1. Regulatory submissions and real-world data in brief

• What an approval application is: the procedure in which the evidence gathered in clinical trials and elsewhere is compiled and a regulator is asked to decide whether the drug may be sold. In the United States it is called an NDA (New Drug Application) or BLA (Biologics License Application), in the EU a MAA (Marketing Authorisation Application) and in Japan an application for manufacturing and marketing approval
• What expedited programs are: to get drugs for serious diseases to patients sooner, Japan, the US and Europe have systems that run in three directions: giving richer advice during development, shortening the review period, and approving on early data and confirming afterwards (this grouping is our own organization)
• What real-world data is: the FDA defines it as data on patients' health status or the delivery of health care that are routinely collected from a variety of sources, and gives electronic health records, claims data and product and disease registries as examplesSourced

2. How a new drug gets approved — from trial notification to approval

The FDA explains that shipping an investigational drug across state lines requires a legal exemption, and that the IND is the means through which the sponsor technically obtains this exemption from the FDASourced. An IND must contain information in the following three areasSourced.

All Sourced (FDA, "Investigational New Drug (IND) Application" [Ref. 1]). The FDA says a clinical trial may not begin until 30 calendar days after the IND is submitted, and that during this time the FDA has the opportunity to review it from the standpoint of safetySourced.

Japan has a mechanism built on the same idea. According to the PMDA, a person who files a clinical trial plan notification for the first time for a drug with a new active ingredient may not ask a medical institution to conduct a trial, or start one, until 30 days have passed from the date of notificationSourced. The PMDA also publishes a sample of how to write up the evaluation and control status of DNA-reactive (mutagenic) impurities to attach to the notificationSourced. Impurity control is thus asked about from the very entrance of clinical trials (our commentary).

3. The shape of the dossier — the five modules of the CTD

Approval dossiers have been put into a common form across Japan, the US and Europe. ICH says that the agreement to assemble all quality, safety and efficacy information in a common format, the Common Technical Document (CTD), transformed regulators' review processesSourced.

All Sourced (ICH, "M4: The Common Technical Document" [Ref. 3]). According to ICH, the CTD was agreed in November 2000 and became the mandatory format for new drug applications in the EU and Japan in 2003 and at the US FDA in 2017. Modules 2 to 5 are intended to be common to all regionsSourced.

4. A materials engineer's view (1): whose dossier does materials information go into?

5. Expedited programs in Japan, the US and Europe

Japan, the US and Europe each have systems for getting drugs for serious diseases to patients sooner. The names differ, but sorting them by what is being speeded up makes the picture clearer (this organization is our own).

All Sourced (FDA [Refs. 4, 5], EMA [Refs. 7, 8, 9], MHLW [Refs. 10, 11, 12]). The assignment to three rows is our own organization; each system can combine several characters (for example, Japan's Sakigake designation includes both consultation and review).

(1) United States — four expedited programs

The FDA's May 2014 guidance compares four programs: Fast Track, Breakthrough Therapy, Accelerated Approval and Priority ReviewSourced. Breakthrough Therapy designation was added to section 506(a) of the FD&C Act by section 902 of the 2012 FDA Safety and Innovation Act (FDASIA)Sourced. Priority Review sets the goal of taking action within 6 months of receipt (10 months under standard review)Sourced. A footnote in the guidance explains that under the PDUFA V "Program" (which covers new molecular entity NDAs and original BLAs received from 1 October 2012 to 30 September 2017), the review clock starts at the end of the 60-calendar-day filing review period that begins on the date of receiptSourced. How Accelerated Approval works, and surrogate endpoints, are covered in our explainer on biomarkers and clinical endpoints.

(2) EU — PRIME, accelerated assessment and conditional marketing authorisation

The EMA says that evaluating a marketing authorisation application under the centralised procedure can take up to 210 days, not counting the clock stops while the applicant provides additional information, and that the CHMP can shorten this to 150 days if sufficient justification is givenSourced. A conditional marketing authorisation is granted on less comprehensive clinical data than normally required where the benefit of immediate availability outweighs the risk inherent in the fact that additional data are still required; it is valid for one year and renewable annually, and can be converted to a standard marketing authorisation once specific obligations are fulfilledSourced. For medicines intended for public health emergencies such as a pandemic, the EMA says less comprehensive pharmaceutical and non-clinical data may also be acceptedSourced.

(3) Japan — Sakigake designation and conditional approval

Under the first designation requirement for Sakigake (pioneering medicinal products), the innovativeness of the therapy, the MHLW lists, alongside a new mechanism of action and others, the use of an innovative drug delivery systemSourced. A drug delivery system (DDS) can itself, under the system, be grounds for innovativeness (our commentary). The fourth requirement is the intent and ability to file in Japan ahead of the rest of the world (or simultaneously), and an application within 3 months of the filing date in the first country is regarded as simultaneousSourced.

The conditional approval notification (31 August 2020, revised 23 October 2024) targets drugs and similar products for serious diseases that are clearly medically superior to existing methods and for which confirmatory clinical trials are difficult to run, or would take a considerable time because patient numbers are small or for other reasonsSourced. It says that confirmation after approval need not be limited to clinical trials, and that studies using medical information databases such as MID-NET, or patient registries, can also be usedSourced. This connects to the real-world data of Chapter 8.

6. Our calculation: how much does the review period shrink?

How much are these programs actually used? According to the FDA (CDER) annual report, of the 46 novel drugs (new active ingredients and new biologics) approved in 2025Sourced, expedited programs were used as followsSourced.

The same report also records that of the 46 drugs, 32 (70%) were approved in the US before any other country, 39 (85%) were approved in the first review cycle and 44 (96%) met their PDUFA goal datesSourced. It also says the FDA took its first actions under the new "Commissioner's National Priority Voucher (CNPV)" program, which aims to cut review time from 10-12 months to 1-2 monthsSourced. How widely this new program will be used from here is Not yet confirmed.

7. A materials engineer's view (2): the faster the review, the earlier manufacturing must run

8. Real-world data (RWD) and real-world evidence (RWE)

(1) Definitions and legal standing

The FDA defines RWE as clinical evidence about the usage and potential benefits or risks of a medical product, derived from analysis of RWDSourced. So RWD is the raw material (data), and RWE is the conclusion drawn from it (evidence) (our commentary).

In response, the FDA created its RWE Program framework in 2018, and says it will evaluate use for new indications of approved drugs and for postapproval study requirementsSourced. The FDA also writes that it has long used RWD and RWE in postapproval safety monitoring and assessment, but that use in support of effectiveness has been more limitedSourced.

(2) An example actually used for approval

On 16 July 2021 the FDA approved a new use of Prograf (tacrolimus), an immunosuppressant that prevents rejection after transplantation: for lung transplant. The FDA describes this as an approval based on a non-interventional (observational) study that provided real-world evidence of effectivenessSourced.

• Data source: RWD from the Scientific Registry of Transplant Recipients (SRTR), supported by the US Department of Health and Human Services: data collected on all lung transplants in the United States, supplemented with Social Security Administration death recordsSourced
• Why it was accepted: the FDA says this shows that a well-designed non-interventional study based on fit-for-purpose RWD and compared with an appropriate control can be considered an "adequate and well-controlled" study under FDA regulations. The comparator was the well-documented natural history without (or with minimal) immunosuppressive therapySourced
• Other evidence: randomized controlled trials in other solid-organ transplants were added as confirmatory evidenceSourced

What matters is that RWD did not decide the approval alone: the conditions "the outcome is objective and the natural history that serves as the control is well known" and evidence from other studies came together (our commentary). This article does not evaluate the effect or safety of this drug.

(3) RWD infrastructure in the EU and Japan

All Sourced (EMA [Ref. 16], PMDA [Ref. 17], MHLW [Ref. 12]).

9. Drug lag and drug loss

The MHLW describes drug loss as a state in which a drug approved in Europe or the US has not had development started in JapanSourced. A state in which development is under way in Japan but approval is late is generally called drug lag (our commentary).

As one countermeasure, an MHLW notification of 25 December 2023 said that for drugs whose clinical development began overseas, a Phase I study in Japanese people before Japan joins a multiregional clinical trial need not, in principle, be run additionally, except where it is considered necessarySourced. As background, the notification cites the growing number of cases, centered on innovative drugs whose early development is done by emerging overseas biopharmaceutical companies, in which Japan's participation is considered only after early clinical development has progressed overseasSourced. It adds, however, that for drugs with a narrow safety margin and similar cases, whether a Japanese Phase I study is needed will be judged more carefullySourced.

10. Open issues, and what has not been settled

(1) How far RWE can show "effectiveness"

The FDA says use of RWE for effectiveness has traditionally been more limitedSourced, and the 2021 example also had the conditions of an objective outcome, a clear natural history and evidence from other studiesSourced. As of our research (September 2026), a general rule for the conditions under which RWE can demonstrate effectiveness cannot be said to be establishedNot yet confirmed.

(2) Where the new expedited mechanisms are heading

The US CNPV (which aims to cut review to 1-2 months) is at the stage where its first actions have been takenSourced. The FDA guidance that would put the new Accelerated Approval rules (the 2023 legal amendment) into practice was also still a draft as of December 2024Sourced. How either will be put into operation is Not yet confirmed.

(3) The effect of drug-loss countermeasures

How far measures such as the rethinking of Japanese Phase I studies, and requests and open calls for development of not-started drugs, will reduce the number of not-started drugs is something for which no confirmable results exist as of our researchNot yet confirmed.

11. Glossary

12. References

1. FDA "Investigational New Drug (IND) Application" (page updated 16 September 2026) — fda.gov
2. Pharmaceuticals and Medical Devices Agency (PMDA) "Clinical trial plan notification system for drugs" (in Japanese) — pmda.go.jp
3. ICH "CTD — M4: The Common Technical Document" — ich.org
4. FDA "Guidance for Industry: Expedited Programs for Serious Conditions – Drugs and Biologics." May 2014 (PDF) — fda.gov
5. FDA "Breakthrough Therapy" — fda.gov
6. FDA "Expedited Program for Serious Conditions — Accelerated Approval of Drugs and Biologics — Guidance for Industry (Draft)." December 2024 (PDF) — fda.gov
7. European Medicines Agency "PRIME: priority medicines" — ema.europa.eu
8. European Medicines Agency "Accelerated assessment" — ema.europa.eu
9. European Medicines Agency "Conditional marketing authorisation" — ema.europa.eu
10. Ministry of Health, Labour and Welfare (MHLW) "On the Sakigake designation system for pioneering medicinal products" (in Japanese) — mhlw.go.jp
11. MHLW, Pharmaceutical Evaluation Division "On the Sakigake designation system for pioneering medicinal products (Sakigake review designation system)," Document 2, 9th Evaluation and Monitoring Committee on Pharmaceutical Administration, 14 September 2022 (PDF, in Japanese) — mhlw.go.jp
12. MHLW, Director of the Pharmaceutical Evaluation Division "Partial revision of 'Handling of conditional approval of medicinal products,'" Notification Iyaku-shinsa-hatsu 1023 No. 2, 23 October 2024 (including the revised notification; in Japanese) — mhlw.go.jp
13. U.S. Congress "21st Century Cures Act," Public Law 114-255, 13 December 2016 (Sec. 3022 Real World Evidence) — govinfo.gov
14. FDA "Real-World Evidence" (page updated 3 June 2026) — fda.gov
15. FDA "FDA approves new use of transplant drug based on real-world evidence." 16 July 2021 — fda.gov
16. European Medicines Agency "Data Analysis and Real World Interrogation Network (DARWIN EU)" — ema.europa.eu
17. Pharmaceuticals and Medical Devices Agency (PMDA) "MID-NET (Medical Information Database Network)" (in Japanese) — pmda.go.jp
18. MHLW "Efforts toward resolving drug loss (from FY2024): status of deliberations," Document 2-3, 65th Meeting of the Study Group on Unapproved and Off-Label Drugs of High Medical Need, 29 September 2025 (PDF, in Japanese) — mhlw.go.jp
19. MHLW, Director of the Pharmaceutical Evaluation Division "Basic approach to conducting Phase I studies in Japanese people before the start of multiregional clinical trials for drugs whose clinical development began overseas," Notification Iyaku-shinsa-hatsu 1225 No. 2, 25 December 2023 (in Japanese) — mhlw.go.jp
20. FDA "Drug Master Files (DMFs)" — fda.gov
21. eCFR (US Code of Federal Regulations) "21 CFR 314.420 Drug master files" — ecfr.gov
22. Pharmaceuticals and Medical Devices Agency (PMDA) "Master Files (MF) for drug substances and similar" (in Japanese) — pmda.go.jp
23. FDA (CDER) "Advancing Health Through Innovation: New Drug Therapy Approvals 2025" (PDF) — fda.gov

13. Claim-to-source audit

Last updated: 26 September 2026 / Sources are limited to primary sources (publications and notifications of the FDA, EMA, MHLW and PMDA, public information from ICH, and US law and federal regulations). Because the article includes readings of the systems and of materials and manufacturing issues, these are separated as "Commentary" from sourced facts. Because review periods differ by country in their start point and treatment of interruptions, the month conversions in Chapter 6 are for seeing the gap between standard and expedited review within one country, not for comparing countries. The operation of the CNPV and the new Accelerated Approval rules, the conditions under which RWE can show effectiveness, and the effect of drug-loss countermeasures are marked "Not yet confirmed" because there is no confirmed primary source. This article explains approval systems; it does not evaluate the effect or safety of any individual drug, and it is not medical advice. All figures are explanatory concept diagrams. Figures combine ImageGen-generated explanatory images with vector drawings. Generated images are not photographs, microscope images or measured data of real objects. The original diagrams with numbers and sources are either shown as they are or kept in a form that expands below the new image.