The Pharmaceutical Industry at a Glance A Study on Drug Lag of Biopharmaceuticals

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Naoto Murakami, Senior Researcher, National Institute of Biomedical Innovation Policy

Introduction

Biopharmaceuticals, unlike small molecule drugs that can be produced by chemical synthesis, are drugs made from bioengineered proteins and biologically-derived substances, etc. Recently, biopharmaceuticals have been used to treat cancer, immune disorders, and rare diseases that are difficult to treat with conventional small molecule drugs. According to Akaha of the National Institute of Biomedical Innovation (NIBIO), the commercialization of biopharmaceuticals began in the 1980s and the number of products has gradually increased, but their share of ethical drug sales was only about 10% in 2000. The share of biopharmaceuticals in sales in 2016 was about ^32%1).

The share of biopharmaceuticals in the top 100 ethical drugs in the world in 2018 was 41 items with a total sales of 49. ^5%2), indicating that the medical value of biopharmaceuticals is widely available to patients around the world. However, only two of these 41 products were created by Japanese pharmaceutical companies, and when compared to the 8 products created by Japanese companies out of 59 small molecule drugs, it must be said that we are currently lagging far behind the rest of the world. Tanaka attributes this lag to the fact that Japanese pharmaceutical companies have lagged behind their European and U.S. counterparts in shifting R&D from small molecule drugs to biopharmaceuticals, coupled with a strong sense of risk regarding the large investment of resources required for the introduction of new technologies and infrastructure development needed to enter the biopharmaceutical field. ^3).

If the resulting increase in the ratio of pharmaceuticals created by foreign companies has led to a so-called drug lag in access to biopharmaceuticals for patients in Japan compared to major overseas countries, this could be detrimental to the maintenance of the health of the Japanese people, and must be minimized.

With regard to drug lag, the Pharmaceuticals and Medical Devices Agency (PMDA) has published the results of drug lag estimates for all drugs containing new active ingredients approved in a given fiscal year every year since fiscal ²⁰⁰⁶⁴⁾. Drug lag is defined here as the sum of the difference in timing of application and the time required for approval review compared to the U.S. In FY 2006, the drug lag was 2.4 years, but in FY 2018, the drug lag was reduced to 0.9 years. It should be noted that this result does not take into account the difference in the timing of the start of development and the time taken to file an application after the start of development.

Tsuji compared the approval status of all new active ingredient-containing drugs in the US, EU, and Japan, and calculated the absolute drug lag as the ratio of the number of products approved in each region to the total number of products approved in any region between 1999 and 2007, and the relative drug lag as the difference between the date of launch in the region and the date of first global launch, based on the date of first global launch in the region. The difference between the date of first launch in the world and the date of launch in the region is analyzed as relative drag ^lag5). The study examines the potential impact of factors such as the country of origin, medical needs (clinical importance), status of the company developing or submitting the application, indications, drug characteristics, and the number of patients treated and marketability on the relative drag lag. The main factor, however, is the delay in the start of development.

In this study, focusing on biopharmaceuticals, we investigated and analyzed the relative drug lag of biopharmaceuticals containing new active ingredients approved in Japan, based on the market launch status in Japan, the US, and Europe, and examined their current status. In addition, some factors that may influence the relative drug lag are discussed. In the following description, relative drug lag will be referred to as drag lag unless otherwise noted.

Survey Method

The drug databases EvaluatePharma (EvPh) and "Tomorrow's New Drugs" were used. The first launch dates in the three regions (for Europe, the earlier launch date among the target countries) were surveyed for drugs containing new active ingredients classified as biotechnology that have been launched in Japan, the U.S., and Europe (EvPh; survey conducted on April 10, 2020).

For products launched in Japan, we also obtained the patent expiration date, including the patent extension period for the exclusive marketing period for the indication at the time of approval, from the San-Ei Report, "Reexamination Period and Pharmaceutical Patent Term Extension (Medical Use) by Single Product" (April 2019 edition).

Biopharmaceuticals Launched in Japan, the U.S., and Europe

Of the biopharmaceutical products (excluding vaccines) marketed in Japan, the U.S., or Europe, 165 products had a market launch date that could be confirmed. Of the 138 products, 59 were antibody drugs and 79 were other biopharmaceuticals, of which 6 and 4 were created by Japanese pharmaceutical companies headquartered in Japan, respectively (Figure 1). Of the 138 products, 133 were launched in Japan, the U.S., and Europe.

It should be noted that 27 of the products that have already been launched overseas but have not yet been launched in Japan are expected to be launched in Japan in the future, which may prolong the relative drug-lag situation in each overseas launch year, as described below. Of the 27 products, 1 was launched before 1999, 2 in 2004, 0 in 2009, 4 in 2014, and 20 in 2015 or later. Of the 20 products, 15 are in Phase 3 trials or have already been filed in Japan, so future trends should be closely monitored.

Biopharmaceuticals marketed in Japan

According to the list of "Biopharmaceuticals approved in Japan (excluding follow-on biologics and combination products)" published by the National Institute of Health Sciences (compiled on May 1, 2020) ⁶⁾, there are 19 enzyme products, 19 blood coagulation system-related factor products, 1 serum protein product, 25 hormone products, and 8 interferon products, Interferon products: 8, erythropoietin products: 4, cytokine products: 7, antibody products: 62, fusion protein products: 5, a total of 150 products are approved in Japan. Among the 133 products extracted from the EvPh database, 9 products were excluded because it was unclear whether or not the product was marketed for the indication at the time of approval.

Figure 2 shows the number of these 124 products by year of launch in Japan, and it can be seen that the number of products launched has been gradually increasing since the early 2000s.

Drug Lag of Biopharmaceuticals in Japan

For each of the 124 biopharmaceutical products surveyed, the earlier of the first launch date in the U.S. or Europe was used as the overseas first launch date, and a comparison was made with the launch year in Japan using a scatterplot (Figure 3).

The comparison by year shows that 4 of the 124 biopharmaceuticals were launched in Japan earlier than the year of the first overseas launch and 12 were launched in Japan in the same year, but most of the dots indicating individual products are located under the auxiliary line indicating the same launch year, indicating that the majority of biotech products launched in Japan had drag-lag. The same data are available for several products with the same value. Note that there are several products with the same data value, and therefore the points overlap.

In order to visually grasp the drag lag of each product, we plotted the drag lag in years by the year of its launch in Japan (Figure 4), However, when we look at the median drag lag since 2010, it appears that the drag lag has been shrinking, although there are variations among individual products.

Since most of the variation in drag lag is due to products that have been on the market for more than 7 years, and since around 2013, many new products with a drag lag of 0 to 2.5 years have been launched overseas, it is presumed that the drag lag of products with a newer overseas launch year has been shorter than that of older products. Therefore, it was presumed that the drag lag of products with a newer overseas initial launch year was shorter than that of older products. Therefore, we decided to check the transition of drag lag for each product from the perspective of the year of first overseas market launch.

The results are shown in Figure 5 as a scatterplot together with an approximate linear approximation curve for the period up to 2009, when the impact of new domestic launches of products not yet launched in Japan was limited. ⁷⁾. 7) The drug lags of products launched in 2010 or later are also shown for reference. Of all the products, seven were launched earlier in Japan than in the U.S. and Europe, and one was launched on the same day. The filled dots in Figure 5 indicate products created by Japanese companies, and although not all of these products were launched in Japan for the first time, the overall drag lag is small.

Orphan Drugs and Drug Lag

Factors that may affect the relative drug lag include the country of origin of the drug, the medical need (clinical importance), the status of the company developing the drug, the number of patients to be treated, and the marketability of the drug. The status of drug lag was examined for drugs for rare diseases.

Of the 124 products covered in this survey, 46 or more than one-third were approved as orphan drugs in Japan (seven of these products were developed and filed as "unapproved drugs " ⁸ before being put on the market). The relationship between the first overseas launch date and drug lag in Japan for each of these products is shown in the upper panel of Figure 6 as a scatter diagram, and the same is shown in the lower panel of Figure 6 for products other than orphan drugs. Although a large number of orphan drugs appear to have been launched in Japan with a drug lag of more than 10 years despite the small number of target products, their first overseas launch dates are limited to before the early 2000s, and at the time of this study, all but one product had a drug lag of more than five years since 2002. In contrast, the number of products launched outside Japan is limited to those launched before the beginning of the 2000s. In contrast, the number of products launched with a drug lag longer than five years in the non-rare disease drug group was slightly larger than that of the rare disease drug group since the early 2000s. However, there was no clear difference in drug lag between orphan drugs and non-orphan drugs during this period.

Other Factors That May Influence Biopharmaceutical Drug Lag

As Tsuji states, the difference in development start dates is an important component of drug ^lag5), but it is not easy to identify the development start date. In this study, we conducted a search using the primary database on approved items based on a questionnaire survey of companies conducted by the National Institute for Policy Studies and the commercial databases on development pipelines and approved drugs, including EvPh, but it was difficult to obtain a comprehensive list of development start dates corresponding to first launch dates, especially in Europe and the United States.

In order to decide to start new drug development in a given region, companies consider business feasibility from multiple perspectives, including development, manufacturing, marketing, and finance. One of the most important indicators is the timing of investment payback and profitability after payback, and the expected period of exclusivity in the region is an essential piece of information for sales forecasting. Based on the report that the patent term, including extensions, defines the exclusivity period for nearly 90% of new ^drugs9), we examined the relationship between the remaining patent term and drug lag at the time of the first overseas market launch and the start of clinical development in Japan. The date of clinical development initiation was defined as the date of initial clinical trial plan notification, but if the date could not be confirmed, the date of Phase I study start was used as a substitute.

Of the 124 products covered by the survey, a scatterplot was conducted for 91 products for which patent expiration date data were available to examine the relationship between the period from the date of first overseas launch to the domestic patent expiration date and drug lag.

Furthermore, for the 76 products for which data on the date of clinical development initiation were also available, a scatterplot analysis of the relationship between the period from the date of initial clinical trial plan notification to the patent expiration date (remaining patent term) and drug lag (Figure 7) revealed no clear correlation between the remaining patent term at the time of development initiation and drug lag. On the other hand, the majority of biopharmaceuticals had patent durations of 10 years or more at the start of development, with 87% of products having patent durations of 14 years or more. It is interesting to note that this may suggest that one of the indicators used in deciding whether to start development of a new drug in Japan is the expected period of exclusivity, taking into account the expected period until approval at the time clinical trials are initiated.

Conclusion

The study examined the approval and launch trends in Japan, the U.S., and Europe for biopharmaceuticals that have a growing presence as therapeutic agents, particularly for oncology and immune system diseases, and the relative drug lag status and factors contributing to drug lag in Japan.

Of the biopharmaceuticals launched in one of the regions identified by EvPh, approximately 80% were launched in Japan. Because the majority of these biopharmaceuticals were developed by foreign companies, relative drug lag was observed in more than 85% of the products. From the late 1980s to the mid-2000s, when biopharmaceuticals were first launched in the world, many products were launched in Japan with a drag lag of more than five years, but at the time of this study, products with a drag lag of more than five years were rare, suggesting a trend toward improved patient access to biopharmaceuticals. This is a point that has been made by the Japanese government to promote the true improvement of Japanese medical care. We view this as a very important change for the improvement of true medical care in Japan. Although it is not easy to identify the reason for this, it was speculated that the successive issuance of various regulations based on the ICH (International Conference on Harmonization of Technical Requirements for Medicinal Products) agreement around 2000, such as guidelines on specifications and test methods for biopharmaceuticals, may be one factor.

Tsuji reported that the main cause of drug lag in drugs created and developed by foreign companies in Japan is the delay in the start of clinical ^{development5)}. 5 ⁾ Kudo et al. reported that there is a positive relationship between drug lag and the probability of success in clinical trials until drug approval in Japan, suggesting that drug lag may be a rational choice for ^companies10). In other words, the drag lag may be the result of a rational decision-making process in terms of development strategy or management strategy, whereby a company decides to develop a new drug in Europe, the U.S., or other overseas regions ahead of the competition, and then begins clinical development in Japan when the business feasibility of the new drug development has been determined, assuming a certain level of acceptable risk-taking. The results suggest that the drag lag is the result of a rational decision-making process in terms of development strategy or business strategy.

In this study, we examined the relationship between the relative drag lag and the remaining patent term at the start of clinical development in Japan, which can be used as an indicator of such strategic decisions. However, nearly 90% of the products had a remaining patent term of more than 14 years at the start of clinical development. Since the period from the start of clinical development to the market launch of a product varies from 4 to 8 years depending on the target therapeutic area and drug ^{characteristics11)}, the majority of products were expected to have at least 6 to 10 years of patent-based exclusivity after the market launch at the start of clinical trials. From a different perspective, one realizes that failure to meet this requirement at the time of making a business feasibility determination suggests the possibility of leading to a so-called absolute drug lag, in which patient access to a new drug is cut off.

One of the reasons why the relative drug lag has been shortening since the late 2000s was pointed out in the previous section as the development of the ICH guidelines, but changes in the regulatory system such as the extension of the reexamination period in 2007 and the additional payment for promotion of new drug creation and resolution of off-label drug use in 2010 also occurred during this period, which may have contributed to the decision to start domestic clinical development of biopharmaceuticals. It is undeniable that these changes may have influenced the decision to initiate clinical development of biopharmaceuticals in Japan. In particular, the reexamination period defines the minimum period of substantial exclusivity under the current system, and an extension of the reexamination period is expected to improve the absolute drug lag.

Acknowledgments

In this study, we obtained the cooperation of voluntary members of the Intellectual Property Committee of the Japan Pharmaceutical Manufacturers Association (JPMA) for the survey on patent expiration dates for the exclusive marketing period of the indications at the time of approval in Japan for the subject biopharmaceuticals. We would like to express our deep appreciation for their cooperation.

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