, products still need to be manufactured, quality-checked, documented and supplied. It does not depict any actual product, facility, container, shipping condition or guaranteed lot release.
What a materials engineer should read here: three realities
  • The quantity is small: MHLW meeting materials give the scale of use assumed in the post-marketing evaluation plan. For example, Amchepry assumes use in about 35 cases over 7 years, and Akuugo about 175 cases over 7 years (about 25 a year)Sourced [Source 19]. Amchepry is described as having a limit on supply because manufacture starts from the differentiation stage of iPS cells for each patient, and its shelf life is stated as 31 hours [Source 19]. Materials used to make a few to a few tens of cases a year are used in small amounts, but the weight of one failed lot is large (commentary)
  • Supply can be tied to the fate of the approval: for HeartSheet, a notice of withdrawal of approval was filed on 25 July 2024, and for Collategene the approval lapsed when the application was withdrawn and the product on the market was to be recovered promptlySourced [Sources 20 and 21]. With a time-limited approval, the term of a materials supply contract and minimum purchase quantities may change with the outcome of the product's approval, and this needs to be built in from the contract stage (commentary)
  • Procedures for change continue after approval: even for a product with conditional and time-limited approval, a partial change of approved matters needs the Minister's approval, and the term is kept as before (notification)Sourced [Source 10]. A change of material or addition of a supplier can amount to a change of approved matters (commentary). See also our explainers on QbD and CMC and on regulatory submissions and real-world data (DMF / MF)

From these it can be read that the materials business for cell and gene therapy tends to move toward "not large volumes at low cost" but "small quantities, unchanged, with reliable records, for a long time" (commentary).

10. Open issues, and what is still undecided

(1) The revised RMAT guidance is not final

Besides the final version of February 2019 [Source 5], the FDA's "Expedited Programs for Regenerative Medicine Therapies for Serious Conditions" has a revised draft of September 2025 [Sources 6 and 8]. It is still a draft in the FDA document of May 2026 [Source 7]. We could not confirm a final version as of this survey (October 2026)Not yet confirmed.

(2) The FDA's published statistics look as if updates have stopped

The RMAT request and approval tables hold data as of 30 September 2025, and the page update date is November 2025 [Sources 2 and 3]. We have not confirmed requests or approvals after thatNot yet confirmed.

(3) Few products with conditional and time-limited approval have reached an "outcome"

Of the 8 products, the outcome of re-application within the term can be confirmed in published materials for two: withdrawal of approval (HeartSheet) and lapse (Collategene) [Sources 20 and 21]. Whether the products given conditional and time-limited approval in March 2026 move on to regular approval is still a matter for the futureNot yet confirmed.

(4) The extent of "flexibility" is decided in individual discussions

The documents of the FDA, EMA and MHLW are all worded as "may consider" or "can be considered", and assume prior discussion [Sources 7, 24 and 10]. How far something is accepted differs by product, process and data, and this article cannot generalise it.

(5) The PRIME figures are data from 2016 to 2021

The figures of ATMPs at about 27% of requests and 46% of grants come from the EMA five-year report (March 2016 to June 2021) [Source 23]. We could not confirm later figures for ATMPs. For GMP of ATMPs in the EU (Part IV), a concept paper for a revision aligned with Annex 1 was published in March 2025 [Source 28]. We have not confirmed the revised versionNot yet confirmed (see our explainers on GMP and on cell manufacturing and cell banking).

(6) Comparing the programs has limits

The definition of review time (starting point, treatment of clock stops), the requirements for designation and the form of approval differ by country. The tables in this article are a map and do not rank countries or compare the efficacy or safety of individual products.

Summary of this article
  • The FDA's RMAT is a designation for regenerative medicine that combines the benefits of Fast Track and Breakthrough. It was created in December 2016, and by the end of September 2025, 14 products had been approved after RMAT designationSourced
  • RMAT was granted for about 54% of requests that had an outcome. Requests rose from 34 in fiscal 2020 to 91 in fiscal 2025Our calculation
  • Japan's conditional and time-limited approval is a system in which the sponsor re-applies within a term of up to 7 years to verify efficacy. 8 products have been approved, and 2 have ended in withdrawal of approval or lapseSourced
  • In the EU's PRIME, ATMPs made up about 27% of requests and 46% of grants (2016 to 2021)Sourced. Among the reasons for reverting from accelerated assessment to standard review, quality concerns were frequent for ATMPs
  • A designation does not change the CMC information needed for approval. Equivalence between the product used in the clinic and the product to be developed, early characterisation, and early fixing of stability and containers are asked of the materials side earlier (commentary)
  • With a time-limited approval, the promise of small quantities, the same quality and long supply extends to materials contracts. If approval is withdrawn or lapses, supply stops (commentary)

11. Glossary

RMAT
Regenerative Medicine Advanced Therapy. A US designation for regenerative medicine that combines the benefits of Fast Track and Breakthrough Therapy.
IND / BLA
The US investigational new drug application (IND) and biologics license application (BLA). Cell and gene therapies are approved through a BLA.
CBER / OTP
The FDA's Center for Biologics Evaluation and Research, and the office within it that handles cell and gene therapies.
Rolling review
A mechanism by which parts of an application can be submitted for review as they become ready (Fast Track and others).
Accelerated approval
A mechanism that approves on the basis of a surrogate or intermediate endpoint and confirms after approval.
Regenerative medicine product
A category of Japan's PMD Act: processed human cell products (including gene-transduced cells) and gene therapy products.
Conditional and time-limited approval
PMD Act Article 23-26 of Japan. A heterogeneous regenerative medicine product is approved with conditions and a term of up to 7 years, and must be re-applied for within the term.
SAKIGAKE-designated regenerative medicine product
A Japanese designation system. Requirements: a novel mechanism of action, seriousness of the disease, markedly high efficacy or safety, and early filing in Japan.
Evaluation of approval conditions
Evaluation after a conditional and time-limited approval that checks efficacy and safety in the cases treated.
ATMP
Advanced therapy medicinal product. In the EU, the category covering cell therapy, gene therapy and tissue-engineered products. Subject to the centralised procedure.
CAT
The EMA's Committee for Advanced Therapies. Responsible for the evaluation of ATMPs.
PRIME
The EMA's priority medicines scheme. Supports development of drugs for unmet medical needs through early dialogue.
CQA / CPP
Critical quality attributes and critical process parameters: the product properties that determine quality, and the process conditions that affect them.
PPQ
Process performance qualification. An important stage of validation that confirms the performance of the commercial-scale process.
Comparability (equivalence / homogeneity)
Showing that product quality is the same (or unaffected) before and after a manufacturing change.
RWE
Real-world evidence. Clinical evidence obtained by analysing data from routine care.

12. References

  1. US FDA (CBER) "Regenerative Medicine Advanced Therapy Designation" (page updated 4 November 2025) https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/regenerative-medicine-advanced-therapy-designation
  2. US FDA (CBER) "Cumulative CBER Regenerative Medicine Advanced Therapy (RMAT) Designation Requests Received by Fiscal Year" (data as of 30 September 2025) https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/cumulative-cber-regenerative-medicine-advanced-therapy-rmat-designation-requests-received-fiscal
  3. US FDA (CBER) "CBER Regenerative Medicine Advanced Therapy (RMAT) Approvals" (data as of 30 September 2025) https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/cber-regenerative-medicine-advanced-therapy-rmat-approvals
  4. US FDA (CBER) "CBER RMAT Designations Withdrawn after Granting or Rescinded by Fiscal Year" (data as of 30 June 2025) https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/cber-regenerative-medicine-advanced-therapy-rmat-designations-withdrawn-after-granting-or-rescinded
  5. US FDA (CBER) "Expedited Programs for Regenerative Medicine Therapies for Serious Conditions - Guidance for Industry", February 2019 (PDF) https://www.fda.gov/media/120267/download
  6. US FDA (CBER) "Expedited Programs for Regenerative Medicine Therapies for Serious Conditions - Draft Guidance for Industry", September 2025 (PDF) https://www.fda.gov/media/188874/download
  7. US FDA (CBER) "Chemistry, Manufacturing, and Controls Flexibilities for Developing Human Cellular and Gene Therapy Products for a Biologics License Application - Guidance for Industry", May 2026 (PDF) https://www.fda.gov/media/192321/download
  8. Federal Register "Expedited Programs for Regenerative Medicine Therapies for Serious Conditions; Draft Guidance for Industry; Availability", 90 FR (25 September 2025, FR Doc. 2025-18653) https://www.govinfo.gov/content/pkg/FR-2025-09-25/pdf/2025-18653.pdf
  9. Director, Medical Device Evaluation Division, Pharmaceutical Bureau, MHLW Notification Iyaku-kishin-hatsu 0329 No. 3 (29 March 2024), "On guidance for conditional and time-limited approval of regenerative medicine products and the subsequent drafting of an efficacy evaluation plan" (in Japanese) https://www.mhlw.go.jp/content/10808000/001631279.pdf
  10. Director, Medical Device Evaluation Division, Pharmaceutical Bureau, MHLW Notification Iyaku-kishin-hatsu 1006 No. 1 (6 October 2025), "On the handling of conditional and time-limited approval of regenerative medicine products" (in Japanese) https://www.mhlw.go.jp/content/10808000/001631280.pdf
  11. Director, Medical Device Evaluation Division, Pharmaceutical Bureau, MHLW Notification Iyaku-kishin-hatsu 0112 No. 1 (12 January 2024), "On the partial revision of the handling of designation of innovative medical devices, in vitro diagnostics and regenerative medicine products" (posted by the PMDA) (in Japanese) https://www.pmda.go.jp/files/000240376.pdf
  12. MHLW press release "Starting to invite candidate products for the SAKIGAKE review designation system", 5 October 2017 (in Japanese) https://www.mhlw.go.jp/stf/houdou/0000179802.html
  13. Pharmaceuticals and Medical Devices Agency (PMDA) "List of approved products, fiscal 2015 (regenerative medicine products)" (PDF) (in Japanese) https://www.pmda.go.jp/files/000228179.pdf
  14. PMDA "List of approved products, fiscal 2018 (regenerative medicine products)" (PDF) (in Japanese) https://www.pmda.go.jp/files/000231456.pdf
  15. PMDA "List of approved products, fiscal 2021 (regenerative medicine products)" (PDF) (in Japanese) https://www.pmda.go.jp/files/000246141.pdf
  16. PMDA "List of approved products, fiscal 2024 (regenerative medicine products)" (PDF) (in Japanese) https://www.pmda.go.jp/files/000274840.pdf
  17. PMDA "List of approved products, fiscal 2025 (regenerative medicine products)" (PDF) (in Japanese) https://www.pmda.go.jp/files/000280052.pdf
  18. PMDA "List of approved products, fiscal 2026 (regenerative medicine products)" (PDF) (in Japanese) https://www.pmda.go.jp/files/000282058.pdf
  19. Medical Device Evaluation Division, Pharmaceutical Bureau, MHLW "On the conditional and time-limited approval of three regenerative medicine products", Chuikyo General Meeting, Sou-11 Reference 2, 8 April 2026 (PDF) (in Japanese) https://www.mhlw.go.jp/content/10808000/001687611.pdf
  20. Medical Device Evaluation Division, Pharmaceutical Bureau, MHLW Notification Iyaku-kishin-hatsu 0725 No. 1 (25 July 2024), "On the withdrawal of approval of regenerative medicine products given conditional and time-limited approval" (attached to Hoi-hatsu 0725 No. 4; PDF) (in Japanese) https://www.mhlw.go.jp/content/10808000/001284995.pdf
  21. Medical Device Evaluation Division, Pharmaceutical Bureau, MHLW Notification Iyaku-kishin-hatsu 0627 No. 1 (27 June 2024), "On the withdrawal of an application made under Article 23-26, paragraph 5" (attached to Hoi-hatsu 0627 No. 1; includes a list of products given conditional and time-limited approval; PDF) (in Japanese) https://www.mhlw.go.jp/content/10808000/001284993.pdf
  22. European Medicines Agency "PRIME: priority medicines" https://www.ema.europa.eu/en/human-regulatory-overview/research-development/prime-priority-medicines
  23. European Medicines Agency "PRIME: Analysis of the first 5 years' experience", 2022 (PDF) https://www.ema.europa.eu/system/files/documents/report/2022-03_prime_5_years_report_updated_2022-04-05-en.pdf
  24. European Medicines Agency "Toolbox guidance on scientific elements and regulatory tools to support quality data packages for PRIME and certain marketing authorisation applications targeting an unmet medical need", April 2022 (EMA/CHMP/BWP/QWP/IWG/694114/2019, PDF) https://www.ema.europa.eu/en/documents/scientific-guideline/toolbox-guidance-scientific-elements-and-regulatory-tools-support-quality-data-packages-prime-and-certain-marketing-authorisation-applications-targeting-unmet-medical-need_en.pdf
  25. EMA / US FDA "EMA-FDA joint Q&As on Quality and GMP aspects of PRIME/Breakthrough therapy applications", 4 December 2023 (EMA/CHMP/531552/2023, PDF) https://www.ema.europa.eu/en/documents/other/ema-fda-joint-qas-quality-gmp-aspects-prime-breakthrough-therapy-applications_en.pdf
  26. European Medicines Agency "Advanced therapies: marketing authorisation" https://www.ema.europa.eu/en/human-regulatory-overview/marketing-authorisation/advanced-therapies-marketing-authorisation
  27. PMDA "List of approved products, fiscal 2025 (new regenerative medicine products)" page (includes an explanation of orphan regenerative medicine products) (in Japanese) https://www.pmda.go.jp/review-services/drug-reviews/review-information/ctp/0017.html
  28. European Medicines Agency "Concept paper on the revision of Part IV Guidelines on Good Manufacturing Practice specific to Advanced Therapy Medicinal Products", 11 March 2025 (EMA/INS/GMP/48771/2025, PDF) https://www.ema.europa.eu/en/documents/scientific-guideline/concept-paper-revision-part-iv-guidelines-good-manufacturing-practice-specific-advanced-therapy-medicinal-products_en.pdf

13. Claim-to-source audit

Claim in the textBasisLabel
The eligibility requirements for RMAT (a regenerative medicine therapy, a serious condition, potential to address an unmet need from preliminary clinical evidence); that the request is made with the IND or as an IND amendment and is not granted during clinical hold; that the FDA replies within 60 calendar days; the scope of regenerative medicine therapies, which can include some gene therapies and xenogeneic cell products. Creation by the Cures Act of 13 December 2016FDA RMAT page. Reference 1 https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/regenerative-medicine-advanced-therapy-designationSourced
RMAT requests, grants, denials and withdrawals by fiscal year (2017 to 2025), and that requests awaiting an outcome are included in the number of requestsFDA cumulative table of RMAT requests. Reference 2 https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/cumulative-cber-regenerative-medicine-advanced-therapy-rmat-designation-requests-received-fiscalSourced
The 14 products approved after RMAT designation (approval date, brand name, nonproprietary name, use), as of 30 September 2025FDA RMAT approvals list. Reference 3 https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/cber-regenerative-medicine-advanced-therapy-rmat-approvalsSourced
That the number of designations withdrawn or rescinded after being granted was 0 for every year (data as of 30 June 2025)FDA table of RMAT withdrawals and rescissions. Reference 4 https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/cber-regenerative-medicine-advanced-therapy-rmat-designations-withdrawn-after-granting-or-rescindedSourced
Comparison of the requirements and benefits of Fast Track, Breakthrough Therapy and RMAT; rolling review; priority review (decision in 60 days, 6-month review goal); accelerated approval and how post-approval requirements can be met under 506(g)(7) (patient registries, RWE and others); that it is essential that preliminary clinical evidence was generated with the product to be developed; the footnote on manufacturing changes. The final version of February 2019FDA 2019 guidance. Reference 5 https://www.fda.gov/media/120267/downloadSourced
That the revised draft will replace the 2019 version once finalised and rests on the commitments of PDUFA VII. CMC preparation (understanding CQAs, validation of analytical methods and the commercial process, a risk-based strategy for manufacturing changes, scale-up and scale-out, early characterisation). That a designation does not change the CMC information requirements. The effect on designation if comparability cannot be shown. The limited cases in which RWE can fill gaps in confirmatory evidence and the factors for acceptance. The reference to platform technology designation. September 2025FDA 2025 revised draft. Reference 6 https://www.fda.gov/media/188874/downloadSourced
Challenges in developing CGT products (complexity, patient-specific manufacture, advanced processes, few patients and runs, analytics, short shelf life). Phase-appropriate CGMP, setting release criteria in advance, risk-based comparability, use of prior knowledge, PPQ batch numbers and concurrent release, flexibility in commercial specifications, verification of analytical methods, re-evaluation of specifications after approval, stability (3 lots, 6 months), exceptions on retention samples, alternative analytical methods. May 2026. That the RMAT revised draft is still described as a draftFDA 2026 CMC guidance. Reference 7 https://www.fda.gov/media/192321/downloadSourced
That the revised RMAT draft was published on 25 September 2025 and, if finalised, will replace the final version of February 2019 (FR Doc. 2025-18653, comment deadline 24 November 2025)Federal Register, 25 September 2025. Reference 8 https://www.govinfo.gov/content/pkg/FR-2025-09-25/pdf/2025-18653.pdfSourced
The category of regenerative medicine products (PMD Act Article 2, paragraph 9); the three requirements of conditional and time-limited approval (Article 23-26: not homogeneous, efficacy presumed, not markedly harmful) and the term of no more than 7 years; the 4 products (as of March 2024); the purpose (heterogeneous products, rare diseases, few cases); that it should not be the final aim and the plan should include verification of efficacy; that continuation of approval is not allowed if efficacy is not confirmedMHLW notification (29 March 2024). Reference 9 https://www.mhlw.go.jp/content/10808000/001631279.pdfSourced
Extension of the term (up to 3 years, Article 23-26 paragraph 2), re-application within the term (paragraph 5) and validity until disposition (paragraph 6), application categories, the draft basic plan for evaluating approval conditions, inclusion of all cases, review and publication of results even when the application is withdrawn or approval withdrawn after re-application, procedure for changing approved matters (the earlier term is kept), quality control strategy, verification and continual improvement (chapter 5)MHLW notification (6 October 2025). Reference 10 https://www.mhlw.go.jp/content/10808000/001631280.pdfSourced
The four requirements for designation as a SAKIGAKE-designated regenerative medicine product (Article 77-2, paragraph 2), the method of designation (about twice a year for now), priority consultation, fuller pre-assessment, priority review and the concierge. The partial revision of 12 January 2024 (amending the notification of 31 August 2020)MHLW notification (12 January 2024). Reference 11 https://www.pmda.go.jp/files/000240376.pdfSourced
That the SAKIGAKE review designation system was created on 1 April 2015, and that the target is 12 months for ordinary new drugs and 6 months for designated products (as explained in October 2017)MHLW press release (5 October 2017). Reference 12 https://www.mhlw.go.jp/stf/houdou/0000179802.htmlSourced
That HeartSheet was given conditional and time-limited approval on 18 September 2015PMDA list, fiscal 2015. Reference 13 https://www.pmda.go.jp/files/000228179.pdfSourced
That STEMIRAC injection (28 December 2018) and Collategene intramuscular injection 4 mg (26 March 2019) were given conditional and time-limited approvalPMDA list, fiscal 2018. Reference 14 https://www.pmda.go.jp/files/000231456.pdfSourced
That Delytact injection was given conditional and time-limited approval on 11 June 2021PMDA list, fiscal 2021. Reference 15 https://www.pmda.go.jp/files/000246141.pdfSourced
That Akuugo for intracerebral implantation was given conditional and time-limited approval on 31 July 2024 and is an orphan product with SAKIGAKE designationPMDA list, fiscal 2024. Reference 16 https://www.pmda.go.jp/files/000274840.pdfSourced
That Elevidys intravenous infusion (13 May 2025) and ReHeart and Amchepry (6 March 2026) were given conditional and time-limited approval. That the approval condition on equivalence / comparability of quality was deleted in the partial-change approval of Akuugo on 8 December 2025. The records of orphan and SAKIGAKE designationsPMDA list, fiscal 2025. Reference 17 https://www.pmda.go.jp/files/000280052.pdfSourced
That no new product was given conditional and time-limited approval in fiscal 2026 (entries up to 17 July 2026)PMDA list, fiscal 2026. Reference 18 https://www.pmda.go.jp/files/000282058.pdfSourced
The application dates, term (7 years), orphan and SAKIGAKE records for ReHeart, Amchepry and Akuugo; Amchepry's shelf life of 31 hours; the scale of use assumed after marketing (Amchepry about 35 cases over 7 years; Akuugo about 175 cases over 7 years, about 25 a year)MHLW Chuikyo material (8 April 2026). Reference 19 https://www.mhlw.go.jp/content/10808000/001687611.pdfSourced
HeartSheet's application (7 September 2023), term (17 September 2023) and date of withdrawal of approval (25 July 2024)MHLW notification (25 July 2024). Reference 20 https://www.mhlw.go.jp/content/10808000/001284995.pdfSourced
Collategene's term expiry (25 March 2024), re-application (31 May 2023), withdrawal of the application (27 June 2024), lapse of the approval and recovery of the product in circulation. The approval dates and terms of the 4 products with conditional and time-limited approval (HeartSheet 5 years plus a 3-year extension, STEMIRAC 7 years, Collategene 5 years, Delytact 7 years)MHLW notification (27 June 2024). Reference 21 https://www.mhlw.go.jp/content/10808000/001284993.pdfSourced
The purpose of PRIME, its benefits (early appointment of a CHMP / CAT rapporteur, kick-off meeting, repeated scientific advice, pre-filing meeting, confirmation of accelerated assessment), Early Entry PRIME, timing of applications, and the cumulative figures as of July 2026 (26% granted, 67% denied)EMA PRIME page. Reference 22 https://www.ema.europa.eu/en/human-regulatory-overview/research-development/prime-priority-medicinesSourced
That ATMPs were about 27% of PRIME requests and 46% of grants; that 7 of 16 PRIME products (44%) that started under accelerated assessment were ATMPs against 1 (4%) for non-PRIME; that reasons for reverting from accelerated to standard assessment included quality concerns for ATMPs (specifications, manufacturing problems, process control); that switching was 56% in the PRIME analysis. Data from March 2016 to June 2021EMA PRIME five-year report. Reference 23 https://www.ema.europa.eu/system/files/documents/report/2022-03_prime_5_years_report_updated_2022-04-05-en.pdfSourced
Stability (a shorter period, possibly fewer than 3 lots), handling of process validation protocols (such as introduction of a new cell bank), the GMP level of starting materials (the exception for MCBs made at academic institutions), comparability of ATMPs (outside ICH Q5E, a separate Q&A), April 2022EMA Toolbox guidance. Reference 24 https://www.ema.europa.eu/en/documents/scientific-guideline/toolbox-guidance-scientific-elements-and-regulatory-tools-support-quality-data-packages-prime-and-certain-marketing-authorisation-applications-targeting-unmet-medical-need_en.pdfSourced
The scope of the joint EMA and FDA Q&A (on the FDA side only products under CDER, ATMPs under CBER being outside it) and its topics (control strategy, process validation, stability, GMP). 4 December 2023EMA-FDA joint Q&A. Reference 25 https://www.ema.europa.eu/en/documents/other/ema-fda-joint-qas-quality-gmp-aspects-prime-breakthrough-therapy-applications_en.pdfSourced
That the EMA subjects all ATMPs to the mandatory centralised procedure with scientific evaluation by the EMA, and that classification can be confirmed in advanceEMA page on ATMP marketing authorisation. Reference 26 https://www.ema.europa.eu/en/human-regulatory-overview/marketing-authorisation/advanced-therapies-marketing-authorisationSourced
The requirements for designation as an orphan regenerative medicine product (fewer than 50,000 target patients in Japan and so on) and that such products are reviewed with priorityPMDA page on lists of approved products. Reference 27 https://www.pmda.go.jp/review-services/drug-reviews/review-information/ctp/0017.htmlSourced
The concept paper (dated 11 March 2025) setting out a plan to revise EU GMP Part IV to align with Annex 1EMA concept paper. Reference 28 https://www.ema.europa.eu/en/documents/scientific-guideline/concept-paper-revision-part-iv-guidelines-good-manufacturing-practice-specific-advanced-therapy-medicinal-products_en.pdfSourced
Finalisation of the revised RMAT guidance, RMAT statistics after November 2025, the move to regular approval of the products given conditional and time-limited approval in March 2026, the latest PRIME figures for ATMPs, and the revised EU Part IVNone could be confirmed from primary sources in this article's survey (October 2026). Some are drafts, under revision or future mattersNot yet confirmed
The RMAT grant rate (193 / 358 = about 54%, 38% to 75% by year), 16 awaiting an outcome (388 − 193 − 165 − 14), about 2.7-fold in requests (91 / 34), approvals 14 / grants 193 = about 7%, approvals by year (2021: 3, 2022: 0, 2023: 4, 2024: 6, 2025: 1), and the count of 8 products given conditional and time-limited approvalOur calculation. The grant rate excludes withdrawals and requests awaiting an outcome; approvals by year are counted from the approval dates in the FDA list; the 8 products are the MHLW's 4 (as of March 2024) plus 4 from the PMDA lists for fiscal 2024 to 2026. There is a lag between designation and approval, so this is not a success rateOur calculation
The grouping in Fig. 1 into three columns (advice in development / review / form of approval) and the three-region table. The reading that the way the programs operate moves materials and manufacturing readiness earlier. The reading that sameness of the product used in the clinic and the product to be developed reaches into early choice of materials. The view of what information is asked of materials makers (relation to CQAs). The commentary on how each item of the FDA's May 2026 CMC guidance bears on materials and containers. The view that post-approval change control supports the customer's evaluation of equivalence. The view of small quantities, no change and long supply. The point that withdrawal or lapse of approval can affect supply contracts. The ordering into stages in Fig. 4This article's own arrangement and commentary based on published material; not views expressed by the FDA, EMA, MHLW or PMDACommentary
Efficacy and indications of individual products, clinical results, evaluation of efficacy or safety, and comparison between productsThis article explains where approval programs meet materials and manufacturing and does not evaluate or compare. Product names are cited only from information published by regulators as examples of how the programs operateCommentary
That Figs. 1 to 4 are drawings made for explanation, not actual procedural documents or review records, and that the hero image and Fig. 5 are AI-generatedA note from this articleCommentary

Last updated 1 October 2026. Sources are limited to primary material (published material and guidance from the FDA and EMA, MHLW notifications and meeting materials, PMDA lists of approved products, and the Federal Register). Because the article includes arrangements of the programs and readings from the materials and manufacturing side, those are marked as Commentary and kept separate from sourced fact. The September 2025 revised draft of the RMAT guidance is not final, and the FDA's RMAT statistics are data as of 30 September 2025. The EMA's PRIME figures for ATMPs cover 2016 to 2021. Review time and designation requirements are defined differently in each country, so nothing here ranks countries. Market-size and share estimates are not used. This article explains approval programs and does not evaluate the efficacy or safety of individual products, nor is it medical advice. Figs. 1 to 4 are vector drawings, the hero image and Fig. 5 are AI-generated, and none of them shows an actual application document, review record or physical product.

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