Pharmaceutical Industry at a Glance Comparison of New Drug Approval Status and Review Periods in Japan, the U.S., and Europe Challenges in Japan, Based on the COVID-19 Vaccine Case

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The Office of Pharmaceutical Industry Research Senior Researcher Masao Yoshida

The Office of Pharmaceutical Industry Research^We continuously collect ^{and analyze} information regarding drug approvals and review periods in Japan, the United States, and Europe based on data published on the websites of the Pharmaceuticals and Medical Devices Agency (PMDA), the U.S. Food and Drug Administration (FDA), and the European Medicines Agency (EMA), ^{respectively¹)}. OPIR Views and Actions^{In Issue No. 61²)}, we compared the status of new drug approvals and review periods in Japan, the U.S., and Europe, focusing primarily on approval results from 2019; in ^{Issue No. 62³)} ( OPIR Views and Actions⁾, we presented the results of an analysis of information on pharmaceuticals approved in Japan in 2020; and in ^{Issue No. 63⁴)}, we reported on the current state of the “drug lag” based on this ongoing survey.In this news article, we investigated the number of new drug approvals and review periods in Japan, the U.S., and Europe in 2020.In addition, we investigated the systems and review period information used in Japan, the U.S., and Europe regarding the authorization of vaccines against COVID-19, which has been raging since 2020, and raised issues concerning Japan’s emergency drug approval system.

Survey Methodology

Based on information published on the respective websites of the PMDA, FDA, and EMA, we used the standard statistical analysis software Stata/IC 14.0 for Windows (Stata Corp LP, College Station, TX, USA) to calculate the review period as the time from the application date to the approval date.Since there are products with significantly long review periods and others with shorter periods due to special exceptions, the median was used as the primary basic statistic, and the sample size, mean, and standard deviation were also listed.

In Japan, as in OPIR Views and ActionsNo. 62, the scope of this study was limited to drugs listed in the “List of Approved New ^Drugs”⁵ on the PMDA website; the number of products was counted based on each review report, and cases where multiple companies simultaneously applied for products containing the same active ingredient, or where multiple ingredients were approved as part of a combination therapy, were counted as a single product.The tally for New Molecular Entities (NMEs) covered applications classified as pharmaceuticals containing new active ingredients.

In the United States, the analysis covered pharmaceuticals corresponding to New Drug Applications (NDAs) and Biologic License Applications (BLAs) listed in the “CDER Drug and Biologic Approvals for Calendar ^Year”⁶) published by the FDA Center for Drug Evaluation and Research (CDER).The tally of NMEs covered pharmaceuticals listed in “New Molecular Entity (NME) Drug & Original BLA Calendar Year Approvals.”

In Europe, the analysis covered pharmaceuticals approved by the EMA through the centralized review procedure and listed in the “European Medicines Agency Annual Reports” ^⁷). The NME tally covered pharmaceuticals classified as “New active substance.”

In addition, as special regulatory measures, Japan has priority review, expedited review, orphan drugs, and the Pioneering Review Designation system;Conditional Early Approval; in the U.S., Priority Review, Accelerated Approval, Orphan, Fast Track, and Breakthrough Therapy; and in Europe, Accelerated Assessment, Orphan, Conditional Approval, Exceptional Circumstances, and Priority Medicine (PRIME).The details of each regulatory special measure are summarized in the appendix at the end of this volume.

Comparison of the Number of Approved New Drugs in Japan, the U.S., and Europe

Figure 1 shows the number of new drugs approved in Japan, the United States, and Europe over the past six years (2015–2020).In Japan, 125 new drugs were approved in 2020, including 38 NMEs. Although this represented a decrease of 5 and 1, respectively, compared to 2019, it was the second-highest number of approvals over the past six years.In contrast, in the United States, the number of approved products was 121 and the number of NMEs was 53, both of which increased compared to 2019. For NMEs, this was the second-highest number of approvals since 2000—the period for which our firm has maintained records—second only to 2018.In Europe, the number of approved products in 2020 was 153, with 42 NMEs, representing a significant increase compared to 2019; the number of approved products was the highest in the past six years.

Number of Approved Products (NMEs) Subject to Special Regulatory Measures

We investigated the number and percentage of NMEs approved in Japan, the U.S., and Europe over the past six years (2015–2020) that received special regulatory measures in each region (Figure 2).

Of the 38 NMEs approved in Japan in 2020, 11 (28.9%) received Priority Review (including orphan drugs), 0 received Expedited Review (excluding Priority Review), 8 (21.1%) were designated as orphan drugs,4 products (10.5%) were designated under the Pioneer Review Designation System, and 3 products (7.9%) were eligible for the Conditional Early Approval System.The proportion of NMEs receiving priority review or designated as orphan drugs has been on a downward trend since 2016. On the other hand, the number and proportion of NMEs approved in 2020 under the Pioneer Review Designation System and the Conditional Early Approval System reached record highs.

In the United States, of the 53 NME products approved in 2020, 12 (22.6%) received Accelerated Approval—the highest number since 2011—and the percentage was the second-highest since 2016.In addition, 31 products (58.5%) received Priority Review, 31 products (58.5%) received Orphan Drug designation, 17 products (32.1%) received Fast Track designation, and 22 products (41.5%) received Breakthrough Therapy designation.The number of NMEs approved as Breakthrough Therapy-designated products and their proportion reached record highs.

In Europe, of the 42 NMEs approved in 2020, 6 (14.3%) received Accelerated Assessment—an increase from 2019—while 18 (42.9%) were designated as Orphan drugs,12 products (28.6%) received conditional approval, 3 products (7.1%) were designated under Exceptional Circumstances, and 9 products (21.4%) were designated under PRIME—each representing the highest number in the past six years.

Comparison of Review Periods for New Drugs in Japan, the U.S., and Europe

Table 1 shows the review periods (in months) for new drugs approved in Japan, the U.S., and Europe in 2020.The median review periods for products approved in 2020 were 10.7 months in Japan, 10.0 months in the U.S., and 12.2 months in Europe; compared to 2019, the gap in review periods between Japan and the U.S. widened.For NMEs, the median review periods for products approved in 2020 were 10.6 months in Japan, 8.0 months in the U.S., and 13.8 months in Europe. Compared to 2019, only Japan saw an increase in the median review period.

Review Periods for Products Subject to Special Regulatory Measures

Table 2 lists the products approved in 2020 that received special regulatory measures aimed at shortening the review period (Japan: Priority Review, Pioneering Review Designation System; U.S.: Priority Review, Breakthrough Therapy; Europe: Accelerated Assessment, PRIME).In particular, the Pioneering Review Designation System, Breakthrough Therapy,PRIME frameworks aim to achieve even faster commercialization by providing preferential treatment—such as advisory services during the development phase, rolling reviews, or priority review—for drugs expected to be highly effective against serious diseases, ^thereby seeking to address unmet medical needs at an early ^stage⁸).

In Japan in 2020, the number of products approved under priority review—both for all approved products (33 products) and NMEs (11 products)—decreased slightly compared to 2019; however, the median review periods were 7.7 months and 6.5 months, respectively, representing a significant reduction compared to 2019.In addition, five products (including four NMEs) were approved under the Pioneering Review Designation system, and it was confirmed that their review periods were shorter than the PMDA’s target of six months.On the other hand, the number of products approved under the standard review process increased compared to 2019, and the median review period was longer than in 2019.This indicates that the reason the median review period in Japan, as shown in Table 1, was longer compared to 2019 was due to a decrease in the number of products under priority review and an increase in the number of products under standard review.

Regarding the number of products designated for Priority Review in the United States in 2020, the total number of approved products (41) decreased compared to 2019, while the number of NMEs (31) increased. The median review periods were 6.9 months and 7.6 months, respectively, which were similar to those in 2019.Furthermore, regarding the variability (standard deviation) in review periods, Priority Review-designated products showed low and stable variability, similar to the PMDA’s Priority Review program. For Breakthrough Therapy-designated products, 23 were approved, and among them, the median review period for NMEs (22 products) was shorter than that for Priority Review.Although the median review period was more than one month longer than that for products designated for “Pioneer Review” in Japan, it is worth noting that the number of designated products was approximately five times higher.

In Europe, although the proportion of products receiving priority review was lower than in Japan and the United States, the median review period for products designated for Accelerated Assessment in 2020 was 8.0 months—more than 4 months shorter than for products not designated for this track.Furthermore, the number of products designated under the PRIME program increased significantly from 2019, with nine products approved.On the other hand, while the median review period was more than two months longer than in 2019, approval was granted in a shorter timeframe compared to products not subject to special measures, confirming that this regulatory system plays a role in the early resolution of unmet medical needs.

Annual Trends in Median Review Times (Japan, U.S., and Europe)

Table 3 shows the review periods (in months) by year of approval (2000–2020) for pharmaceuticals approved in Japan, the U.S., and Europe, while Figure 3 shows the annual trends in median review periods.Furthermore, for NMEs, the analysis covered the period from 2013 to 2020, following a significant reduction in review periods in Japan; Table 4 shows the review periods (in months) by year of approval, and Figure 4 shows the annual trends in median review periods.

The median examination period over the entire study period was 11.1 months in Japan, 10.2 months in the United States, and 13.4 months in Europe (Table 3).Looking at the annual trends (Figure 3), from 2000 to 2010, examination periods tended to be longest in the United States, followed by Europe and then Japan. However, in 2011, Japan saw a significant reduction in examination periods, and since then, the median examination periods in Japan and the United States have been similar (approximately 10 months),followed by Europe, where review periods were the longest. Europe also saw a reduction in review periods starting in 2015 (to approximately 12 months), and review periods remained at a similar level until 2020.

Meanwhile, for NMEs, the median review periods over the entire study period were 10.3 months in Japan, 9.6 months in the U.S., and 14.1 months in Europe (Table 4).During the 2014–2016 period, the review period for NMEs in Japan (approximately 10 months) was consistently shorter than that in the U.S.; however, in 2017, the U.S. review period for NMEs was shortened by 3 months, and since then, the order has been the U.S., Japan, and Europe (Figure 4).

Comparison of Review Periods for COVID-19 Vaccines in Japan, the U.S., and Europe

To conclude this study, we will discuss the status of approvals and emergency use authorizations, review periods, and issues with Japan’s response regarding COVID-19 vaccines—which are indicated for the “prevention of infectious diseases caused by the novel coronavirus (SARS-CoV-2),” an infection that continues to spread worldwide—as well as Japan’s approach to vaccine reviews in the U.S. and Europe.

As of September 2021, a total of four types of COVID-19 vaccines (Table 5, ① through ④) were authorized for use in Japan, the U.S., and Europe; in Europe, all four were approved under “conditional approval,” a special measure subject to conditions.In Japan, three vaccines (①, ②, and ③) are in use under ^{special approval³)} pursuant to Article 14-3 of the Act on Pharmaceutical and Medical Devices, ^{and it was announced} on May 24, 2021, that an application for domestic manufacturing and marketing approval had been submitted for vaccine ^④⁹).In contrast, in the United States, only vaccine ① had received statutory approval, while vaccines ② and ③ were still at the stage of being temporarily authorized for use under Emergency Use Authorization ⁽ EUA ^)¹⁰.

Next, we compare the timing of approval and review periods across the three regions. Regarding Vaccine ①—which became available earliest in all three regions (Japan, the U.S., and Europe)—applications were submitted in the U.S. and Europe from mid- to late November 2020, and authorization for use was granted in December 2020, just 21 days later.In contrast, in Japan, the application was submitted in mid-December 2020, and special approval was granted in February 2021—58 days later—which was approximately two months behind the approvals in the U.S. and Europe.Furthermore, for Vaccine ②, there was a lag of more than four months compared to the U.S. and Europe, and for Vaccine ③, approval came about four months later than in Europe. It was found that, in addition to the timing of approval, the review process for each vaccine was also slower in Japan.

One issue is that Japan’s special approval requires meeting the following criteria: (1) emergency use is necessary to prevent the spread of disease, (2) there is no appropriate alternative to the use of the drug in question,③ the product is authorized for sale in a country with an approval system equivalent to Japan’s³ ^,¹¹). It ^is clear that ^, particularly as long ^{as condition ③ applies,} the timing of approval applications in Japan cannot precede those in other countries, and approval reviews will not begin earlier in Japan.In other words, special approval is a rule designed to rapidly procure overseas products when it is difficult to develop treatments domestically for diseases that threaten the lives and health of the public; even drugs with a track record of domestic use through clinical trials, for example, are excluded if they lack a track record of overseas sales.In other words, it has become clear that there is no pharmaceutical regulatory system in Japan that allows regulatory authorities to independently assess the risk-benefit ratio during emergencies, make regulatory decisions under emergency conditions, and authorize emergency use ahead of the rest of the ^world¹¹).

Furthermore, regarding domestic approval of vaccines, the government’s requirement for domestic clinical trial results is considered one of the reasons for the delay compared to other countries. According to the “Guidance on the Evaluation of COVID-19 (SARS-CoV-2) ^{Vaccines”12)} published by the PMDA in September Reiwa 2,it is explicitly stated that “even when large-scale confirmatory clinical trials are conducted overseas to evaluate the vaccine’s efficacy in preventing disease onset, we consider it highly necessary to conduct clinical trials domestically to evaluate the vaccine’s efficacy and safety in Japanese subjects.” As shown in Table 5, for vaccines ①, ②, and③, ^{the respective} deliberation ^{reports indicate} that domestic Phase I/II trials had been underway since October 2020 for vaccine ①, January 2021 for vaccine ②, and August 2020 for vaccine ^③¹³).In other words, the approach taken for the approval of these vaccines in Japan involved evaluating their efficacy based on the results of confirmatory trials conducted overseas and, in addition, confirming their immunogenicity and safety in Japanese individuals based on the results of domestic clinical trials.While the requirement for clinical trials in Japan is standard practice under the PMDA’s drug approval review process, whether it is necessary as part of the regulatory approval process during an emergency such as a pandemic will likely require further discussion.

Another point is that the review period for COVID-19 vaccines in Japan took more than twice as long as in the U.S. and Europe; given the emergency nature of the situation, this was a significant difference.While it is difficult to pinpoint the exact cause of this, regarding Vaccine ③, for example, according to ^the Deliberation Results ^Report¹³), many pages were devoted to safety concerns related to thrombosis, thromboembolism, and neurological events reported after the vaccine’s launch overseas;On April 7, 2021—approximately 1.5 months before the approval date—the EMA ^{announced that} thrombosis accompanied by thrombocytopenia could occur in extremely rare cases following administration of this vaccine and should be classified as an adverse ^{reaction¹⁴)}; one can surmise that time was required to verify and address these safety-related events.Furthermore, it may have taken time to confirm the efficacy and safety in Japanese patients based on the aforementioned domestic Phase I/II trials and to bridge the data with overseas clinical trials. Regarding Beclury(generic name: remdesivir), which received special approval on May 7, 2020, for the treatment of SARS-CoV-2 infections ^{, the Deliberation} Results ^Report¹³ confirms ^that Japan participated in the international Phase III clinical trial ^— which served as the primary clinical trial data during the approval review ^— and this is believed to have contributed to expediting the approval process.However, given the state of the COVID-19 outbreak in Japan at the time of vaccine development, it may have been difficult to conduct international collaborative clinical trials that included Japan.Furthermore, as will be discussed in detail later, Europe implemented measures such as conducting a “rolling review” of all COVID-19 vaccines even before approval applications were submitted. No precise information is available regarding whether the review had begun prior to the submission of the approval application in Japan, and this factor may also have contributed to the difference in approval review periods.

On the other hand, the U.S. Emergency Use Authorization (EUA) functioned as an emergency measure, enabling COVID-19 vaccinations to begin at an early stage. However, issues have also arisen regarding the EUA; although this does not pertain to vaccines,the EUA for the antimalarial drugs hydroxychloroquine and chloroquine phosphate—which had initially been authorized for the treatment of COVID-19—was revoked a few months later based on the determination that they were unlikely to be effective against COVID-19 and could carry the risk of serious side effects, ^{a situation that further} fueled public ^{confusion¹⁵)}.This case likely arose because sufficient time could not be secured to conduct a proper review of the pharmaceuticals.

While the approach in Europe was based on conditional approval, it has come to light that measures such as those described below—which are not typically implemented during standard review processes—were taken. According to the European Public Assessment Reports (EPARs) for COVID-19 vaccines,for example, regarding ^{the vaccine listed as (1) in Table 5 (16)}, the report stated that the Committee for Medicinal Products for Human Use (CHMP) had begun a “rolling review” as early as October 6, 2020—more than 50 days prior to the application date.The same was true for ^{the vaccines} listed as (2), (3), ^{and (4) in} Table ^5¹⁷); it was confirmed that the CHMP had begun reviewing each of these vaccines prior to their respective application dates.To determine whether there were any other cases besides these vaccine examples where reviews had begun prior to the application date, we investigated all products approved by the EMA under conditional approval between 2015 and 2020. The results revealed that the approach taken for these vaccines—where reviews began before the application date—was an exceptional measure.It is believed that, in response to the COVID-19 pandemic—a public health challenge—special measures were implemented through cooperation between the regulatory authority and pharmaceutical companies to begin reviews prior to the submission of applications for conditional approval. This was done to secure the necessary time for conducting reviews and to expedite access to vaccines as much as possible.

Discussion and Summary

In this paper, we compiled and compared data on the number of new drug approvals and review periods for products approved in Japan, the United States, and Europe in 2020, based on information published by the respective regulatory authorities.In addition, we examined the systems and review period data used in Japan, the U.S., and Europe for COVID-19 vaccines—which have been in high demand since 2020—and raised issues regarding Japan’s emergency drug approval system.

In 2020, the number of approved products in Japan was the second highest in the past six years; in the U.S., it increased from 2019 and, in terms of the number of NMEs, was the second highest since 2000; and in Europe, it was the highest in the past six years.It was confirmed that, despite various restrictions caused by the COVID-19 pandemic, active review of new drug approvals took place in Japan, the U.S., and Europe in 2020; this appears to demonstrate that a cooperative framework between regulatory authorities and the pharmaceutical industry was successfully established to address challenges related to patient health and public health.However, some analyses suggest that clinical development has been affected by the COVID-19 pandemic, which has increased the burden on healthcare workers and raised the risk of infection for trial participants; ^{therefore, it will be necessary to closely monitor} the status of new drug approvals ^{from 2021 onward18)}.

A survey of the number of approved NMEs and products subject to special regulatory measures revealed two notable characteristics. The first is that the proportion of NMEs undergoing priority review or designated as orphan drugs in Japan has been on a steady downward trend since 2016.In contrast, no such trend was observed for products designated for “Priority Review” or “Orphan Drug” status in the U.S., or for those designated for “Accelerated Assessment” or “Orphan Drug” status in Europe; in fact, the proportion of approved NMEs with Orphan Drug designation in the U.S. and Europe reached its highest level in the past six years.It is necessary to closely monitor the situation regarding this matter from 2021 onward, and at the same time, to investigate the causes of these differences. However, since various factors are likely involved—such as differences between Japan’s definition of “rare diseases” and the international definition of “orphan drugs”—we intend to address this as a topic for future consideration.

On the other hand, the second characteristic is that for pharmaceuticals expected to be highly effective against serious diseases, the proportion of NMEs approved under special regulatory measures—such as the Pioneering Review Designation system, Breakthrough Therapy, and PRIME, which aim to shorten review periods to expedite patient access—as well as conditional early approval systems,Accelerated Approval, and Conditional Approval—all aimed at shortening review periods to expedite patient access to drugs expected to be highly effective against serious diseases—had consistently increased. As summarized in the appendix to this paper, eligibility for these special regulatory measures requires, among other things, high efficacy against serious diseases; thus, these drugs represent a group that meets those conditions.Furthermore, the increase in conditional approvals among these cases suggests a growing effort to tackle intractable diseases where conducting confirmatory clinical trials is difficult. In other words, it appears that companies worldwide continue to actively invest in the development of pharmaceuticals addressing high unmet medical needs and are steadily achieving results.

Regarding review periods for new drugs, while Japan’s median review period in 2020 was 0.7 months longer than that of the United States, it tended to be shorter than Europe’s; this trend, which has continued since 2011, persisted in 2020.When limited to New Molecular Entities (NMEs), the United States had the shortest median review period, followed by Japan and then Europe; this trend has continued since 2017.To understand this difference in more detail, when comparing the proportion of products designated for priority review among Japan’s NMEs and their review periods with those of the U.S. and Europe, it was found that while the proportion of priority review products in Japan is on a downward trend,in the U.S., the proportion of products designated for “Priority Review” or “Breakthrough Therapy” among NMEs was overwhelmingly higher than the proportion of products designated for “Priority Review” or “Pioneer Review” in Japan.On the other hand, for European NMEs, while the review period for products designated for Accelerated Assessment is comparable to that of Japan’s priority review, the proportion of such designated products is significantly lower. Furthermore, for NME review candidates other than those under Accelerated Assessment, even PRIME-designated products have a review period (median) comparable to that of Japan’s standard review,while the review periods for other products were significantly longer. Based on the above, it is clear that there is a difference in the median review periods for NME products across each region.

A comparison of the approval status and review periods for COVID-19 vaccines reveals that each region responded to the crisis of the rapid spread of COVID-19 through its respective regulatory systems: Japan used special approval, the U.S. used Emergency Use Authorization (EUA), and Europe used conditional approval.Under these circumstances, it was found that not only was the timing of vaccine approval in Japan later than in the U.S. and Europe, but the review period itself also took more than twice as long as in those regions. Furthermore, issues with Japan’s special approval system were exposed.In light of this pandemic, it will be necessary to discuss and formulate measures for establishing a review and approval framework to enable emergency responses during crises. In doing so, I hope that an investigation will be conducted into the causes of the differences observed when comparing the timing of approval and review periods for COVID-19 vaccines between Japan and the U.S. and Europe (i.e., the lag in approval timing and the lag in review periods).In ^{its “} Pharmaceutical Industry Vision 2021 ^”¹⁹, formulated in September 2021, the Ministry of Health, Labor and Welfare explicitly stated its intention to “accelerate the pharmaceutical approval process and establish standards for emergencies,” and we look forward to improvements in the near future.

Currently, Japan (PMDA),the United States (FDA), and Europe (EMA) have all established special measures aimed at shortening review periods with the primary goal of accelerating patient access to innovative medicines. We believe a virtuous cycle is effectively in place, in which companies strategically utilize these systems and continue to invest, thereby achieving this objective and contributing to addressing patient health and public health challenges.However, the experience of the COVID-19 pandemic has also exposed weaknesses in Japan’s emergency response systems. As pharmaceutical research and development becomes increasingly diverse and sophisticated, and in preparation for potential future pandemics, we hope that systems appropriate for the times will be further refined.

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