Pharmaceutical Industry at a Glance New Drugs Approved in Japan and Their Review Periods 2020 Approval Results and Survey of Trends over the Past 10 Years

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The Office of Pharmaceutical Industry Research Masao Yoshida, Senior Researcher

The Office of Pharmaceutical Industry Research The Japan Pharmaceutical Manufacturers Association (JMPMA) continuously collects and analyzes information on drug approvals and review periods based on information published by regulatory ^{authorities1, 2, 3)}. In this newsletter, we survey the approval status and review periods of new drugs and new regenerative medicine products approved in Japan from January to December 2020. In addition, the current status emerging from the ongoing survey from 2010 to 2020 is discussed through analysis of each of the following categories: drugs containing new active ingredients, modality categories, disease categories, the pioneering drug designation system, and items pertaining to special approval.

Survey Methodology

The survey covered drugs listed in the "List of New Drugs Approved " ⁴⁾ on the website of the Pharmaceuticals and Medical Devices Agency (PMDA). Items were counted for each review report, and those for which multiple companies simultaneously submitted public knowledge applications for the same ingredient in response to requests from academic societies, etc., and those for which multiple ingredients were approved for concomitant drug therapy, etc., were counted as a single item. Approval information for each item was extracted from review reports, lists of approved items for new drugs, package inserts, and pharmaceutical bulletins. Standard statistical analysis software Stata/IC 14.0 for Windows (Stata Corp LP, College Station, TX, USA) was used for analysis, and the review period was calculated as the period from the date of application for approval to the approval date.

Number and breakdown of new drug approvals

Figure 1 shows the annual trend in the number of new drugs approved in Japan between 2010 and 2020. The number of new drug items approved in Japan in 2020 was 125, a decrease of 5 items from 2019, but higher than the average number of items approved (117) during 2010-2019. Of these, 38 new molecular entities (NMEs) were approved, one less than in 2019 and similar to the average number of NMEs approved in 2010-2019 (40).

Table 1 then shows the breakdown of approved items. The breakdown by application category shows that in 2020, in addition to the aforementioned NMEs, there were 2 new dosage form drugs and 12 new dose drugs, and these numbers decreased from 2019. On the other hand, the number of new efficacy drugs was 58, an increase of 13 over 2019, which is the second highest number since the Firm's record of 59 in 2011 after 2000. In addition, the number of biosimilars (biosimilars) was 2, ⁵⁾ a decrease of 6 compared to 2019 and the fewest since 2017.

By review category, 91 items were under regular review and 33 items were under priority review. Priority review items accounted for 26% of all approved items, about the same as the level since 2014 (around 30%). However, 23 of the priority review items were orphan drugs, a decrease of 12 items from 2019. As for items subject to the accelerated review designation system, a record number of five items were approved since the first eligible item was approved in 2018. In addition, "VECRULEY for intravenous infusion 100 mg and 100 mg for intravenous infusion" were approved for the indication of "infection caused by a new type of coronavirus (SARS-CoV-2)," which continues to spread worldwide today. This was the first time since 2010 when two imported vaccines were approved for the prevention of new strains of influenza (H1N1).

Review period for new drugs

Table 2 and Figure 2 show the review period for new drugs approved between 2010 and 2020. the median review period for all 125 drugs approved in 2020 was 10.6 months, 0.7 months longer than in 2019, which was the longest review period by a small margin since 2011, when the review period was significantly reduced The median value of the examination period was 10.6 months, 0.7 months longer than in 2019.

Next, by examination category, the median duration was 11.0 months for normal examination items excluding expedited processing items, which was the same as the duration since 2011. On the other hand, the median review period for priority review items was 7.7 months, 0.7 months shorter than that in 2019, and was the shortest since 2010. The 80th percentile of the review period for both regular review items (excluding expedited processing) and priority review items was 11.9 months and 8.9 months, respectively, confirming that approval was granted within 12 months and 9 months, respectively, which are the target ^values6).

The median review period for the 38 NMEs approved in 2020 was 10.4 months, 0.4 months longer than in 2019. For non-NMEs, the median review time was 10.8 months, 0.9 months longer than in 2019, which is the longest review time since 2011. In 2020, the variation (standard deviation: SD) in the review period for NMEs was larger than in previous years, but this could be attributed to the fact that some items took more than 60 months for review. (Figure 3)

Analysis of New Drug Items for Approval

The NME-approved drugs were analyzed by review category and by domestic/foreign ^companies7), while the total number of approved new drugs was analyzed by modality ( ^{biotech8) and} small ^molecule9), and by disease category (rare disease drugs and anti-malignant drugs). The survey was conducted on NMEs for orphan drugs and anti-tumor drugs.

First, Figure 3 shows the number of NMEs approved by review category. 38 NMEs were approved in 2020, of which 26 (68%) were for regular review, 7 (18%) for priority review, 4 (11%) for pioneering review, and 1 (3%) for special exception approval. The number of items designated for pioneering review was 26 (68%). The number of NME-approved items designated for pioneering review was the highest since the first approval in 2018. The percentage of priority review items (including items subject to pioneering review designation) in the number of NME-approved items increased from around 20% in 2010 and 2011 toward 2014, but peaked at 47% in 2014 and then began to decline, reaching 29% in 2020, down from the 2012 level.

The annual trend of the number of NMEs approved by domestic and foreign firms is shown in Figure 4 ^.7) Looking at NME applicants by domestic and foreign firms, domestic firms accounted for 17 NMEs (45%) and foreign firms accounted for 21 NMEs (55%) in 2020. The percentage of approved items accounted for more than half of the total number of NMEs in only two years, 2012 and 2019, and although the percentage decreased from 2012 to 2017, it reversed in 2017 and was the highest percentage (56%) in 2019 since 2010.

Figures 5 and 6 then show the annual changes in the number of approved biotech ^{drugs8) and} other small molecule ^drugs9) for all new drugs approved, not limited to NMEs.

Of the total 125 drugs approved in 2020, the number of approved biopharmaceuticals was 46. The number of biopharmaceutical NMEs (9) in 2020 accounted for 24% of the total 38 NMEs. The number of biopharmaceutical NMEs accounted for 37% of all approved NMEs in 2020, after declining to 22% in 2010 and 16% in 2012. However, while biopharmaceutical NMEs have been consistently approved, there has been no significant growth in the number of NMEs. The number of biopharmaceuticals approved in the last three years shows that a large percentage of the approvals were for items such as biologics follow-on products and new indications.

In contrast, with regard to the number of approved small molecule and other drugs, in 2012 they accounted for 84% of all approved drugs, but by 2018 the percentage had dropped to 62%. However, there has been no significant change in that percentage in the last three years, and in 2020 it will be 63% (79 products). Also, NMEs for small molecule and other drugs were approved steadily in the most recent three years, despite a drop to 16 in 2017, and accounted for 76% (29 drugs) of all NMEs (38 drugs) in 2020, continuing on from 2019 and approximately three times as many as biopharmaceutical NMEs were approved.

Next, Figure 7 shows the annual trend in the number of orphan drug approvals (review category) for all new drug approvals: in 2020, 23 (18%) orphan drugs were approved, a decrease of 12 from 2019, but similar to the average number (23) approved between 2010 and 2019, and This was similar to the average number of approved products from 2010 to 2019 (23). In the period 2010-2020, the number of approved orphan drugs accounted for about 10% of the total number of approved items in 2010, but in 2018 it accounted for 29%, and in 2019 it was the highest ever number of items (35%). For NMEs alone, the number of approvals has not increased since 2016, and has remained around 10 in the last four years, with the number of NMEs for orphan drugs (8) in 2020 representing 21% of the total 38 NMEs.

At the end of this section, Figure 8 shows the annual number of approved antineoplastic drugs for all new drugs. ¹⁰⁾ The number of approved antineoplastic drugs in 2020 was 45, an increase of 9 compared to 2019, which was the highest number of approved drugs since 2000 recorded by the Firm. 2010 ～In the period 2010-2020, the number of approved anti-cancer drugs accounted for only 13% (13 drugs) of the total number of approved drugs in 2010, but has been increasing steadily since then, accounting for 36% of the total 125 approved drugs in 2020. The change in the number of approved anti-cancer drugs during this period was characterized by a significant increase in the number of new indications other than NMEs, etc. Although the number of approved NMEs has not grown significantly, they have been steadily approved every year, and in 2020, 10 anti-cancer NMEs, or 26% of all 38 NMEs, were approved. 26% of all NMEs.

Approval and review period for items subject to the pioneering review designation system

Table 4 shows the products subject to the Pioneer Review and Designation System that were approved by 2020. 5 products were approved in 2020, the largest number ever for this system.

The Pioneer Evaluation and Designation System has been implemented on a trial basis since 2015 to promote the development of innovative pharmaceuticals, medical devices, and regenerative medicine products for early commercialization in Japan, and a total of 10 products were approved under this system by 2020. A breakdown of the companies that applied for approval shows that all of these products were from different companies. The breakdown by review field shows that one product was approved in each of the first four fields, and six in the anti-malignant field, indicating that although many products were in the anti-malignant field, products in a wide range of fields were approved.

The median review period for the entire list of items was 5.2 months (mean 5.2 months, standard deviation 0.73), which was significantly shorter than the median review period for priority review items for new drugs in 2020, which was 7.7 months. All items showed a review period of 6 months or less, indicating that the target approval period of 6 months or less was ^achieved6). 6 ⁾ In addition, a review of the global approval status of these products showed that all NMEs were approved in Japan ahead of the rest of the world, and that the products for which partial change applications were submitted were also approved for the first time in the world for the indications subject to the pioneering review designation ^system12).

The Pioneer Drug Designation System, which had been operating on a trial basis, became law in November 2019 with the enactment of the revised Pharmaceutical Affairs Law and its enforcement in September 2020, and was newly established as the Pioneer Drug Designation System. This system aims to provide patients with the world's most advanced therapeutic drugs at the earliest possible stage, and designates epoch-making new drugs that meet certain requirements as pioneering drugs from a relatively early stage of development, making them subject to priority handling in consultations and reviews related to pharmaceutical approval, as well as to the development of manufacturing systems at the applicant and the approval process after the approval review schedule. In addition, it is clearly stated that the applicant should take sufficient measures to establish a manufacturing system and smoothly provide the drug to the medical community after approval in accordance with the approval review schedule to further expedite the practical use of the ^drug13).

Approval of items subject to special approval and their review period

Table 5 shows the items approved for special approval up to 2020. 2020 saw the special approval of "VECRULEY for intravenous infusion 100 mg and 100 mg for intravenous infusion" for the indication of "infection caused by a new type of coronavirus (SARS-CoV-2)," which is still spreading ^worldwide14). The review period was three days.

Special approval is granted under Article 14-3, Paragraph 1 of the Act on Quality, Efficacy and Safety Assurance of Pharmaceuticals and Medical Devices, etc., to drugs that meet the following requirements: (1) urgent use is necessary to prevent the spread of disease, (2) there is no other appropriate way to use the drug, and (3) the drug is approved for sale overseas. The system provides for special approval for drugs that meet the following conditions: (1) urgent use is necessary to prevent the spread of disease, (2) there is no other appropriate method than the use of the drug in question, and (3) the drug is approved for sale overseas. However, it is clearly stated that the approval may be revoked when it is deemed necessary to prevent the occurrence or spread of health hazards or when it is deemed that any of the above conditions are no longer ^met14). Looking back in time, this was the first time that an item under special approval was approved since 2010, when two imported vaccines were approved for the prevention of a new strain of influenza (H1N1). The review periods for those two vaccines were 106 days (3.5 months) and 75 days (2.5 months), respectively.

Here, we would like to compare and organize information on the approval review period for VECRY (generic name: Lemdecivir) in Japan, the U.S., and Europe. In Japan, following the Emergency Use Authorization (EUA) of lmdecivir for COVID-19 in the U.S., an application was filed on May 4, and special approval was granted on May 7. The approval of the application required the company to "report the results of ongoing clinical trials or clinical studies as soon as they become available, given the extremely limited information on the efficacy and safety of the drug," among other requirements. ⁽¹⁴⁾. The EUA in the U.S. is a temporary measure that permits the supply and emergency use of the drug and does not replace the formal New Drug Application submission, review and approval process, which ends when the cause of the emergency ends or the drug receives formal New Drug ^Approval15), and the special exception approval in Japan was the first legislative approval for Lemdecivir in the world. The special approval in Japan was the first legislative approval of Lemdesivir in the world. On the other hand, in the U.S., after the above EUA was approved on May 1, a New Drug Application (NDA) was filed on August 7, and the drug was officially approved on October ²²¹⁶⁾. In Europe, a Compassionate Use Recommendation allowing the use of unapproved drugs was issued on April 2, ¹⁷⁾ and the review of various data began on April 13, followed by a Marketing Authorization Application (MAA) on June 5 and a New Drug Application (NDA) on July 3. The review of various data began on April 13, and a Marketing Authorization Application (MAA) was submitted on June 5, followed by Conditional Approval on July 3 ^.18). 18) Thus, it can be seen that the company was coping with this difficult situation by taking advantage of the respective systems in Japan, the U.S., and Europe.

As of the end of January 2021, the three drugs approved by the MHLW for use in the treatment of new coronary infections are Beclury, the steroid Decadron (dexamethasone), and Heparin to address the risk of blood ^clots19). There are several other clinical trials and specific clinical studies underway, but please refer to the MHLW data for more ^{information20)}.

Approval of new NMEs and their review period

The following is a list of approved new regenerative medicine products and their review periods (Table 6). 2 new regenerative medicine products were approved in 2020, bringing the total number of products approved by 2020 to 11 (including partial change as an approval category). The total number of products approved by 2020 is 11 (including partial changes as approval categories). Of these, six products, including the two approved in 2020, were approved as regenerative medical products for rare diseases. In addition, one new product was approved in 2020 as a regenerative medicine product designated for pioneering review.

Regarding the review period for new regenerative medical products, the median review period for all eligible products approved by 2020 was 11.7 months (mean 15.6 months, standard deviation 10.4). In addition, the median review period for the nine products approved after the establishment of the new category of regenerative medical products under the Pharmaceuticals and Medical Devices Act (enacted in November 2014) was 11.1 months (mean value 11.0 months, standard deviation 3.2). When these results were compared to the aforementioned review periods for new drugs in the 2010-2020 period, no significant differences were identified.

However, two drugs approved in 2020 were for rare diseases and subject to priority review, and one of them was subject to pioneering review, both of which took more than 12 months to review. The target for the review period for regenerative medicine products is to process 50% of all priority products within 9 ^months6), and it is difficult to say that this target has been achieved. 6) In particular, for the items designated for pioneering review, there was a delay of approximately 10 months from the approval in the U.S. (May 2019), although the main purpose of this system is "to provide patients with the world's most advanced therapeutic agents as soon as possible. This case led to the tightening of the requirements for withdrawal of the designation "in cases where the application was submitted without sufficient prior evaluation or the application materials were found to be substantially flawed, and as a result, early development in Japan cannot be achieved" as stated in the MHLW's "Pioneer Drug Designation System " ^13).22)

Discussion and Summary

This paper investigates the approval status of new drugs and new regenerative medicine products approved in Japan in 2020 and their review periods. In addition, we conducted a chronological analysis of new drugs approved between 2010 and 2020 by category. We also compiled information on the approval and review periods for the pioneering drug designation system that came into effect in the fall of 2020, as well as information on items with special approval that are indicated for the treatment of new coronaviruses, which are still raging today.

The number of new drugs approved in Japan in 2020 was 125, which is higher than the annual average number of approved drugs over the past 10 years. A breakdown of the number of approved new drugs shows that the number of new indications increased by 13 compared to 2019. The median review period for approved drugs was 10.6 months, the longest since 2011, when the review period was significantly shorter. However, the number of approved drugs and their review periods indicate that the impact of COVID-19 was kept to a minimum. However, there are analyses that indicate that the COVID-19 outbreak has increased the burden on healthcare workers and the risk of infection in subjects, which has affected clinical ^{development23)}, so the status of new drug approvals in 2021 and beyond will need to be monitored closely.

Regarding the analysis of NME approvals by category over time, the percentage of priority review items in the survey by review category showed a decreasing trend after peaking in 2014. This is thought to be due in part to a decrease in the number of NMEs for orphan drugs that are subject to priority review. On the other hand, the steady increase in the number of NMEs approved for priority review is a bright spot for patients and pharmaceutical companies. In addition, a survey of the number of NMEs approved by domestic and foreign-funded companies confirmed an increase in the percentage of approvals for items submitted by domestic companies from 2017 to 2019. As pharmaceutical R&D has become more diverse and sophisticated, it can be assumed that the R&D efforts of domestic-funded companies in recent years have been successful. In 2020, however, the ratio had begun to decline slightly. From the perspective of promoting the domestic pharmaceutical industry, we expect another turnaround in 2021 and beyond.

The analysis of biopharmaceutical approvals over time confirms that the increase in new indications and follow-on biologics is more significant than the increase in NME approvals as the reason for the large increase in the ratio of biopharmaceuticals to all approved products compared to 2010. One of the reasons is that, as in the case of the antibody drugs Opdivo and Keytruda, drugs that are versatile in terms of their mechanism of action were approved as NMEs in the past decade, followed by the approval of many new indications. In addition, given that it is not easy to create a single new drug, especially NMEs, in recent years, many pharmaceutical companies have adopted the development strategy of selecting target diseases with a high probability of success, even if the market is small at the entry point, and obtaining approval, then aiming to expand the market by adding new indications, as one of the strategies to increase sales. Biopharmaceuticals may be a good match for this strategy. In addition, the number of biopharmaceutical NMEs has been steadily increasing during the 2010-2020 period, and since these products will eventually reach the end of their patent and reexamination periods, combined with the government's policy of reducing healthcare costs, they are expected to continue to be approved steadily in the future.

On the other hand, the number of small molecule drugs approved as a percentage of all new drug approvals has been on a downward trend since 2010, but the decline has been halted in the last three years, with NMEs receiving about three times as many approvals as biopharmaceutical NMEs last year and this year. It has been a long time since the hurdle for the creation of new drugs has been said to be increasing due to the depletion of target molecules and the increasing difficulty of research and ^{development24)}. 25), and it is expected to continue to be steadily produced in the future. In addition, the definition of small molecule drugs in the current classification is other than biopharmaceuticals, and includes nucleic acid drugs produced by chemical synthesis, such as "Virtepso Intravenous Injection," which was approved in 2020. The impact of the development of these new modalities on the approval and review process will need to be monitored closely in the future.

With regard to the approval status of drugs for rare diseases, the number of approved drugs in 2020 decreased significantly, perhaps in reaction to the record number of approved drugs in 2019. However, this decrease is not expected to continue in the future, and the "List of Drugs Designated as Orphan Drugs " ²⁶⁾ available on the MHLW website shows that 49 drugs were designated as orphan drugs in 2020 alone, indicating that efforts by pharmaceutical companies and others to create drugs for patients suffering from rare and intractable diseases continue. This indicates that pharmaceutical companies are continuing their efforts to create drugs for patients suffering from rare and intractable diseases.

The number of approved anti-cancer drugs has been steadily increasing since 2010, and in 2020, a record 45 drugs were approved, accounting for 36% of all new drugs approved. The data surveyed in this study shows that development of anti-cancer drugs is steadily advancing and the number of approved drugs is increasing every year. On the other hand, the "Drugs that are unapproved or off-label under the Pharmaceutical Affairs Law in Japan" published by the National Cancer Center indicates that there are still a significant number of oncology drugs approved in the US and Europe but unapproved or off-label in ^Japan27). Although it has been confirmed from past analyses that the drug lag has been eliminated in Japan, the U.S. and ^Europe28), we would like to discuss the differences in this area in the future.

A survey of the approval and review period for new drug items subject to the Pioneer Review Designation System showed that the median review period for all 10 items approved by 2020 was 5.2 months, and by item, all items were reviewed within 6 months, indicating that all items were approved in Japan ahead of the rest of the world. The central value of the overall review period was 5.2 months, and all items were approved in Japan before the rest of the world. The approval in a short period of time after the formal review process was not only a benefit to patients who are waiting for a breakthrough new drug, but also an incentive for the companies, which was a desirable outcome for both parties. In addition, cooperation between the review and application sides is essential to achieve a shorter review period, and the results of this survey suggest that this cooperative system is functioning well. The system has become even better since it was legislated and enforced as a pioneering drug designation system in the fall of 2020, with the announcement that designation will be made twice a year (generally in April and October), instead of once a year as was previously the ^case13). In addition, the Ministry of Health, Labor and Welfare (MHLW) has established a system for the designation of "Drugs for Specific Uses" to contribute to the promotion of research and development of drugs for pediatric use and for the treatment of drug-resistant ^bacteria29), and has taken measures to address areas where there is still a shortage of such drugs. In the future, pharmaceutical companies will need to take advantage of these systems and respond to social demands.

In the survey on approved items and their review periods for special approval, we not only reconfirmed the speed of response to the special approval this time by comparing the review period of VECRULEE and past imported influenza (H1N1) vaccines, and by organizing information on the approval review period for COVID-19 in Japan, the US, and Europe, using VECRULEE as an example, but also confirmed the speed of the response to the special approval in Japan and the US. In addition, he reported on the differences between the Japanese special exception approval and the US emergency use authorization, as well as the way Europe handled the situation. As for future special approval, Pfizer's novel coronavirus vaccine (mRNA vaccine) was submitted for approval in Japan on December 18, ^202030) and will reportedly receive special approval by the end of February 2021. If the report is correct, this will be the fastest approval for a vaccine in Japan, as it took more than 2.5 months for the past imported influenza (H1N1) vaccine to be reviewed. However, it will be necessary to conduct further comparative studies of COVID-19 in Japan, the U.S., and Europe, including those approved in the future, in anticipation of new infectious diseases, and to deepen the analysis. There are differences in efficacy, hemodynamics, safety, and other hurdles required for drugs used for severely ill patients, drugs used for mildly ill patients, and vaccines used for people before infection, and each product has its own formulation and production system for mass and stable supply. In addition, each product has its own formulation and production system for mass production and stable supply, making it difficult to understand the approval status, development status, and systems in place in each country to deal with this difficult situation.

A survey of approved items and review periods for new regenerative medicine products showed that the median review period for all 11 items approved by 2020 (including partial changes as approval categories) was 11.7 months. More than half (6) of the approved products were approved as regenerative medical products for rare diseases and two as regenerative medical products designated for pioneering review, and are establishing themselves as new treatment options for intractable diseases that have been difficult to treat in the past. However, because new regenerative medicine products are a new modality that differs from conventional new drugs (small molecules and biopharmaceuticals), the PMDA's review period targets have a wide ^range6), and some products were not actually reviewed on schedule. As of the end of January 2021, one product had already been approved (Yescarta for intravenous infusion; approval date: January 22), and four applications for approval were ^pending31). In addition, there is a "conditional and time-limited approval system" that is unique to regenerative medical products, although it did not apply to items approved in 2020. This system was introduced when the category of regenerative medical products was newly established in November 2014, and has been applied to three products so far (Table 6). For non-homogeneous regenerative medical products, the system allows for special early approval with conditions and time limits if efficacy is presumed and safety is confirmed. In such cases, efficacy and safety must be verified again after approval, and the approved product must be accompanied by materials on the results of use within the time limit, It is required to submit a new application for approval again. In other words, while ensuring early access to patients with limited treatment options, there is a legal basis for revoking approval if efficacy is not verified after marketing, making the system responsive to the nature of the product while pursuing scientific evaluation. Table 6 shows that the three targeted products will face that deadline between 2023 and 2025 to apply for approval again. The fact that three of the four products currently under review have been designated as Rare Disease Regenerative Medicine Products also suggests that early approval of these products as new treatment options is desirable.

In the above, we have discussed the trends of the past 10 years and the current status of the characteristic systems, as well as a survey of the items to be approved in 2020 and their review periods. As pharmaceutical R&D becomes increasingly diverse and sophisticated, we hope that new innovation and value will be created in response to changes in the environment and with a view to contributing to patients' health and public health issues.

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