The Pharmaceutical Industry at a Glance Comparison of New Drug Approval Status and Examination Periods in Japan, the U.S. and Europe Issues in Japan based on the case of the COVID-19 vaccine

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Masao Yoshida, Senior Researcher, Pharmaceutical and Industrial Policy Research Institute (PIIPRI)

The Pharmaceuticals and Medical Devices Agency (PMDA), the U.S. Food and Drug Administration (FDA), and the European Medicines Agency (EMA) have published 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. 61 ⁽²⁾, we compared the approval status and review period of new drugs in Japan, the U.S., and Europe, focusing on the approval results in 2019; in the Policy Research Institute News No. 62 ^{(3), we} analyzed information on drugs approved in Japan in 2020; and in No. 63 ^(4), based on this ongoing survey, we reported on the current drug lag situation. In this issue of the News, we surveyed the number of new drugs approved in Japan, the U.S., and Europe in 2020, as well as the review periods for these drugs. In addition, we also examine the systems and review periods used in Japan, the U.S., and Europe for the approval of vaccines against COVID-19, which will be rampant from 2020, and raise the issue of emergency drug approval systems in Japan.

Survey Method

The information published on the PMDA, FDA, and EMA websites was used to calculate the review period from the date of application to the date of approval using standard statistical analysis software Stata/IC 14.0 for Windows (Stata Corp LP, College Station, TX, USA). 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. 62, the target drugs were those listed in the "List of New Drugs Approved " ⁵⁾ on the PMDA website, and the number of items was counted per review report, and when multiple companies simultaneously submitted applications for an item with the same ingredient or multiple ingredients were approved for combination drug therapy, the number of items was counted as one. 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 " ⁶⁾ were included. NMEs were counted for drugs listed in the "New Molecular Entity (NME) Drug & Original BLA Calendar Year Approvals. The NME count included drugs listed in the New Molecular Entity (NME) Drug & Original BLA Calendar Year Approvals.

NMEs were included in the table for drugs classified as "New active substance".

The special regulatory measures included Priority Review, Accelerated Review, Orphan, Fast Track, and Breakthrough Therapy in the U.S., Priority Review, Accelerated Approval, Orphan, Fast Track, and Breakthrough Therapy in Europe, and Priority Review, Expedited Review, Orphan, Pioneer Review Designation System, and Conditional Accelerated Approval System in Japan. Therapy in the U.S., and Accelerated Assessment, Orphan, Conditional Approval, Exceptional Circumstances, and Priority Medicine (PRIME) in Europe. The details of each special regulatory measure are summarized in the Supplement at the end of this report.

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

Figure 1 shows the number of new drugs approved in Japan, the U.S., and Europe over the past six years (2015-2020). The number of new drugs and NMEs approved in Japan in 2020 was 125 and 38, respectively, the second highest number of new drugs and NMEs approved in the past six years, although they decreased by 5 and 1, respectively, compared to 2019. In contrast, the U.S. approved 121 items and 53 NMEs, both up from 2019; for NMEs, this was the second highest number of approvals on record since the Firm's records began in 2000, after 2018. Europe had 153 approved products and 42 NMEs in 2020, a significant increase compared to 2019 and the highest number of approved products in the past six years.

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 six years (2015-2020) that received special regulatory measures in each region were surveyed (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%) received orphan drugs, 4 (10.5%) received designation under the Pioneer Review Designation System, and 3 (3.5%) received conditional accelerated approval. Conditional Accelerated Approval System was applied to 3 items (7.9%). The percentage of NMEs for priority review and orphan drugs has been on a downward trend since 2016. On the other hand, the number and percentage of NMEs approved in 2020 under the Pioneer Review Program and the Conditional Accelerated Approval Program were the highest ever.

In the U.S., 12 (22.6%) of the 53 NMEs approved in 2020 received accelerated approval, the highest number since 2011, and the second highest percentage since 2016. In addition, 31 (58.5%) received Priority review, 31 (58.5%) received Orphan designation, 17 (32.1%) received Fast Track designation, and 22 (41.5%) received Breakthrough Therapy designation. The number and percentage of NMEs approved as Breakthrough Therapy-designated products were the highest ever.

In Europe, of the 42 NMEs approved in 2020, 6 (14.3%) had Accelerated Assessment, an increase from 2019, 18 (42.9%) received Orphan designation, 12 (28.6%) received Conditional approval, and 12 (28.6%) received Exceptional Circumstances designation. ), 3 (7.1%) received Exceptional Circumstances, and 9 (21.4%) received PRIME designation, the most in the past 6 years, respectively.

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

The review periods (in months) for new drugs approved in 2020 in Japan, the U.S., and Europe are shown in Table 1.The respective median review periods (median) for 2020-approved items were 10.7 months in Japan, 10.0 months in the U.S., and 12.2 months in Europe, with the difference in review periods between Japan and the U.S. widening compared to 2019.For NMEs, The median review period (median) for NMEs approved in 2020 was 10.6 months in Japan, 8.0 months in the U.S., and 13.8 months in the E.U. Compared to 2019, the median review period was longer only in Japan.

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

Among the products approved in 2020, 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, US: 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 the treatment of diseases, and to quickly resolve unmet medical ^needs8).

The number of approved priority review items in Japan in 2020 decreased slightly from 2019 for both all approved items (33 items) and NMEs (11 items), but the median review period was 7.7 months and 6.5 months, respectively, significantly shorter than in 2019. In addition, five items (including four NMEs) were approved as designated items under the Pioneer Review Designation System, and the review period for those items was shorter than the PMDA's target of 6 months. On the other hand, the number of approvals of items under normal review increased and the median review period (median) was longer than in 2019. This indicates that the longer review period (median) in Japan seen in Table 1 compared to 2019 was due to a decrease in the number of Priority review items and an increase in the number of Normal review items.

Regarding the number of Priority review-designated items approved in the U.S. in 2020, the number of all approved items (41 items) decreased from 2019, while the number of NMEs (31 items) increased. Median review times (median) were 6.9 and 7.6 months, respectively, similar to 2019. The median review time (standard deviation) of 23 Breakthrough Therapy-designated products was shorter than that of Priority review, and the median review time (standard deviation) of 22 NMEs (22 products) was shorter than that of Priority review. The median review time for NMEs (22 items) was shorter than that of Priority Review. Although the median review period is more than one month longer than that of Japan's Priority Review-designated items, it is worth noting that the number of designated items is approximately five times larger.

In Europe, the percentage of items that received priority review was smaller than in Japan and the U.S. However, the median review period (median value) for Accelerated Assessment-designated items in 2020 was 8.0 months, more than four months shorter than that for items that did not receive designation. In addition, for PRIME-designated items, nine items were approved, a significant increase from 2019. On the other hand, the median review period was more than two months longer than in 2019, but was shorter than that for items not receiving special measures, confirming that this regulatory system is playing a role in the early resolution of unmet medical needs.

Annual median review time (Japan, US, EU)

Table 3 shows the review period (in months) for each approval year (2000-2020) for drugs approved in Japan, the U.S., and Europe, and Figure 3 shows the annual changes in median review period. For NMEs, the period from 2013 to 2020, after the Japanese review period was significantly shortened, was included in the study. Table 4 shows the review period (in months) by year of approval, and Figure 4 shows the annual trend of the median review period.

The median examination periods for the entire period covered by the survey were 11.1 months in Japan, 10.2 months in the U.S., and 13.4 months in Europe (Table 3). Looking at annual trends (Figure 3), the examination periods from 2000 to 2010 tended to be longer in the order of the U.S., Europe, and Japan, but in 2011, Japan showed a significant reduction in the examination period, and since then, the median examination periods for Japan and the U.S. have been similar (approximately 10 months), followed by Europe, in that order. Since then, the median examination periods in Japan and the U.S. have been similar (approximately 10 months), followed by Europe, which has been taking longer. Europe also allowed a shortening of the examination period from 2015 (approximately 12 months), and since then, the examination period has remained the same until 2020.

In contrast, the median review periods for NMEs during the entire survey period were 10.3 months in Japan, 9.6 months in the U.S., and 14.1 months in Europe (Table 4). NME examination period in the U.S. shortened by 3 months, and thereafter the order of the U.S., Japan, and Europe remained in the same order up to the present (Figure 4).

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

As the last part of the investigation in this paper, we will address the status of approval and emergency use authorization in Japan, the U.S., and Europe for COVID-19 vaccine, which is indicated for "prevention of infectious diseases caused by novel coronavirus (SARS-CoV-2)" that continues to spread worldwide today, review period, problems with the Japanese response, and the response to the vaccine review in the U.S. and Europe. The following topics will be covered.

As of September 2021, there were a total of four COVID-19 vaccines approved for use in Japan, the U.S., and Europe (Table 5, (1) to (4)), and all four were approved in Europe under Conditional Approval, a special measure with conditions. In Japan, three types of vaccines (1), (2), and (3) are available with special approval under Article 14-3 of the Pharmaceuticals and Medical Devices ^Act3), and it was announced that an application for approval of domestic production and marketing of the vaccine (4) was filed on May 24, ²⁰²¹⁹⁾. In the U.S., on the other hand, only one vaccine (1) has been approved under the U.S. law, and the two vaccines (2) and (3) are still at the stage where they are temporarily approved for use as an emergency use authorization (EUA) ¹⁰⁾.

Next, we will compare the timing of approval and review periods among the three regions. For the vaccine (1), which became available earliest in each of the three regions, applications were submitted in the U.S. and Europe from mid to late November 2020, and approval was granted just 21 days later, in December 2020. In Japan, on the other hand, the application was submitted in mid-December 2020 and received special approval 58 days later in February 2021, approximately two months after the U.S. and Europe. In addition, the approval of vaccine (2) was delayed by more than four months from the U.S. and Europe, and the approval of vaccine (3) was also delayed by about four months from Europe, indicating that Japan was later in the review of each vaccine as well as the approval timing.

One problem is that special approval in Japan requires that the following conditions be met: (1) urgent use is necessary to prevent the spread of the disease, (2) there is no other appropriate method than the use of the drug in question, and (3) the drug is approved for sale in a country with an approval system comparable to that of ^{Japan3, 11)}. In other words, special approval is not a requirement for the approval of a drug in Japan. In other words, special approval is a rule that allows for the rapid procurement of foreign products when it is difficult to develop a cure or treatment for a disease that threatens the life or health of the Japanese people in their own country, and even drugs that have been used in Japan in clinical studies are not covered if they have not been sold overseas. In other words, the situation exposed the fact that there is no pharmaceutical system that allows Japanese regulatory authorities to evaluate the risk-benefit of a drug on their own initiative, make regulatory decisions under emergency conditions, and be the first in the world to approve emergency use of a ^drug11).

Another possible reason for the delay from overseas is that the government required the results of clinical trials in Japan regarding the domestic approval of vaccines. According to the "Concept on the Evaluation of the SARS-CoV-2 Vaccine, " ¹²⁾ published by the PMDA in September 2020, "Even if a large-scale validation clinical trial is conducted overseas to evaluate the efficacy of the vaccine in preventing the onset of disease, the clinical trial should be conducted in Japan and the efficacy and safety of the vaccine should be evaluated in Japanese subjects, We believe that it is highly necessary to investigate the efficacy and safety of the vaccine in Japanese subjects. The respective discussion result reports clearly state that the domestic Phase I/II trials for the vaccines listed in Table 5 (1), (2), and (3) had been conducted since October 2020 for (1), January 2021 for (2), and August 2020 for (3). ¹³⁾ In other words, the COVID-19 vaccine was not tested in Japan. In other words, the response to the approval of the vaccine in Japan was to evaluate the efficacy of the COVID-19 vaccine based on the results of validative studies overseas and, in addition, to confirm the immunogenicity and safety of the product in Japanese patients based on the results of domestic clinical studies This was the response to the approval of the vaccine in Japan. This requirement for clinical trials in Japan itself is business as usual from the PMDA's drug approval review, but whether it is necessary as a regulatory approval process in an emergency situation such as a pandemic will need to be discussed further.

Another point is that the review period for the COVID-19 vaccine in Japan was more than twice as long as in the U.S. and Europe, which is an important difference considering that this was an emergency situation. It is difficult to pinpoint the cause in this regard, but for example, with regard to the vaccine in (3), according to the Report of Deliberation ^Results13), many pages are devoted to describing safety related to thrombosis, thromboembolism, and neurodeficiency events reported after overseas marketing, approximately 1.5 months before the approval date. On April 7, 2021, the EMA announced that blood clots with thrombocytopenia may occur very rarely after inoculation with the drug and should be considered an adverse reaction of the ^drug14), and one can imagine that it took time to confirm and respond to this safety-related event. In addition, it may have taken time to confirm efficacy and safety in Japanese patients based on the aforementioned domestic phase I/II study and to bridge the gap with overseas clinical trials.15) As for VECRY (generic name: Lemdecivir), which was approved on May 7, 2020 as a special exception for the indication of infection caused by SARS-CoV-2 (generic name: Lemdesivir), which received special exception approval on May 7, 2020 for the indication of infection caused by SARS-CoV-2, it was confirmed from the Report of Discussion ^Results13) that Japan also participated in the international phase III study, which was treated as the main clinical trials and other study results at the time of approval review, and this may have contributed to expediting the approval review. However, given the prevalence of COVID-19 in Japan at the time of vaccine development, it may have been difficult to conduct an international joint trial including Japan. In Europe, rolling reviews were conducted for all COVID-19 vaccines even before the application for approval was submitted, as will be described in detail later. In Japan, no accurate information is available on whether or not rolling review was initiated prior to application for approval, and this may have contributed to the difference in the approval review period.

On the other hand, the EUA in the U.S. functioned as an emergency response, allowing COVID-19 vaccination at an early stage. However, problems also arose with the EUA, and although not the case of the vaccine, it was decided that the antimalarial drugs hydroxychloroquine and chloroquine phosphate, once approved for COVID-19 treatment, were not likely to be effective against COVID-19 and could be associated with serious side effects, and the EUA The grant was withdrawn a few months later, creating a situation that added to the social ^confusion15). This case may be an example of a situation that arose because a period of time could not be secured for a proper review of a pharmaceutical product.

The following measures, which are not normally taken at the time of review, were taken for the COVID-19 vaccine in Europe, although the European Commission had taken action on Conditional Approval. According to the European public assessment reports (EPAR) for the COVID-19 vaccine in Europe, the Committee for Medicinal Products for Human Use (CHMP), which is the European Committee for Medicinal Products for Human Use (CMP), has been conducting a review of ^{the 16)} vaccine in Table 5 (1) since October 6, 2020, more than 50 days before the application date. The rolling review by the Committee for Medicinal Products for Human Use (CHMP) was initiated on October 6, 2020, more than 50 days prior to the date of application. This was also the case for vaccines (2), (3), and (4) in Table 5, ¹⁷⁾ confirming that the CHMP had begun its review of each vaccine prior to the date of application. In addition to these vaccines, we investigated all products approved by the EMA with Conditional Approval during the period 2015-2020 to see if there were other cases where the review was initiated prior to the date of application. The results showed that these vaccines that were under review prior to the application date were unique. In response to the COVID-19 pandemic, which is a public health challenge, the review authorities and pharmaceutical companies have taken the special step of collaborating to initiate review prior to filing for Conditional Approval in order to allow time for review to take place and to provide access to the vaccine as soon as possible. This is considered to be a special measure that could have been achieved through cooperation between the reviewing authorities and pharmaceutical companies.

Discussion and Summary

In this report, we conducted a comparative study of the number of new drugs approved in Japan, the U.S., and Europe in 2020 and their review periods, based on information published by the respective regulatory authorities. In addition, information on the systems and review periods used in Japan, the U.S., and Europe for vaccines against COVID-19, which will be rampant in 2020, was investigated, and issues related to the emergency drug approval system in Japan were raised.

In 2020, Japan will have the second highest number of approved products in the past six years, the U.S. will have the second highest number of approved NMEs since 2000, and Europe will have the highest number of approved NMEs in the past six years. The number of new drug approvals in 2020 was the second highest since 2000, and the highest in the past six years in Europe. However, there are analyses that indicate that the COVID-19 epidemic has increased the burden on healthcare workers and the risk of infection in subjects, which has affected clinical development, so it will be necessary to closely monitor the status of new drug approvals in 2021 and ^beyond18).

Two characteristics were observed from the survey on the number of NMEs approved and the number of NMEs under special measures in pharmaceutical affairs: First, the percentage of the number of NMEs for priority review and orphan drugs in Japan has been declining steadily since 2016. In contrast, no such trend was observed for Priority review and Orphan items in the U.S. and Accelerated Assessment and Orphan items in Europe, and for the percentage of the number of approvals of Orphan-designated items in the U.S. and European NMEs, the highest in the past six years The situation in this case has been in place since 2021. This issue requires careful monitoring of the situation after 2021, and at the same time, it is necessary to investigate the cause of the difference in this area. However, since various factors are assumed to be involved, such as the difference between the definition of rare diseases in Japan and that of Orphan in other countries, this issue should be considered in future studies.

On the other hand, the second feature is the Pioneer Review Designation System, Breakthrough Therapy, PRIME, and Conditional Accelerated Approval System, which are special measures under the Pharmaceutical Affairs Law to shorten the review period for drugs that are expected to be highly effective in treating serious diseases in order to speed up access to patients, The percentage of NMEs that fall under the conditional accelerated approval system, Accelerated approval, and Conditional approval increased across the board. As summarized in the Supplement to this report, in order to qualify for these special measures, a drug must be highly effective against serious diseases, etc., and it is a group of drugs that satisfy these conditions. The increase in the number of conditional approvals also means that more and more companies are taking on the challenge of treating intractable diseases for which it is difficult to conduct validated clinical trials. In other words, it was thought that companies around the world continue to invest aggressively in the development of drugs with high unmet medical needs, and are steadily accumulating results.

The median review time for new drugs in Japan was 0.7 months longer than in the U.S. in 2020, but shorter than in Europe, a trend that has continued since 2011 and will continue in 2020. This trend has continued since 2017. To understand this difference in detail, a comparison of the percentage of priority review-designated items and review periods in Japan's NMEs with those of the U.S. and Europe shows that while the percentage of priority review items in Japan is on a declining trend, the percentage of Priorityreview and Breakthrough Therapy-designated items in the U.S. NMEs has been In the U.S., the percentage of NMEs with Priorityreview and Breakthrough Therapy designations was overwhelmingly higher than that of Japan. On the other hand, in European NMEs, although the review period for Accelerated Assessment-designated items is comparable to that of Japan's Priority Review, the percentage of such items is much lower, and for NMEs other than Accelerated Assessment, even PRIME-designated items are subject to the same review period as Japan's regular NMEs. The median review time for NME review items other than Accelerated Assessment was comparable to that of Japan's normal review, while the review time for other items was significantly longer. The above indicates that there are differences in the median review period for NMEs in each region.

The comparison of the approval status and review period of COVID-19 vaccines shows that each of the poles responded to the difficult situation of the rapid spread of COVID-19 infection under their respective systems, with special approval in the case of Japan, emergency use authorization (EUA) in the case of the United States, and conditional approval in the case of Europe. In the case of Japan, special approval was granted. Under these circumstances, it was found that not only was the timing of vaccine approval slower in Japan than in the U.S. and Europe, but the review period itself was more than twice as long as in the U.S. and Europe. In addition, the review period itself took more than twice as long as in the U.S. and Europe. In Japan, the problem of special approval was also exposed. This pandemic should be used as an opportunity to discuss and formulate a framework for review and approval in order to respond urgently to emergencies. At that time, we hope that an investigation into the causes of the difference in approval timing and review period (i.e., lag in approval timing and lag in review period) between Japan and the U.S. and Europe for COVID-19 vaccine will be conducted. In its "Vision 2021 for the Pharmaceutical Industry " ¹⁹⁾ formulated in September 2021, the Ministry of Health, Labour and Welfare (MHLW) clearly states that it will "expedite the regulatory approval process and establish standards in emergency situations," and we hope to see improvements in the near future.

Currently, Japan (PMDA), the U.S. (FDA), and Europe (EMA) all have special measures in place to shorten review times with the main goal of speeding up access to innovative drugs for patients. We believe that the cycle is well underway, with companies strategically leveraging and continuing to invest in these programs to achieve their objectives and contribute to patient health and public health issues. However, the experience of the COVID-19 pandemic has also exposed weaknesses in the emergency system in Japan. As pharmaceutical R&D becomes more diversified and sophisticated, and in preparation for possible new pandemics in the future, we hope that the system will be further developed to meet the needs of the times.

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