The Pharmaceutical Industry at a Glance Comparison of New Drug Approval Status and Review Periods in Japan, the U.S., and Europe
-In light of the approval status of biopharmaceuticals

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Hiroshi Azuma, Senior Fellow, Pharmaceuticals and Industrial Policy Research Institute
Masao Yoshida, Senior Fellow, Pharmaceuticals and Industrial Policy Research Institute

The Pharmaceuticals and Medical Devices Agency (PMDA), the U.S. Food and Drug Administration (FDA), and the European Medicines Agency (EMA) publish information on approval and review periods for pharmaceutical products in Japan, the United States, and Europe. (PMDA), the U.S. Food and Drug Administration (FDA), and the European Medicines Agency (EMA), respectively, have been continuously collecting and analyzing information published on their respective ^websites1). In the Policy Research Institute News No. 64 ^(2), a comparison of the approval status and review period of new drugs in Japan, the U.S., and Europe, focusing on the approval results in 2020, and in the Policy Research Institute News No. 65 ^{(3), the} results of analysis of information on drugs approved in Japan in 2021. In No.63( ^{4) and (5)} and No.66 ^{(6) and (7),} we reported on the current status of drug lag based on this ongoing survey. In this newsletter, we examine the number of new drugs approved in Japan, the U.S., and Europe in 2021, as well as the review periods for these drugs. The study also examined drugs for the treatment of new coronavirus disease 2019 (COVID-19), which received special approval in Japan. In addition, we report on the approval status of biopharmaceuticals, which has been increasing in recent years, focusing on the application of special measures in pharmaceutical affairs.

Survey Method

The information published on the respective websites of PMDA, FDA, and EMA was used, and standard statistical analysis software Stata/IC 14.0 for Windows (StataCorp LP, College Station, TX, USA) was used to calculate the review period as the period from the date of application for approval to the date of approval. The review period was calculated as the period from the date of application for approval to the date of approval. Since some items have significantly longer periods or shorter periods due to special exceptions, the main basic statistic is the median, and the number of samples, mean, and standard deviation are shown together.

In Japan, as in the Policy Research Institute News No. 65, the target drugs were those listed in the "List of New Drugs Approved " ⁸⁾ on the PMDA website, and the number of items was counted for each review report. New Molecular Entity (NME) was counted only if the application was classified as a new active ingredient. In the U.S., New Drug Applications (NDA) and New Biologic License Applications (BLA) approved by the FDA Center for Drug Evaluation Research (CDER) and listed in the "CDER Drug and Biologic Approvals for the Calendar Year " ⁹⁾ were included. NMEs were counted for drugs listed in the "CDER New Molecular Entity (NME) Drug & Original BLA Calendar Year Approvals " ⁹⁾ approved by the FDA Center for Drug Evaluation Research (CDER). The NME count covered drugs listed in the "CDER New Molecular Entity (NME) Drug & Original BLA Calendar Year Approvals.

NMEs are those classified as "New active substance".

It should be noted in advance as a limitation of the survey that the types and scope of pharmaceuticals included in the scope of the survey for each of the three regions indicated above are different, and that comparisons among the three regions regarding trends in the number of approved pharmaceuticals cannot be strictly ^made11).

In addition, as special measures on pharmaceutical affairs, Japan has Priority Review, Expedited Review, Orphan Drug, Pioneer Review Designation ^System12), and Conditional Accelerated Approval System, while the United States has Priority Review, Accelerated Approval, Orphan, Fast Track, and Breakthrough Therapy, while Europe has Priority Review, Accelerated Approval, Orphan, and Fast Track, Breakthrough Therapy in the U.S., and Accelerated Assessment, Orphan, Conditional Approval, Exceptional Circumstances, and Priority Medicine (PRIME) in Europe. The content of each special measure is shown in the table below. The details of each special regulatory action are summarized in the Supplement (Page 138).

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

The number of new drugs approved in Japan, the U.S., and Europe over the past seven years (2015-2021) is shown in Figure 1. In Japan, 135 new drugs were approved in 2021, of which 52 were NMEs. This was the highest number of approvals in the past seven years. In the U.S., 115 products were approved in 2021, 50 of which were NMEs, both down from 2020, but the third highest number of NMEs approved after 2018 and 2020. In Europe, there were 170 products in 2021, of which 51 were NMEs. This was the highest number of approvals for both NMEs and approved products since 2013, the year in which the Firm's data was compiled.

Number of items approved under special regulatory measures (NME)

The number and percentage of NMEs approved in Japan, the U.S., and Europe over the past seven years (2015-2021) that received special regulatory treatment in each region were examined (Figure 2).

Of the 52 NMEs approved in Japan in 2021, 21 (40.4%) received priority review (including orphan drugs), 20 (38.5%) were for orphan drugs, 0 were for expedited review (excluding priority review), 0 were eligible for the conditional accelerated approval system, and 2 (3.8%) were designated under the Advance Review Designation System. The number of items designated under the Pioneer Review Designation System was 2 (3.8%). The percentages of NMEs for Priority Review and Orphan Drugs rebounded from the trend of the previous year and were near record highs. On the other hand, the number of NMEs under the Pioneer Review Program declined, and no products were approved under the Expedited Approval and Conditional Accelerated Approval Programs.

In the U.S., of the 50 NMEs approved in 2021, 35 (70.0%) were Priority review, 26 (52.0%) were Orphan designation, 14 (28.0%) were Accelerated approval, 18 (36.0%) were Fast Track designation, and 18 (36.0%) were Breakthrough Therapy designation. Breakthrough Therapy designation was granted to 14 (28.0%). Accelerated approval was particularly high, surpassing last year's 12 items, the highest number since 2011.

In Europe, of the 51 NMEs approved in 2021, 4 (7.8%) received Accelerated Assessment, 19 (37.3%) received Orphan designation, and 14 (27.5%) received Conditional approval, Conditional approval was the highest number of items since 2014 and the second highest percentage after 2020.

Comparison of review periods for new drugs between Japan, the U.S., and Europe

Table 1 compares the review periods (in months) for new drugs approved in Japan, the U.S., and Europe in 2021 with those of last year. Note that the median and other median values for specially approved drugs in Japan were excluded from the calculations due to differences in the review process.

The median review period for NMEs approved in 2021 was 9.9 months in Japan, 9.9 months in the U.S., and 12.3 months in Europe, indicating that the difference in review periods between Japan and the U.S. narrowed compared to that in 2020. months in Japan, 8.0 months in the U.S., and 13.8 months in Europe. Compared to last year, the median review period was shortened only in Japan, while it remained unchanged in the U.S. and Europe, thus narrowing the gap in review time between the U.S. and Japan.

Review periods for items that received special measures by the pharmaceutical affairs bodies (NME)

Among the products approved in 2021, those that received special regulatory measures to shorten the review period (Japan: Priority review, Pioneer review designation system; U.S.: Priority review, Breakthrough Therapy; Europe: Accelerated Assessment, PRIME) are shown in Table 2. Table 2 shows the items that received priority review (Japan: Priority Review System, USA: Priority Review, Breakthrough Therapy, Europe: Accelerated Assessment, PRIME). In particular, the Pioneer Review Designation System, Breakthrough Therapy, and PRIME frameworks are designed to give priority treatment to drugs that are expected to be highly effective against serious diseases by providing advice at the development stage, conducting rolling reviews, or conducting priority reviews. This is intended to further expedite the commercialization of drugs that are expected to be highly effective in treating serious diseases, and to quickly resolve unmet medical ^needs13). (Supplement Page 138)

The number of approved priority review items in Japan in 2021 was 44 for all approved items and 21 for NMEs, an increase from 2020, and the median review period was 8.3 months and 8.8 months, respectively. Although it took more months for approval than last year, the median was within 9 months. It was also confirmed that the variation (standard deviation) in the review period was very small and stable. On the other hand, two products (both NMEs) were approved as designated products under the Pioneer Review Designation System, but the review period for one of them exceeded the PMDA's target of six months. The reasons for this are discussed in the Summary and Discussion section. The number of NMEs approved was lower than in 2020, and the median review period was slightly longer than in 2020.

The number of Priority Review items approved in the U.S. in 2021 increased from 2020 for all approved items (54 items), as well as for NMEs (35 items). For Breakthrough Therapy-designated products, 18 products (including 14 NMEs) were approved, with median review times of 8.0 months and 8.0 months, respectively, similar to Priority review. The median review times were 8.0 months and 8.0 months, respectively, which were similar to those for Priority Review. Compared to the number of items designated for Priority Review in Japan, the number of designated items is very large, as was the case last year.

In Europe, although the percentage of items that received Priority review is smaller than in Japan and the U.S., the median review period for Accelerated Assessment-designated items in 2021 was 8.2 months, more than 4 months shorter than that for items that did not receive designation, which was the same as last year. In addition, five items (all NMEs) were approved under the PRIME designation, with a median review period of 10.2 months. This is a result of the NME's special measures.

Annual median review time (Japan, US, EU)

Table 3 shows the review period (in months) by year of approval (2000-2021) for drugs approved in Japan, the U.S., and Europe, and Figure 3 shows the annual change in median review period. For NMEs, the period from 2013 to 2021, after the Japanese review period was significantly shortened, was included in the survey.

The median review period for the entire period covered by the survey was 11.1 months in Japan, 10.1 months in the U.S., and 13.3 months in Europe (Table 3). 2021 maintained the same review period as last year with 9.9 months in Japan, 9.9 months in the U.S., and 12.3 months in Europe. In terms of annual trends, since the significant shortening of the examination period in Japan in 2011, the median examination period has been about 10 months, which is comparable to that of the U.S. Europe has also shortened its examination period (about 12 months) since 2015.

The median review period for NMEs for the entire period surveyed was 10.2 months in Japan, 8.1 months in the U.S., and 14.1 months in Europe (Table 4). For the period 2014-2016, the review period for NMEs in Japan (about 10 months) was shorter than that in the U.S. In 2017, the review period for NMEs in the U.S. shortened by 3 months, and since then the review period has remained in the order of the U.S., Japan and Europe (Figure 4).

Comparison of review periods for COVID-19 drugs between Japan, the U.S., and Europe

In the previous tabulations, Japanese NMEs were excluded from the calculation of median and other median values due to differences in the review process. Many COVID-19 drugs are among the exceptionally approved drugs. In the past, the National Institute for Health Policy Research (NIPS) has conducted a number of research reports, and in NIPS News No. 64 ⁽²⁾, a comparison of the review period for COVID-19 vaccine between Japan, the U.S., and Europe was reported. In this report, Table 5 lists the items approved in Japan for COVID-19-related special approval, which are classified as small molecule drugs and antibody drugs other than vaccines, and the respective review periods for each. Partial change approvals for the same items are excluded.

The differences in the special measures in the various regions and the outline of designation in each system are reported in detail in the Policy Research Institute News No. 64 ^(2). It should be noted that a direct comparison of the review period for each drug is not easy to make because of the status of prior review and other factors.

In Japan, a total of 6 drugs have been approved as special exceptions since 2020, with a median review time of 21.0 days, a mean of 29.0 days, and a standard deviation of 27.2 days. With the exception of the most recent one, all of the drugs were approved within 4 weeks, confirming that approval is granted with a high degree of urgency, even if there is a track record of approval overseas.

The median review time was 63.0 days, with a mean of 59.0 days and a standard deviation of 19.3 days. Under the circumstances where the first review is conducted internationally, it is not surprising that the review period is longer than in other regions.

In Europe, there was one unapproved drug, and the median review time for five drugs was 28.0 days, with a mean of 25.0 days and a standard deviation of 9.3 days. The median review time was 28.0 days, with a mean of 25.0 days and a standard deviation of 9.3 days. It appears that rolling reviews (sequential review) based on the phased provision of clinical trial data were well utilized, resulting in smooth approval or approval with conditions with little variation. However, it should be noted that the statistics may change significantly depending on the future approval status of unapproved drugs.

Comparison of review periods for biopharmaceuticals between Japan, the U.S., and Europe

In recent years, the presence of biopharmaceuticals has been increasing compared to conventional small molecule drugs, with the top 100 drugs in the pharmaceutical market accounting for more than half of the global sales as reported in the previous ^report14). In this regard, we attempted to compare each region in terms of approval periods and special measures for biopharmaceuticals. First, the background of this study is described below. We hypothesized that biopharmaceuticals would be more directly effective against the cause of disease due to their higher targeting ability than small molecule drugs, and therefore would be more likely to receive special measures under the Pharmaceutical Affairs Law due to their higher efficacy and timeliness. As a result, we wondered if there would be any change in the review period.

Table 6 shows the review periods (in months) of biopharmaceuticals approved in Japan, the U.S., and Europe by year of approval (2013-2021) in the NME, and Figure 5 shows the annual changes in median review periods. In Japan, 114 biopharmaceuticals were approved as NMEs in the aggregate year as a whole, and the overall median approval period was 10.2 months. In particular, 24 items were approved in 2021, a very large number in recent years. In the U.S., 101 items were approved, with a median approval time of 10.1 months. The median duration of approval varied from year to year. In Europe, 131 products were approved in the aggregate for the year. On the other hand, the overall median approval time was 13.8 months, but a trend toward expeditious approval was observed from 2018 onward. As a comparative reference, Table 7 shows the review period (in months) by approval year (2013-2021) for non-biopharmaceutical NMEs.

Next, we examined the ratio of biopharmaceutical NMEs approved in Japan, the U.S., and Europe from 2015 to 2021 that received special regulatory measures in each region, broken down by biopharmaceutical category (Figure 6). In Japan and the U.S., the ratios of biopharmaceuticals and non-biopharmaceuticals tended to be close and overlapped, although there were differences from year to year. In Europe, on the other hand, the percentage of biopharmaceuticals receiving special regulatory treatment was always higher than that of non-biopharmaceuticals during the survey period.

Discussion and Summary

In this report, the number of NMEs approved in Japan, the U.S., and Europe in 2021 and their review periods are tabulated and compared based on information published by the respective regulatory authorities.

The number of new drug approvals in 2021 was the highest in Japan and Europe, and also high in the U.S. While various restrictions and impacts of the COVID-19 pandemic will surface in earnest from 2020, at least in terms of drug approvals, companies, review authorities, and even hospital facilities that conducted clinical trials to obtain data for approvals are expected to continue to work together to improve the quality and safety of their products. In terms of drug approval, at least, the companies, the review authorities, and the hospital facilities that conducted the clinical trials to obtain data for approval were able to skillfully overcome the most difficult period of time. However, if there are any delays in clinical trials, it will take some more time to directly affect the number of approvals, so we should pay attention to future trends.

As shown in Tables 1 and 2, the year 2021 was characterized by a very small variation in approval periods in Japan. One item did not meet the 6-month target under the Pioneer Review Designation System, but the reason was clearly stated by the regulatory ^{authorities15)}. (1) The period from submission of materials to application for approval was too short, (2) it was difficult to confirm clinical trial results within the target review period, (3) reevaluation of oncogenicity study results was necessary, etc.). We believe that not only short but also stable review periods allow each stakeholder, including medical professionals, to make robust predictions and preparations, and above all, steadily bring bright hope to patients waiting for a new drug. We look forward to the continuation of a swift and steady review process in the future.

In the area of special measures on pharmaceutical affairs, the number of applications for the Pioneer Review Designation System, Breakthrough Therapy, and PRIME for drugs that are expected to be highly effective in treating serious diseases decreased compared to last year. If the trend continues, it could be a challenge for access to medicines in areas of high unmet medical needs. In particular, it will be interesting to see whether the number of designated pioneering drugs will increase in Japan, in order to improve access to highly innovative drugs.

Regarding the comparison of COVID-19 in Japan, the U.S., and Europe, the U.S. is characterized by earlier approval dates for emergency use and approval, and longer review periods. This is a reflection of the history of the infection situation and the position of Japan in the world of drug development. In other words, the U.S. had the highest cumulative number of COVID-19 cases in the world during the period when it was the region with the greatest need for ^drugs16). In addition, the U.S. is the center of the world in terms of drug development. It is interesting to note that the time from formal application to submission was approximately 20 to 30 days, regardless of whether or not prior review was required in the two regions or for each drug product. Of course, exceptions can be made for longer or shorter periods depending on the individual review status or the situation of use, but it can be said that this is part of the minimum time required for procedures for urgent and exceptional cases.

The results of the survey of biopharmaceuticals by application showed no clear difference in the review period when comparing the figures in Tables 5 and 6. In Japan, the review period was 10.2 months for both biopharmaceuticals and non-biopharmaceuticals, and in Europe, there was a slight difference for biopharmaceuticals, while in the U.S., the review period was longer for biopharmaceuticals. As shown in Figure 6, the ratio of biopharmaceuticals receiving special measures in Japan and the U.S. did not differ significantly. In Europe, the ratio of biopharmaceuticals receiving special measures is higher than that of non-biopharmaceuticals, which may have led to the slight difference in the time period. Overall, it is difficult to say whether or not a drug falls under the category of biopharmaceuticals influences the approval period, and the difference in the application rate of each special measure should be taken into consideration. Additional analysis (details not disclosed) conducted by pooling the review periods of the three regions (Japan, the U.S., and Europe) suggested that an increase in the application rate of special measures in the pharmaceutical affairs contributed to a reduction in the review period for all items, but the effect was small, suggesting that the effect may be offset by an increase in the review period for items that are not applicable.

The status and review periods of approvals and special regulatory measures in Japan (PMDA), the U.S. (FDA), and Europe (EMA) have been investigated thus far, and it was confirmed that each region has achieved faster approvals compared to the normal review process. As summarized in the Supplement (Page 138), various special measures on pharmaceutical affairs have been enacted with significant meaning, and their utilization is proof that the pharmaceutical industry is able to contribute to society. The key will be how well the industry can respond to advances in medical science and technology and provide a high standard of medical care in a timely manner.

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