The Pharmaceutical Industry at a Glance Changes in FDA Approval Trends for Antineoplastic and Neurological Drugs: Background to the Increase in Unapproved Drugs in Japan

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Shinichiro Iida, Senior Researcher, Pharmaceuticals and Industrial Policy Research Institute
Tomoyuki Shibuguchi, Former Senior Researcher, Pharmaceuticals and Industrial Policy Research Institute
Masao Yoshida, Senior Researcher, Pharmaceuticals and Industrial Policy Research Institute

1. Introduction

The number of unapproved drugs in Japan in the late 2010s for anti-cancer and neurological agents has been increasing as reported in Policy Research Institute News No. 63 (July 2021) ^{1) and a} survey by the National Cancer ^Center2), and the reality is that many of these products are from emerging biopharmaceutical companies without Japanese corporations or domestic managers, It has been suggested that development has not been initiated in Japan.

In order to track the background of the increase in unapproved drugs in the late 2010s, this paper focuses on FDA-approved drugs (new active ingredients) for anti-cancer and neurological agents from 2011 to 2020, and surveys and analyzes the trends of FDA applicant companies and pivotal trials.

2. research methods

Unapproved drugs in Japan were identified in the same way as in Policy Research Institute News No. 63 (July 2021) ¹⁾. The FDA-approved drugs (2011-2020) analyzed in this report include 104 anti-cancer drugs and 32 neurological drugs in the disease areas with a large number of unapproved drugs. ³ FDA-approved drugs (New Molecular Entity; NME) were aggregated by the Center for Drugs (excluding diagnostics) listed in the Center for Drug Evaluating Research's (CDER) "New Molecular Entity (NME) Drugs & Original BLA Calendar Year Approvals" were included. Comparisons were made for the first half of the 2010s (2011-2015) and the second half (2016-2020). Pivotal studies at the time of FDA approval were conducted.

Pivotal trials at the time of FDA approval were identified from the clinical section of Prescribing Information, and clinical trial information, including the countries participating in the trials, was obtained from ClinicalTrials. ^{gov5, 6)}.

For company classification, the year of establishment of the company was investigated by Evaluate Pharma, and start-ups were defined as those established after 1990. Non-emerging firms were classified as pharmaceutical firms. The domestic development trends of emerging companies are reviewed in Tomorrow's New Drugs.

Results

FDA Approval Trends for Antineoplastic Agents

In the latter half of the 2010s, the number of drugs approved by the FDA and changes in the number of companies that applied for approval were ^{reported1, 7)}. In order to confirm the trend of approved anti-cancer drugs, changes from the previous period (2011-2015) to the latter period (2016-2020) were investigated (Table 1). In particular, we analyzed the major clinical trials that provide the basis for FDA approval and evaluate efficacy and safety: pivotal trials.

Figure 1 shows a breakdown of the companies that submitted applications for anti-cancer drugs and the clinical trial phases of pivotal trials. In the first semester, of the 44 total approved products, 32 (73%) were from pharmaceutical companies and 8 (18%) were from startup companies. In the second half of the year, 35 (58%) were from pharmaceutical companies and 25 (42%) from start-ups. While the number of pharmaceutical companies increased slightly, the number of start-ups more than tripled, accounting for 40% of the items in the second half of the year. In the area of anti-cancer drugs as well, emerging companies made a significant contribution, contributing to the increase in the number of approvals.

Pivotal studies were broken down into 26 (59%), the largest number of Phase 3 studies in the first semester, and 3 (7%), including a small number of Phase 1/2 and Phase 1 studies. In the second half of the year, Phase 3 declined to 22 items (37%), while Phase 1/2 and Phase 1 increased significantly to 18 items, accounting for 30% of the total.

Among startups, the proportion of Phase 1/2 and Phase 1 (36%) was higher, and the number of products in Phase 2 and below increased significantly from 5 to 17 (68%).

For pharmaceutical companies as well, while the total number of products remained unchanged, the number of products in Phase 2 and below increased from 13 to 21 (60%), indicating that pivotal trials are becoming earlier and earlier.

In the FDA-approved anti-tumor drugs, the emergence of new companies and the early development of pivotal trials were evident.

The number of patients enrolled in the earlier and later phases of pivotal trials was compared (Figure 2).

The median number of patients enrolled in the first phase was 472.0 patients, while in the second phase, 330.5 patients, a reduction of about 30%, was observed. 300 or fewer patients were enrolled in 27 drugs (45.0%), up from 13 drugs (29.5%), doubling the number of drugs and increasing the ratio to nearly one half in the second phase. FDA-approved items for antineoplastic agents showed an increase in smaller pivotal trials.

In order to find out the background of the earlier and smaller pivotal trials, items of personalized medicine for approved drugs were identified.

Genome analysis of cancer has progressed, and many molecular-targeted drugs have been developed as a result of the elucidation of cancer-causing gene mutations. After diagnosing driver mutation genes, treatment with drugs specific to the target (so-called personalized medicine) has come to contribute. Looking at the change in the number of personalized medicine items between the first and second terms (Figure 3), the number of items was 14 (32%) in the first term, but in the second term, the number of items was 26 (43%), slightly doubling, and the ratio increased.

Looking at the relationship with early clinical trial phases (Phase 1/2 or Phase 1) of pivotal trials, the number of items was not particularly high/the percentage was not particularly high for personalized medicine items.

Looking at the Orphan Drug-designated items, since the development of anti-cancer drugs for rare cancers and rare segments is expected to increase, the number of items increased from 33 (75%) in the previous period to 45 (75%) in the latter period (Table 1), although the percentage did not change. In the area of antineoplastic agents, we observed the rise of emerging companies and an increase in the number and percentage of items in the early clinical trial phase over Phase 2 in the approved items. It was inferred that this was due to the fact that the science is advancing, and high efficacy is being verified even on a small scale.

FDA Approval Trends for Neurological Drugs

FDA-approved drugs for the nervous system were similarly categorized by 2011-2015 (early phase) and 2016-2020 (late phase), and their characteristics were compared (Table 2, Fig. 4). The number of drugs for the nervous system increased in the second half of the period, from 12 in the first half to 30 in the second half. While the number of approved drugs remained unchanged from 9 to 10 for pharmaceutical companies, there was a marked increase from 3 to 20 for startup companies. The increase in all approved products was due to an increase in the number of products by startups.

There was also a change in the number of pivotal trials, from 10 (83%) in the first half to 18 (60%) in the second half. While there was an increase in the number of items in international trials, the ratio of international trials decreased due to an increase in single-country trials. In addition, none of the neurological agents had Phase 1/2 as a pivotal trial.

4. summary and discussion

In pursuing the factors of drugs not approved in Japan, the FDA-approved drugs were identified as the overseas approval trend.

In the area of anti-cancer drugs, an increase in the number of items was observed in the latter half of the period (2016-2020). While the number of items by pharmaceutical companies remained flat, there was a marked increase in the number of items by startups.

As for pivotal trials, an increase in the number of early phase pivotal trials, a downsizing of trial size, and an increase in personalized medicine products were observed.

In the field of cancer drug therapy, progress has been made in cancer genome analysis, which has led to the elucidation of cancer-causing genetic mutations and the development of a number of drugs to treat these mutations. The practical application of these drugs was confirmed to be in full swing in the 2010s. Intervention with targeted molecular agents according to individual gene mutations is considered to have been verified to be useful even on a small trial scale. In personalized medicine, targeted molecular drug intervention is performed from a heterogeneous cancer population to a scientifically uniform population based on genetic mutation and other diagnoses. Therefore, the probability of observing high efficacy is considered to be increased and validation in small and early clinical trial phases is considered to be possible.

The same phenomenon as that of personalized medicine was also observed in the case of non-personalized medicine items, since most of them are so-called molecular-targeted drugs that target molecules that cause or characterize the target cancer. It can be inferred that the progress of science and technology has contributed significantly to the background of changes in the characteristics of pivotal trials of approved items and their bearers.

Although we have not been able to analyze the factors behind the recent remarkable success of startup companies, the fact that the burden of financing is also decreasing in the field of oncology, as verification in the early clinical phase is now possible, is probably a contributing factor.

In both the anti-cancer and neurology areas, there was a marked increase in the number of products from startups in the latter half of the year. Emerging companies do not have abundant R&D funds and ^{resources7,8)} and are unlikely to have all the capabilities of drug development. Although we have not yet been able to investigate what is behind the increase in the number of products from startups, several changes in the environment can be inferred. The increase in the scale of investment in the healthcare sector by U.S. investors may be enabling startups to secure R&D funds. In the area of drug development, the outsourcing of clinical trial operations and manufacturing of investigational drugs and products is also expanding the scope of activities of startups. As seen in the personalized medicine of anti-cancer drugs, the target diseases and segments are becoming more segmented, and the value chain of basic research, clinical development, and commercialization is shifting to so-called specialty areas, areas that can be completed on a small scale by specializing in a specialty. Further analysis of the background to the change will be necessary.

In order to reduce the number of unapproved drugs in Japan, it was suggested that not only should pharmaceutical companies promote international joint clinical trials, but also allowances should be made for items from emerging companies. In order to maintain and ensure access to the latest drugs in Japan, we hope that the policy will evolve in response to changes in overseas trends.

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