Policy Research Institute page Development and Approval Status of Drugs for Unmet Medical Needs -Trends in 2022-.

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Based on the FY2019 Treatment Satisfaction Survey by the Japan Health Sciences Foundation, we surveyed the number of new drugs in the development pipeline in Japan as of the end of May 2022 for 60 diseases and the number of new drugs approved for 60 diseases in the last three years. In addition, the survey also reviewed the evolution of drug treatment for "lung cancer," which has the largest number of drugs in development in recent years, in relation to changes in the number of new drug approvals, treatment satisfaction, and drug contribution to treatment*1.

1. Introduction

Based on the results of a survey on medical needs conducted by the Human Science Foundation ("HS Foundation")*2, Policy Research Institute compiles data on new drug approvals and development pipelines and continuously analyzes the status of pharmaceutical companies' efforts to address unmet medical needs*3 *4.

In the previous Policy Research Institute News No.61 (November 2020), based on the results of the FY2019 Treatment Satisfaction Survey, we reported the number of development pipelines as of the end of August 2020 for 60 diseases, as well as information on already approved drugs for the 8 diseases newly added to the 60 diseases in the FY2019 survey This paper reports the number of development pipelines as of the end of May 2022 for the latest 60 diseases and the number of new drug items approved for 60 diseases for the three years from 2019 to 2021, based on the results of the FY2019 treatment satisfaction survey. In addition, we will review the evolution of drug treatment for "lung cancer," which has the largest number of drugs in development in the recent survey, including the relationship between the number of new drug approvals, treatment satisfaction, and drug contribution.

2) New Drug Development Status by Treatment Satisfaction Level

Figure 1 plots diseases along the treatment satisfaction*6 (horizontal axis) and drug contribution*7 (vertical axis) in the 2019 HS Foundation survey, and shows the number of development items*8 surveyed this time in terms of circle size and numerical value. The same 20 pharmaceutical companies*9 as in the previous survey*10 were included in the total number of development items (Phase I to Filed) in Japan as of the end of May 2022*11. 330 items*12 were under development, of which 126 (38%) were new active ingredients (NME*13). The number of NMEs*12 increased by 4 out of 46 for 60 diseases compared to the previous survey, although this includes the effect of some companies that changed the stage of publication on their websites from Phase III or later to Phase II or later. The percentage of products under development in the so-called Quadrant 1, which indicates treatment satisfaction of 50% or more and drug contribution to treatment of 50%, was 78.2% (79.6% in the previous survey), indicating that the percentage of products under development in this survey was the same as in the previous survey, although it slightly decreased from the previous survey. The percentages of the number of developed products in the second and fourth quadrants remained almost unchanged from the previous survey at 4.2% and 9.1%, respectively (4.6% and 8.8%, respectively, in the previous survey). The percentage of products in the third quadrant, where both treatment satisfaction and drug contribution are below 50%, was 8.5%, a slight increase of 1.5% from 7.0% in the previous survey, but the number of products in this quadrant increased from 20 to 28.

Figure 1 Number of new drugs developed (as of the end of May 2022) by level of treatment satisfaction and drug contribution (FY 2019)

Note: Numbers (including those in parentheses) indicate the number of development of the corresponding new drugs.
Source: Prepared by the Pharmaceutical Industry Policy Institute based on the results of a survey by the HS Foundation, information published by each company, the Pharmaceutical Manufacturers Association of Japan website, and New Drugs for Tomorrow.

Of the 46 items that increased, 40 were related to oncology diseases, and the ratio of the number of items developed for oncology diseases to the total number of items developed for 60 diseases, which was 50% in the previous survey, increased to 55% (183/330) ( Figure 2 left ). In addition, the percentage of NMEs in the number of cancer disease development items decreased from 31% (44/143) in the previous survey to 27% (49/183). In other words, of the 40 products that increased, 5 are NMEs and 35 are additional indications (including some additional dosage and administration), suggesting that products developed for one specific cancer disease are being developed for other indications for the same cancer disease or for other cancer diseases ( Figure 2, right).

Figure 2 Outline of development items in 60 diseases (left: number of NME items in 10 cancer diseases out of 60 diseases; right: number of NME items in 10 cancer diseases)

Note: NMEs include those classified as new regenerative medicine products at the time of approval, such as gene therapy and cell therapy.
Source: Compiled by the Pharmaceutical Industry Policy Institute based on the results of a survey by the HS Foundation, information published by each company, the Pharmaceutical Manufacturers Association of Japan (PMAJ) website, and New Drugs for Tomorrow.

As mentioned earlier, in this survey as well as in the previous survey, the percentage of products developed in the first quadrant, which is the area where both treatment satisfaction and drug contribution are 50% or higher, was 78.2%, accounting for a large percentage of the products developed in this quadrant. The number of products developed in this area (78.2%) is quite large considering the fact that 61.7% (37/60) of the 60 diseases are included in the first quadrant. In this regard, as mentioned in the previous news (Policy Research Institute News No. 61 (November 2020)), 10 of the 60 diseases are cancer diseases, and 9 cancer diseases other than pancreatic cancer are included in the first quadrant. In addition, cancer is a disease caused by gene mutation, and since there are various types of gene mutation, one disease, "XX cancer," is subdivided into various indications, and many therapeutic drugs are developed accordingly, etc. This is why the ratio of new drug development items in the first quadrant, which includes nine cancer diseases, is considered to be high. The ratio of new drug development items in the first quadrant, which includes the nine cancer diseases, is considered to be high.

Even if the percentages indicating satisfaction with treatment and contribution to drug development both exceed 50, the breakdown of satisfaction and contribution is that "somewhat satisfied (contribution)" greatly exceeds "fully satisfied (contribution). Most of the remaining percentages that do not reach 100 are "unsatisfied" and "not contributing much," including some who say they are not satisfied with the treatment or that there are no drugs that work. For example, for the nine cancer diseases in the first quadrant, the average percentage of "unsatisfactory" responses was 25.1% (11.7-42.1), the average percentage of "not well treated" was 6.2% (3.3-9.8), the average percentage of "not contributing much" was 16.5% (6.0-31.8), and the average percentage of "no effective drugs" was This indicates that even if a disease is in the first quadrant, there is still plenty of room and demand for pharmaceuticals to contribute to the treatment of the disease.

Looking at the number of items under development for each of the 60 diseases by disease, the most common are: lung cancer (53), breast cancer (34), malignant lymphoma (17), liver cancer (17), prostate cancer (16), and leukemia (15), followed by stomach cancer (11), CKD/chronic kidney disease (11), and Alzheimer's disease ( The number of products in development is dominated by oncology diseases. Since the January 2014 survey (Policy Research Institute News No. 41 (March 2014)), the number of developed items for "lung cancer" has been the highest among the 60 diseases*14.

3) Approval status of new drugs by level of treatment satisfaction 4) Lung cancer drug treatment

Figure 3 plots diseases along the treatment satisfaction (horizontal axis) and drug contribution (vertical axis) in the 2019 HS Foundation survey and shows the number of new drugs*15 approved in Japan in the last three years (2019-2021) with indications for 60 diseases in terms of circle size and numerical value. Of the 294 products approved during the period, 133 (130 products) were for 60 diseases*16, of which 53 (52 products) were NMEs for new active ingredients and 6 (5 products) were new regenerative medicine products. Of the 133 products, 54 (54 products) were approved by domestic companies and 79 (76 products) were submitted by foreign companies*17.

Figure 3 Number of New Drug Approvals (2019-2021) by Treatment Satisfaction and Drug Contribution (FY 2019)

Note: Numbers (including those in parentheses) indicate the number of approved new drugs in question; if the same drug is approved for two different diseases out of 60 diseases, they are counted separately.
Source: Prepared by the National Institute of Health Care Policy based on review reports, tomorrow's new drugs, and each drug's package insert.

Looking at the number of approved products related to 60 diseases by quadrant, 85.7% (114/133), the majority of the approved products were in the first quadrant, where both treatment satisfaction and drug contribution were 50% or higher, as in the previous analysis of the number of products under development. In the 37 diseases in the first quadrant, 114 new drugs were approved, which was calculated to be 3 drugs per disease, or one drug per year.

On the other hand, the number of approved drugs for diseases in quadrants 2, 3, and 4 were 3.8% (5/133), 4.5% (6/133), and 6.0% (8/133), respectively. Nineteen products were approved for 23 diseases in these three quadrants, of which 15 had zero products approved in the past three years.

Looking at the number of approved items related to the 60 diseases by disease, the most common were malignant lymphoma (17), lung cancer (11), leukemia (8), CKD/chronic kidney disease (7), colorectal cancer (6), and breast cancer (6) (numbers indicate number of items).

One of the unique features of this survey of approvals was the inclusion of several new regenerative medicine products in the list of approved products related to the 60 diseases. Between 2019 and 2021, nine new regenerative medicine products were approved, six of which (five products) were related to the 60 diseases. Specifically, Kymriah(R) "Tisagenlecleucel" (leukemia and malignant lymphoma), Yescarta(R) "Axicabtagene Siroleucel" and Breyandji(R) "Lithocabtagene Malalucel" (both malignant lymphoma) for CAR-T cell therapy, and human mesenchymal stem cell AlofiCel(R) "Dalbadostrocel" (Crohn's disease) was approved, and Collategene(R) "Beperminogen perplasmid" (peripheral arterial disease (PAD)) for gene therapy was approved with conditions and a time limit. All of these six products (five products) are therapeutic drugs for diseases located in the first quadrant and not in the other three quadrants, but the former four products were approved after being designated as "regenerative medicine products for rare diseases," and the latter Collategene (R) was approved for the peripheral arterial disease "obstructive The latter product, Collategene(R), was indicated for the improvement of ulcers in the peripheral arterial disease "arteriosclerosis obliterans" as well as the designated intractable disease "Buerger's disease".

In addition to conventional small molecule drugs, antibody drugs and recombinant protein drugs as biopharmaceuticals, various modalities such as nucleic acid drugs and gene cell therapy have been added as options, and the number of treatment methods for diseases that have been difficult to treat has increased. This is expected to further improve treatment satisfaction and drug contribution in the future.

The second characteristic is the large number of approved drugs for cancer. Figure 4 shows the percentage of new drugs approved for the latest 60 diseases since 2009 that are for oncology diseases (10 cancer diseases) for the three years 2009-2011, the three years 2014-2016, and the most recent three years 2019-2021.

Figure 4: Percentage of 10 cancer diseases among 60 approved drugs

Note: Numbers indicate the number of approved new drugs; when the same drug is approved for two different diseases out of 60 diseases, they are counted separately.
Source: Prepared by the Pharmaceutical Industry Policy Institute based on review reports, tomorrow's new drugs, and each drug's package insert.

The number of approved drugs related to 60 diseases in each of the three-year periods 2009-2011, 2014-2016, and 2019-2021 was 110, 124, and 133, respectively, compared to 28, 45, and 62 new drug approvals for 10 cancer diseases, or a ratio of In the last three years, about half of the 60 approved drugs were for the 10 cancer diseases.

Changes in Lung Cancer Drug Therapy

The following is a review of the drug treatment of lung cancer, which had the largest number of items in the survey of products developed by 20 Japanese companies as of the end of May 2022, along with the changes in treatment satisfaction and drug contribution to treatment related to the 60 diseases.

About Lung Cancer

Lung cancer is the third most common cancer among all cancers, after colorectal cancer and gastric cancer, with approximately 120,000 cases per year. The five-year relative survival rate (2009-2011) is 34.9%, which is considerably lower than the 64.1% five-year relative survival rate for all cancer types*18.

Treatment for lung cancer consists of surgery, radiation therapy, drug therapy, and palliative care, and a combination of these therapies is used. In the early stages, surgery is the mainstay of treatment, but as the stage progresses, drug therapy becomes the mainstay. Lung cancer is broadly classified into small cell lung cancer and non-small cell lung cancer, with non-small cell lung cancer accounting for about 85-90% of cases. Non-small cell lung cancer is further classified into squamous cell carcinoma, adenocarcinoma, and large cell carcinoma*19*20 ( Figure 5 ).

Figure 5 Types of Lung Cancer

Source: Created by the Pharmaceuticals and Industrial Policy Research Institute based on the National Cancer Center's Cancer Information Service and other sources.

Changes in Drug Treatment

Figure 6 shows the trends in treatment satisfaction and drug contribution for lung cancer and the number of new lung cancer drugs approved (new active ingredients + additional indications) by indication category. Although not limited to lung cancer, it is said that there are three paradigms of cancer drugs: cytotoxic anticancer drugs, molecular targeted drugs, and immune checkpoint inhibitors.21 By 1993, before the medical needs assessment was started, many cytotoxic anticancer drugs had already been developed. Platinum-based drugs such as cisplatin were developed in the late 1980s, and combination therapy with plant-derived chemotherapeutic agents developed in the 1990s and later was developed. While platinum-based chemotherapy remains the standard of care in lung cancer drug treatment today, it is also important to note the development of antiemetic agents and other supportive therapies to alleviate the side effects associated with anticancer drug therapy.

Figure 6: Treatment Satisfaction, Drug Contribution, and Number of New Drugs Approved for Lung Cancer

Source: HS Foundation Domestic Basic Technology Survey Report "Medical Needs Survey on 60 Diseases" (FY1994, 2000, 2005, 2010, 2014, 2019), review reports, and New Drugs of Tomorrow (drugs with new active ingredients and new indications approved by the end of March 2022 are (counted by year and by indication).

Advances in science, technology, and molecular biology have led to the clarification of the mechanisms of cancer development, growth, and metastasis, and in 2002, gefitinib, an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), was approved. Subsequently, it was found to be highly effective against tumors with mutations in the EGFR gene*22*23, leading to the development of second- and third-generation EGFR-TKIs. In parallel, molecular-targeted drugs were developed for other gene mutations (ALK, ROS1, BRAF, MET, RET, and KRAS) ( Table 1 ).

Table 1: Tyrosine Kinase Inhibitors Approved for Non-Small Cell Lung Cancer

Note 1: The year when the drug was first approved for non-small cell lung cancer, and does not include additional indications within non-small cell lung cancer.
Note 2: Combination of each drug.
Source: Compiled by the Pharmaceutical Industry Research Institute based on review reports and new drugs of tomorrow (drugs containing new active ingredients and drugs with new indications approved by the end of March 2022).

The anti-PD-1 antibody drug nivolumab, which had already been approved for melanoma in 2014, was approved in 2015 for the treatment of non-small cell lung cancer. Subsequently, the anti-PD-1 antibody drug pembrolizumab was approved in 2016, and the anti-PD-L1 antibody drugs atezolizumab and durvalumab were approved for non-small cell lung cancer in 2018.

The trends in treatment satisfaction and drug contribution for "lung cancer" show that while more than 20 drugs had been approved by the 2005 survey, both treatment satisfaction and drug contribution were below 20% and were in the third quadrant of Figure 1 or Figure 3 With the advent of molecular-targeted drugs in the early 2000s In the 2010 survey, treatment satisfaction increased from 19% to 40%, and drug contribution increased from 16% to 56%, moving to the second quadrant; in the 2014 survey, treatment satisfaction was almost unchanged from the previous survey at 37%, but drug contribution increased to 73%, moving to the second and third quadrants from the early 2010s. With the advent of second and third generation EGFR-TKIs since the early 2010s, the introduction of molecular targeted drugs other than EGFR, and the introduction of immune checkpoint inhibitors since 2015, treatment satisfaction improved to 52% in the 2019 survey, and the drug contribution finally reached the first quadrant at 83%.

As mentioned earlier, although more than 20 drugs had been approved by the time of the 2005 survey, both treatment satisfaction and drug contribution were below 20%. I would like to examine in more detail the factors behind the increase in treatment satisfaction and drug contribution from FY2005 to the FY2010 survey.

Increase in Treatment Satisfaction and Drug Contribution in FY2010

Following the discovery that gefitinib was effective in treating EGFR mutation-positive tumors, two randomized controlled trials conducted in Japan (gefitinib vs. chemotherapy: WJOG3045*24 and NEJ002*25 trials) in non-small cell lung cancer patients with EGFR mutation-positive tumors both showed (gefitinib vs. chemotherapy: WJOG3045*24) and NEJ002*25), both trials demonstrated an approximately two-fold increase in progression-free survival (PFS) in patients treated with gefitinib*26.

The PFS of the combination therapy with platinum and chemotherapy, which was the standard of first-line treatment for advanced or recurrent non-small cell lung cancer established in the early 2000s, was approximately 6 months. The number of new drugs approved for non-small cell lung cancer between 2005 and 2009 was not large, consisting of the EGFR-TKI erlotinib, the angiogenesis inhibitor bevacizumab (in combination with other anti-cancer agents), and the folate metabolism antagonist pemetrexed, but the results of clinical trials for gefitinib and bevacizumab, as well as the results of clinical trials for gefitinib, pemetrexed, and bevacizumab, were very promising. The results of clinical trials on gefitinib and erlotinib suggested that physicians' direct clinical experience with gefitinib and erlotinib may have led to increased treatment satisfaction and drug contribution*28.

Although the development and approval of molecular-targeted agents since the 2000s and the development and approval of immune checkpoint inhibitors since the mid-2010s seemed to correlate with increases in treatment satisfaction and drug contribution in lung cancer, how did lung cancer survival rates change? The following chart shows the 5-year relative survival rate for lung cancer according to the National Cancer Center by stage of progression*29 (localized, regional, and distant) ( Fig. 7 ). Although the survival rate declines as the lesion spreads, the survival rate increases with each passing year in all three groups ( Fig. 7, left ). Although the survival rate in the stage of distant metastasis (equivalent to stage IV), where drug therapy is considered to be the mainstay of treatment, is still in the single-digit range, the improvement point*30 in the survival rate after 2003 was greater than that before 2002. It was reported*31 that approximately 50% of adenocarcinomas (one of non-small cell lung cancers), which account for 50-60% of all lung cancers, have EGFR mutations, and it was thought that the advent of molecular targeted drugs called EGFR-TKI and their clinical efficacy may have contributed to the improved survival rate of lung cancer ( Figure 7 right ).

Figure 7: 5-year relative survival rate for lung cancer - by stage of progression

Note 1: The analysis excludes "DCO, second or subsequent cancer, nonmalignant, age unspecified and over 100 years old, or retrospective survey patients.
Note 2: Localized = confined to the primary organ; regional = regional lymph node metastasis (with metastasis to the primary organ's lymph nodes but without invasion of adjacent organs) or adjacent organ invasion (with direct invasion of adjacent organs but without distant metastasis); distant metastasis = metastasis or invasion to distant organs, distant lymph nodes, etc.
Source: National Cancer Incidence Monitoring Tabulation 2009-2011 Survival Report (National Cancer Center, Cancer Control and Information Center, 2020). National Cancer Center, Cancer Research and Development Fund, "Research on Improvement of Accuracy and Utilization of Community Cancer Registries," FY2010 report.
Source: Created by the Pharmaceutical Industry Policy Institute based on cancer survival rate data from the National Cancer Center Cancer Information Service Regional Cancer Registries.

Future Prospects

The second and third paradigms, molecular targeted drugs and immune checkpoint inhibitors, were both indicated for non-small cell lung cancer, but "atezolizumab" and "durvalumab" were approved for advanced small cell lung cancer in combination with chemotherapy from 2019. In addition to combination therapies, a wide variety of drugs are under development, including drug-antibody conjugates (ADCs) that combine a cytotoxic anticancer drug and an antibody with a linker, novel tyrosine kinase inhibitors, and novel antibody therapeutics. These drugs have been confirmed to be highly effective. We expect that the high efficacy of these drugs in development will lead to an increase in the lineup of drug therapies for lung cancer, which will further improve treatment satisfaction and increase the level of "satisfaction" for all stakeholders, including patients.

Conclusion

According to the latest cancer statistics, the probability of being diagnosed with cancer in one's lifetime is 65.0% (1 in 2) for men and 50.2% (1 in 2) for women, and the probability of dying from cancer is 26.7% (1 in 4) for men and 17.9% (1 in 6) for women*18.

It is hoped that the development and approval of new drugs not only for the 60 cancer diseases but also for other cancer diseases in Japan will improve the mortality rate due to cancer, and that the continued development of new drugs for other unmet medical needs will increase the healthy life expectancy of people living in Japan. The development of new drugs for other unmet medical needs is expected to extend the healthy life expectancy of Japanese people.

( Akira Nakao, Senior Researcher, Pharmaceutical and Industrial Policy Research Institute)

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