Introduction

The attention given to rare cancers has increased over the past decade, largely due to: (i) they collectively comprise 20% of cancers, (ii) their mortality rate is higher than that of common cancers, and (iii) proper therapeutic management is not readily available [1, 2]. Despite this increased attention, however, drug development for rare cancers remains insufficient. A major reason for this is that, due to their rarity, the cost of drug development for rare diseases cannot be recovered by the expected sales of the drug under normal market conditions [3].

Health authorities and regulatory agencies have introduced orphan drug designation systems to stimulate research and development (R&D) of drugs for rare diseases, including those for rare cancers in the United States (US) in 1983 and in Japan in 1993 [3]. Orphan drug designation provides pharmaceutical companies with incentives to conduct drug development for rare diseases. In Japan, these incentives include the following: (i) subsidy payment, (ii) extra guidance and consultation on R&D for the drugs, (iii) preferential tax treatment, (iv) priority review by the Pharmaceuticals and Medical Devices Agency (PMDA), and (v) extension of the re-examination period for up to ten years after approval of the drugs [4]. The number of drugs designated as orphan drugs has increased in the US and Japan since the designation systems were first put in place [5].

Drug lag, namely the approval lag of a drug as compared to other countries such as the US, is recognized as a social issue in Japan, in terms that the unavailability of new drugs due to the approval lag negatively impacts the population’s health. An approval lag consists of two types of delay, a submission lag and a review-time lag [6].

Anticancer drugs are prescribed for the treatment of cancer, a life threatening disease. An approval lag for anticancer drugs therefore constitutes a direct threat to life, and has historically attracted substantial attention [7]. While several studies have examined the approval lag and its components for anticancer drugs [7,8,9], we are unaware of any studies which have investigated the lag for orphan anticancer drugs, despite the increasing approval of orphan anticancer drugs in Japan [10].

In this study, we first investigated whether an approval lag for orphan anticancer drugs still exists. Second, we compared the submission lag between orphan and non-orphan anticancer drugs. We also analyzed factors associated with the submission lag for orphan anticancer drugs. We specifically investigated the lag between Japan and the US because the approval lag for anticancer drugs is longer between Japan and the US than that between Japan and the EU [7], and also because a larger number of new molecular entities are approved in the US than in the EU [11].

Materials and methods

Sample identification

This study targeted all anticancer drugs approved in Japan as new active ingredients or as a new indication from April 2004 to November 2017 for systemic therapy to treat malignant tumors. Figure 1 shows the flowchart of sample identification. Of 255 indications of 129 anticancer drugs approved in Japan, the following indications were excluded: (i) indications whose PMDA review reports were not available; (ii) indications that were approved for benign tumors, palliative therapy or supportive therapy, including adjuvant therapy; (iii) indications that were not approved for comparable indications in the US; and (iv) indications whose new drug application (NDA) or biologics license application (BLA) dates in the US were not available. As a result, 142 indications of 84 anticancer drugs were analyzed in this study.

Fig. 1
figure 1

Flowchart of sample identification

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Data collection

Data on anticancer drugs approved in Japan were obtained from lists of approved products, review reports, package inserts, and common technical documents available from the PMDA website. Information related to the review of drugs by the US Food and Drug Administration (FDA) was collected from approval letters, review reports, package inserts, and NDA and BLA approval reports available from the FDA website.

If several indications were approved in one NDA based on different pivotal studies, each indication was treated as a different NDA. The approval lag was calculated by subtracting the approval date in the US from that in Japan. The submission lag was calculated by subtracting the date of the NDA or BLA in the US from the date of the NDA in Japan. We defined review time as the period between the date of the NDA or BLA and approval in the US and between the date of the NDA and approval in Japan. We calculated the review-time lag by subtracting the review time by the FDA from that by the PMDA.

We defined an orphan anticancer drug as an anticancer drug designated as an orphan drug in Japan [4]. If the applicants of a drug were different between Japan and the US, the R&D strategy of the drug was recognized as an external collaboration, in reference to a previous study [12]. Development strategy consisted of four components: bridging strategy, global clinical trial, independent development in Japan, and public knowledge-based application. A bridging strategy is defined as a strategy that extrapolates foreign pivotal studies as the main clinical data in a data package in Japan. A public knowledge-based application is a system in Japan in which a current off-label use drug can be approved without further clinical studies if sufficient evidence for the drug is available and the drug is sufficiently well known [13]. Type of drug consisted of four kinds of drug, namely cytotoxic drug, hormonal drug/ antagonist, molecular targeted drug, and other anticancer drug. We defined a molecular targeted drug as a drug known to target a specific molecule, in reference to a past study [14].

Statistical analysis

Correlations between the approval lag and submission lag or review-time lag for orphan anticancer drugs were identified based on Pearson’s product moment correlation coefficient. The Mann-Whitney U test was used to compare the submission lag and review-time lag between orphan and non-orphan anticancer drugs. We used a multiple regression analysis to identify potential factors associated with a submission lag. Independent variables were selected using backward/forward stepwise selection according to Akaike’s Information Criterion. All statistical analyses were performed using EZR software [15] version 1.36, with α = 0.05 as the statistically significant threshold.

Given that the submission lag is caused by delays in or extended periods of clinical development in Japan [6], we hypothesized that it was potentially affected by the factors “company characteristics”, “R&D strategy”, “drug characteristics”, and “regulatory status in the US.” For company characteristics, we selected “company nationality” as an independent variable because a previous study reported a shorter submission lag in drug development by Japanese companies than non-Japanese companies [12]. Three independent variables were selected for the R&D strategy, namely “external collaboration”, “bridging strategy”, and “global clinical trial”. A previous study demonstrated that an alliance or licensing for drug development has a major impact on the submission lag [12]. A bridging strategy tends to be adopted when there is a time lag in drug development [12], and is associated with a lag in the start of development of anticancer drugs in Japan [9]. In contrast, a global clinical trial is associated with a shorter submission lag [6]. Among drug characteristics, “cytotoxic drug” was used as an independent variable, because these drugs are associated with a greater lag at the start of the development of anticancer drugs in Japan [9]. Furthermore, we speculated that cytotoxic drugs may require longer clinical development in Japan, especially in dose escalation studies, compared to the other types of drugs because of their narrow therapeutic range [14]. For regulatory status in the US, we selected “breakthrough therapy designation by the FDA” and “accelerated approval by the FDA” because these represent FDA programs intended to facilitate and expedite the development of new drugs [16].

Results

Approval lag for orphan anticancer drugs

From April 2004 to November 2017, 84 anticancer drugs were approved for 142 indications, of which 64 indications were for orphan anticancer drugs and 78 were for non-orphan drugs. A list of these 142 indications for 84 anticancer drugs and the factors analyzed in this study is shown in Table S1.

Figure 2 shows the trend in the approval lag for orphan anticancer drugs between 2004 and 2017. The median approval lag in 2016–2017 was 727.0 days (interquartile range, IQR, 310.0–1054.3).

Fig. 2
figure 2

Trend in the approval lag for orphan anticancer drugs between 2004 and 2017. The bold horizontal line in each box shows the median. The line at the upper edge of each box shows the 75th percentile and that at the lower edge shows the 25th percentile. The upper limit of the vertical line is the maximum value within the 75th percentile plus 1.5 times the interquartile range and that at the lower limit is the minimum value within the 25th percentile minus 1.5 times the interquartile range. The plotted points are outliers

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We next investigated correlations between the approval lag and its components, submission lag and review-time lag, for orphan anticancer drugs. Figure 3 presents a scatter plot of the approval lag and submission lag for orphan anticancer drugs. Figure 4 shows a scatter plot of the approval lag and review-time lag for orphan anticancer drugs. The approval lag was significantly correlated with the submission lag (correlation coefficient = 1.00, P < 0.001), but was not correlated with the review-time lag (correlation coefficient = −0.16, P = 0.22). These results suggest that the submission lag is the main component affecting the approval lag for orphan anticancer drugs.

Fig. 3
figure 3

Scatter plot of the approval lag and submission lag for orphan anticancer drugs. The diagonal line indicates the least-squares regression. The box-and-whisker plots on the left and bottom show the distribution of the approval lag and submission lag, respectively

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Fig. 4
figure 4

Scatter plot of the approval lag and review-time lag for orphan anticancer drugs. The diagonal line indicates the least-squares regression. The box-and-whisker plots on the left and bottom show the distribution of the approval lag and review-time lag, respectively

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Comparison of the submission lag between orphan and non-orphan anticancer drugs

Based on our finding that the submission lag is the main component affecting the approval lag for orphan anticancer drugs, we compared the submission lag between orphan and non-orphan anticancer drugs. We also compared the review-time lag between orphan and non-orphan anticancer drugs as a supplemental analysis. Table 1 presents the characteristics of analyzed orphan and non-orphan anticancer drugs. Figure 5 compares the submission lag between orphan and non-orphan anticancer drugs, showing that this lag was significantly longer for orphan anticancer drugs than non-orphan drugs (median, 712.5 days [IQR, 186.0–1448.3] vs. 387.0 days [92.8–1096.0], P = 0.023). In contrast, the review-time lag was significantly shorter for orphan anticancer drugs than non-orphan drugs (median, 107.0 days [IQR, 36.0–152.0] vs. 157.5 days [61.5–215.5], P = 0.018).

Table 1 Summary of the analyzed anticancer drugs
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Fig. 5
figure 5

Comparison of the submission lag between orphan and non-orphan anticancer drugs. The bold horizontal line in each box shows the median. The line at the upper edge of each box shows the 75th percentile and that at the lower edge shows the 25th percentile. The upper limit of the vertical line is the maximum value within the 75th percentile plus 1.5 times the interquartile range and that at the lower limit is the minimum value within the 25th percentile minus 1.5 times the interquartile range. The plotted points are outliers

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Factors associated with the submission lag of orphan anticancer drugs

To investigate the longer submission lag of orphan anticancer drugs in more detail, we performed multiple regression analysis to identify factors associated with this lag. Table 2 shows the independent variables used to analyze orphan anticancer drugs. We observed a longer submission lag for external collaboration as R&D strategy than for non-external collaboration. In contrast, we saw a shorter lag for global clinical trial as development strategy than bridging strategy. Cytotoxic drugs had a longer submission lag than the other types of drug, including molecular targeted drugs. Orphan anticancer drugs designated as breakthrough therapy by the FDA had a shorter submission lag than drugs without breakthrough therapy designation, whereas accelerated approval did not appear to affect the submission lag.

Table 2 Independent variables for orphan anticancer drugs
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Table 3 presents factors associated with the submission lag for orphan anticancer drugs. External collaboration was significantly associated with a longer submission lag (coefficient = 762.1, P = 0.017), while breakthrough therapy designation by the FDA was significantly associated with a shorter submission lag (coefficient = −832.8, P = 0.035).

Table 3 Factors associated with the submission lag for orphan anticancer drugs
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To explore factors affecting relationships between submission lag and breakthrough therapy designation or accelerated approval, we conducted a supplemental analysis of development status in Japan at approval in the US of orphan anticancer drugs with or without breakthrough therapy designation and accelerated approval. As shown in Table 4, the percentage of orphan anticancer drugs with breakthrough therapy designation whose clinical development was started in Japan before approval in the US was higher than that of drugs without breakthrough therapy designation (91.7% vs. 55.8%). On the other hand, the percentage of orphan anticancer drugs with accelerated approval whose clinical development was started in Japan before approval in the US was almost the same as that of drugs without accelerated approval (61.3% vs. 63.6%).

Table 4 Development status in Japan at approval in the US of orphan anticancer drugs with or without breakthrough therapy designation and accelerated approval
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Discussion

We demonstrated that submission lag is the main component affecting the approval lag for orphan anticancer drugs in Japan. Given that the submission lag is longer for orphan anticancer drugs than non-orphan drugs, we consider that the submission lag for orphan anticancer drugs can potentially be reduced. In contrast, the review-time lag was shorter for orphan anticancer drugs than non-orphan drugs. This is likely due to an incentive associated with orphan drug designation, namely priority review by the PMDA. All drugs designated as orphan drugs in Japan are reviewed under priority review: the target period is nine months, compared to the 12 months for normal review [17].

We identified two factors associated with the submission lag between Japan and the US for orphan anticancer drugs, “external collaboration” and “breakthrough therapy designation by the FDA”. We speculate that this longer submission lag in Japan may be affected by cases of external collaboration in the development of an orphan anticancer drug that starts long after the approval of the drug in the US. For example, pralatrexate, an orphan anticancer drug approved in July 2017 in Japan for the treatment of patients with relapsed or refractory peripheral T-cell lymphoma, had a long submission lag (2716 days). The applicant for the drug was Mundipharma K.K. in Japan and Allos Therapeutics, Inc. in the US. At the time of approval in the US in September 2009, development in Japan had not started. Mundipharma started clinical development in Japan after the execution of a license agreement with Allos Therapeutics in 2011 and filed the NDA in August 2016 in Japan [18,19,20]. Nevertheless, we consider that this type of external collaboration is necessary to resolve the existence of drugs or indications that are not approved in Japan but are approved in other countries. We also speculate that external collaboration might require more time for drug development than in-house development because (i) due diligence and deal negotiations are required before the start of external collaboration [12, 21] and (ii) all parties are required to reach consensus on decisions made during drug development. The submission lag may be reduced by establishing a skilled business development and alliance management team for efficient due diligence, deal negotiation, and alliance management. Flexible deal design to mitigate conflicts and realize a win-win philosophy may also be important in reducing the submission lag. Assuming that external collaboration will continue to play a major role in the pharmaceutical industry, these improvements for external collaboration are expected to reduce the submission lag for orphan anticancer drugs.

The breakthrough therapy designation is intended to expedite the development and review of drugs for serious or life-threatening conditions. The criteria for breakthrough therapy designation require preliminary clinical evidence demonstrating that the drug may substantially improve at least one clinically significant endpoint over available therapies. The FDA generally expects evidence derived from phase I or II studies [16]. It is acknowledged that one of the factors affecting submission lag is a lag in starting clinical development in Japan [9]. According to our analysis, the clinical development of almost all orphan anticancer drugs with breakthrough therapy designation in Japan is started before approval in the US, and their percentage is higher than that of drugs without breakthrough therapy designation. This might underlie an association between breakthrough therapy designation and a shorter submission lag. A previous study targeting general anticancer drugs supports our findings: the median difference in development start date between the US and Japan for anticancer drugs with breakthrough therapy designation was significantly shorter than that without breakthrough therapy designation [22].

Accelerated approval is a program started by the FDA to promote drug development for highly serious indications. This program allows the use of surrogate endpoints to evaluate drug efficacy [16]. Our analysis indicates that, unlike the case of breakthrough therapy designation, there is no clear difference in development status in Japan between orphan anticancer drugs with and without accelerated approval at the time of approval in the US. This might therefore underlie the lack of an association between accelerated approval and a shorter submission lag.

There are some limitations associated with this study. We only evaluated drugs that were successfully approved in both Japan and the US. Inclusion of drugs whose development failed or is ongoing in one country might have resulted in longer or shorter approval lag and submission lag, depending on the country where the drug development failed or the approval is delayed. Despite this exclusion of drugs with failed or ongoing development, however, we are confident that the data we analyzed were sufficient to achieve the purpose of this study.

In conclusion, we revealed that an approval lag for orphan anticancer drugs still existed in 2016–2017. Of the two components of approval lag for orphan anticancer drugs, submission lag was the main determinant, and was longer than that for non-orphan drugs. External collaboration in drug development was associated with a longer submission lag, while breakthrough therapy designation in the US was associated with a shorter submission lag. External collaboration in drug development may be a potential factor in reducing the submission lag for orphan anticancer drugs.