2025 Volume 48 Issue 8 Pages 1255-1259
Cancer is an age-related disease that affects one in two Japanese individuals, placing a significant burden on both patients and caregivers due to its clinical characteristics, high treatment costs, and associated adverse events (AEs). Consequently, cancer treatment remains a major public concern. In recent years, patient-centered medical care has gained increasing attention and is strongly desired in cancer treatment. Companion diagnostics (CDx) are expected to facilitate personalized treatment; however, their current status remains unclear. In this study, we evaluated the role of CDx in anticancer drug treatment based on data available at the time of drug approval. Our analysis revealed that the benefit–risk ratio, defined as the objective response rate of an anticancer drug divided by the incidence of severe AEs, was significantly higher for anticancer drugs requiring CDx (wCDx) in Japanese patients (1.54-fold, p < 0.0135) than for anticancer drugs not requiring CDx. Although the objective response rate did not differ between the 2 groups, the incidence of severe AEs was lower in the wCDx group. These findings suggest that CDx helps identify patients who are better suited for specific anticancer treatments and/or that active pharmaceutical ingredients in wCDx therapies carry a lower risk of severe AEs. To further promote patient-centered medical care, the active development of CDx alongside new anticancer drugs should be encouraged, despite the higher development hurdles, through regulatory support, particularly since drug pricing does not differ between the 2 groups.
Cancer is an age-related disease. In Japan, where the population is aging, one in two individuals will develop some form of cancer in their lifetime, making it the leading cause of death.1,2) Consequently, cancer represents a major public health concern. The landscape of anticancer drug treatment has evolved significantly with the discovery of new molecular mechanisms and the development of novel treatment modalities, contributing to more diverse therapeutic options. Additionally, cancer treatment policies have led to an increase in the number of patients receiving outpatient care.3)
Due to the inherent nature of the disease, no anticancer drug is 100% effective, and a certain degree of adverse events (AEs) is generally tolerated. Moreover, in cases where no standard treatment options are available, off-label use of anticancer drugs is common.4) As a result, the occurrence of serious AEs is often considered inevitable. Notably, AEs associated with anticancer drugs are, in principle, excluded from the Pharmaceutical and Medical Devices Agency (PMDA) Adverse Drug Reaction Relief System, underscoring the critical role of preventive measures by healthcare professionals, including pharmacists, in mitigating risks.5)
In the United States (U.S.), the Precision Medicine Initiative, introduced in the 2015 State of the Union address, heightened awareness of patient-centered medicine.6) Similarly, in Japan, the Third Basic Plan for Promoting Cancer Control (approved by the Cabinet on March 9, 2018) identifies “realizing patient-centered cancer care” as a key objective.7) This policy reflects a shift from conventional drug therapy targeting the general patient population to a more personalized approach, aiming to optimize treatment efficacy and safety while ensuring the efficient use of medical resources.
Companion diagnostics (CDx) play a pivotal role in advancing patient-centered medicine. Both Japanese and U.S. regulatory authorities define CDx as in vitro diagnostics or medical devices used to identify patients for whom a specific drug is expected to be effective and safe, based on biomarker analysis. Thus, CDx is an essential component of personalized therapy. In recent years, CDx has been integrated into the treatment of certain cancers to facilitate appropriate patient selection and drug administration. The use of CDx in anticancer drug treatment does not differ between Japan and the U.S. Therefore, if the same anticancer drugs are approved in both countries, the approval status of CDx is also expected to be similar. However, drug approvals are based on independent benefit–risk assessments in each country, and regulatory decisions do not always align due to factors, such as ethnic differences, national policies, and other region-specific considerations. Indeed, Saito and Narukawa have highlighted regulatory differences between Japan and the U.S. in the approval process for CDx.8)
For companies developing anticancer drugs and CDx, business optimization is essential to recover development investments, enhance profitability, and secure funding for future innovations. Typically, this is achieved through high drug pricing, targeting a broad patient population, and ensuring sustained prescription duration post-launch. Concurrently, development strategies aimed at cost reduction include conducting smaller-scale clinical trials, leveraging early-phase clinical data for regulatory submissions, and limiting development regions. Moreover, CDx development frequently requires collaboration between pharmaceutical companies and medical device/diagnostic drug manufacturers, adding complexity and increasing development hurdles.
As patient-centered medicine gains traction in cancer treatment, the role of CDx is receiving increasing attention. While considerable information is available regarding the development of anticancer drugs that do not require CDx,9–11) there is limited information on the development of those that do. To address this gap, we examined the status of CDx utilization in anticancer drug treatment in Japan based on approval decision-making data from regulatory applications.
Information on CDx in Japan was obtained from the PMDA website (September 19, 2024 edition).12) The approval dates of individual CDx were identified using the PMDA in vitro diagnostics/medical devices information search. Anticancer drugs requiring the use of CDx (wCDx) were identified from this list, and relevant information was retrieved using the PMDA prescription drugs information search.13) Additionally, anticancer drugs approved between January 2013 and September 2024 that do not require CDx (woCDx) were similarly identified. In the U.S., information on CDx was obtained from the U.S. Food and Drug Administration (FDA) List of Cleared or Approved Companion Diagnostic Devices (In Vitro and Imaging Tools) (accessed October 22, 2024).14) The Drug@FDA search was used to classify anticancer drugs into wCDx and woCDx categories.15)
Daily Drug Prices for Anticancer DrugsDrug price information was obtained from the Drug Price List and Calculated Drug Prices for New Drugs published by the Ministry of Health, Labour and Welfare (MHLW), Japan. Daily drug prices were calculated based on the approved indications and standard dosing regimens. When dose calculations were based on body surface area (BSA), a standard BSA of 1.68 m2 was used for adults, while a BSA of 1.0 m2 was used for a 10-year-old child.16) For wCDx drugs, the approval dates of each indication and the corresponding CDx were examined. The drug price was calculated based on the later approval date; if multiple CDx were approved for the same drug, the earliest CDx approval date was used. Daily drug prices were averaged for each active pharmaceutical ingredient (API) and indication. Drugs for which daily prices could not be determined, as well as those requiring combination therapy with 2 or more drugs, were excluded from the analysis.
Benefit and Risk of Anticancer DrugsThe clinical benefit and risk of anticancer drugs were evaluated using approval review reports, interview forms, and package inserts. Clinical trial results included in approval evaluation documents were extracted, and the objective response rate (ORR) was defined as the measure of benefit (B). The incidence of Grade 3 or higher AEs (≥G3AE), classified according to Common Terminology Criteria for Adverse Events versions 3.0–5.0, was used as the measure of risk (R). If multiple ORR and ≥G3AE values were available for a given API or indication, the average values were calculated. The B/R ratio was determined as B divided by R.
Statistical AnalysesThe approval status of CDx and wCDx in Japan and the U.S. was compared, and the differences in proportions were calculated along with 95% confidence intervals (CIs). The average daily drug price, B, R, and B/R values of anticancer drugs were compared between the wCDx and woCDx groups using Student’s t-test, Welch’s t-test, or the Mann–Whitney U-test, as appropriate. All statistical analyses were conducted using EZR version 1.68 (R 4.2.1, Jichi Medical University Saitama Medical Center, Saitama, Japan),17) with the significance level set at 5%.
Table 1 summarizes the comparison of CDx requirements for anticancer drugs in Japan and the U.S. The number of approved CDx products for anticancer drugs was 45 (corresponding to 42 APIs) in Japan and 51 (corresponding to 63 APIs) in the U.S. Some CDx products were used in combination anticancer drug therapies; however, individual APIs were counted separately to avoid duplication. A total of 37 APIs required CDx in both countries. Discrepancies were observed for 3 APIs in Japan and 10 APIs in the U.S. Additionally, 2 APIs in Japan and 16 APIs in the U.S. were not comparable due to their unapproved status in the other country. Excluding anticancer drugs with undetermined CDx requirements, the proportion of discrepancies in CDx requirements was 7.5% in Japan and 21.2% in the U.S. The difference was 13.7% (95% CI: −0.5 to 28), which was not statistically significant.
| Japan | United States | |
|---|---|---|
| Approved CDx product | 45 | 51 |
| Agreed APIs | 37 | |
| Disagreed APIs | 3 (7.5%) | 10 (21.2%) |
| Not determined APIs | 2 | 16 |
| Total APIs | 42 | 63 |
The difference in disagreement was 13.7% with a 95% confidence interval of −0.5 to 28. Agreed APIs: wCDx approved both in Japan and the U.S.; APIs: active pharmaceutical ingredients; disagreed APIs: wCDx approved either in Japan or the U.S.; not determined APIs: APIs that have not been approved in Japan or the U.S.; wCDx: anticancer drugs that require the use of CDx.
The average daily drug price and B/R values for wCDx and woCDx were analyzed by indication and API (Table 2 and Supplementary Materials). By indication, woCDx drugs were more expensive for skin and prostate cancers, whereas for other indications, the cost of wCDx drugs was either similar to that of woCDx drugs or, in cases where wCDx drugs were more expensive, the price never exceeded twice that of woCDx drugs. The average daily drug price for wCDx and woCDx drugs was 41280 Japanese yen (median: 25961) and 141870 Japanese yen (median: 22813), respectively. However, due to large variations, no significant difference was observed between the groups (p = 0.62) (Table 2). The B/R values varied from 0.09 to 2.75, depending on the indication, with an average of 0.84 for wCDx drugs and 0.63 for woCDx drugs. A statistically significant difference was observed (p = 0.0294) (Table 2).
| Indications | Average daily drug price (JPY) | Average B/R value | |||
|---|---|---|---|---|---|
| Organ | ICD-10 | wCDx (n) | woCDx (n) | wCDx (n) | woCDx (n) |
| Salivary gland | C08 | 94206 (1) | ND | 0.60 (1) | ND |
| Esophageal | C15 | 20428 (1) | ND | 0.23 (1) | ND |
| Stomach | C16 | 23358 (1) | 20311 (1) | 0.10 (1) | 0.25 (1) |
| Colon/rectum | C18, C20 | 25197 (5) | 14429 (2) | 0.61 (5) | 0.09 (2) |
| Biliary tract | C24 | 46136 (3) | ND | 0.49 (3) | ND |
| Pancreas | C25 | 20740 (1) | ND | 0.51 (1) | ND |
| Lung | C34 | 24877 (21) | 27749 (3) | 0.94 (19) | 0.89 (3) |
| Skin | C43 | 4936 (1) | 69335 (1) | 2.75 (1) | 0.16 (1) |
| Breast | C50 | 26240 (7) | 26137 (1) | 1.07 (3) | 0.53 (3) |
| Ovary | C56 | 22235 (2) | ND | 0.49 (1) | ND |
| Prostate | C61 | 19946 (2) | 156551 (4) | 0.49 (2) | 0.63 (2) |
| Thyroid gland | C73 | 27938 (2) | 19681 (2) | 1.24 (2) | 0.70 (2) |
| Lymphoma | C82–85 | 279445 (2) | 120693 (12) | 1.41 (1) | 0.59 (11) |
| Myeloid leukemia | C91–95 | 295275 (3) | 131939 (14) | 0.46 (3) | 0.80 (9) |
| Solid tumor | — | 29697 (4) | ND | 0.91 (4) | ND |
| Number of anticancer drug | 39 | 56 | 48 | 49 | |
| Mean [interquartile range] | 41280 [8994] | 141870 [21446] | 0.84 [0.53] | 0.63 [0.38] | |
| Median | 25961 | 22813 | 0.62 | 0.54 | |
| p-Value | 0.62 | 0.0294 | |||
wCDx: anticancer drugs that require the use of CDx; woCDx: anticancer drugs that do not require the use of CDx. Average daily drug prices were calculated from the information listed in the national health insurance drug price standards. B/R values were calculated as the objective response rate (Benefit; B) divided by the incidence of CTCAE grade 3 or higher adverse events (Risk; R). p-Values were calculated by Mann–Whitney U-test and Welch’s t-test for the comparison of daily drug price and B/R value, respectively.
The B/R values, calculated from efficacy and safety data obtained during the approval review of anticancer drugs, were compared between wCDx and woCDx groups (Fig. 1). The B/R values were significantly higher for wCDx drugs than for woCDx drugs in both Japanese patients (p = 0.0135) and the overall patient population, including non-Japanese patients (p = 0.0294).
Box-and-whisker plots show B/R value on anticancer drugs that do not require the use of CDx (woCDx: white) and that require the use of CDx (wCDx: gray). p-Values were calculated by Welch’s t-test (for Japanese patients only) and Student’s t-test (for all patients).
In anticancer drug treatment, both Japanese and U.S. regulatory authorities position CDx as an essential tool for ensuring the safe and effective use of anticancer drugs, ultimately improving patient outcomes. Given the absence of regional differences in this fundamental role, the rate of wCDx should theoretically be similar in both regions, assuming an equal number of approved anticancer drugs, excluding factors such as ethnic differences. Regarding the development and approval of CDx, regulatory guidelines were introduced in the U.S. in 2011 and in Japan in 2013,18,19) leading to a 2-year delay in Japan’s regulatory framework. As a result, the total number of approved CDx products in Japan remains lower than that in the U.S. However, our analysis found no significant differences in the agreement rate of wCDx approvals between the 2 countries, as expected. This finding highlights a drug loss issue in anticancer drug approvals between the 2 countries. There are 16 APIs yet to receive approval in Japan, which have been approved in the U.S. as wCDx. The handling of Japanese data, participation in multiregional clinical trials, and domestic-only development by Japanese companies are thought to be some of the causes of this drug loss.9,11)
Interestingly, the number of anticancer drugs available per approved CDx product was 1.32 times higher in the U.S. than in Japan. This discrepancy may be attributed to broader cross-sectional CDx use in the U.S.; for example, a single CDx detecting EGFR (HER1) gene mutations can be used across 22 tyrosine kinase inhibitors applicable to non-small cell lung cancer. In Japan, MHLW issued a notice regarding such cross-sectional CDx use in 2022,20) but given the recency of this policy, its impact may not yet be fully realized. Additionally, the CDx list published by the PMDA does not clearly indicate whether cross-sectional use is permitted, making it difficult for healthcare providers to interpret, warranting further improvements.
With the emergence of various treatment modalities and evolving cancer care policies, the number of cancer patients receiving outpatient treatment in Japan is increasing.3) Anticancer drug treatment imposes substantial burdens on patients and caregivers, including high treatment costs, loss of work productivity, and treatment interruptions due to severe AEs or lack of efficacy.21,22) Since the introduction of the Precision Medicine Initiative in the U.S. in 2015,6) patient-centered care has gained significant attention, with CDx expected to play a crucial role in its realization. We compared wCDx and woCDx anticancer drugs by focusing on the average daily drug price and the B/R ratio. While no significant difference in daily drug price was observed between the 2 groups, the B/R ratio was significantly higher for wCDx drugs than for woCDx drugs. The B/R ratio was calculated as the ORR, used as a reference clinical trial endpoint, divided by the incidence of ≥G3AE. As a dimensionless quantity, this ratio provides a universal index that transcends variations in indications, APIs, and treatment modalities, with a higher value indicating a more favorable therapeutic profile. Further analysis revealed no significant difference in benefit between the 2 groups; however, the incidence of severe AEs was significantly lower in the wCDx group. Similar benefit and risk profiles were observed between Japanese patients and all patients (Table 3). Focusing on anticancer drugs with B/R >1, which are considered to be preferable for patient-centered anticancer drug treatment, there were 12 drugs in the wCDx group, 50.0% of which were indicated for non-small cell lung cancer and 16.7% for colorectal cancer; the drug type was tyrosine kinase inhibitors in 50.0% and antibodies in 33.3%. In the woCDx group, there were 9 drugs, 66.7% for blood cancer, and the drug types were tyrosine kinase inhibitors in 33.3% and antibodies in 33.3%. Comparing the 2 groups, the cancer types differed, but the drug types were similar. It can be speculated that patients with a better safety profile, including a low risk of AEs, are not narrowed down for the woCDx group because CDx is not used. This finding suggests that CDx may improve patient selection, leading to more precise treatment, and/or that APIs requiring CDx inherently carry a lower risk of severe AEs. Although wCDx drugs incur additional CDx testing costs, the higher B/R ratio suggests that patients undergoing CDx-guided treatment may receive superior medical care, with improved treatment outcomes and reduced AE-related burdens. Despite the clear advantages of CDx-guided treatment, the true efficacy differences between wCDx and woCDx drugs are unclear, and there is a need for post-marketing studies to verify overall survival, which could serve as the primary and definitive endpoint. In clinical practice, unlike in clinical trials, patient backgrounds vary significantly, further emphasizing the need for real-world data to assess long-term treatment efficacy.
| Item | wCDx | woCDx | p-Value |
|---|---|---|---|
| Benefit for all patients including foreign patients (% [IQR]) | 42.7 [25.6] | 41.4 [26.1] | 0.872 |
| Benefit for Japanese patients (% [IQR]) | 50.0 [34.6] | 42.5 [34.0] | 0.276 |
| Risk for all patients including foreign patients (% [IQR]) | 59.9 [17.7] | 70.9 [25.0] | 0.0030 |
| Risk for Japanese patients (% [IQR]) | 53.5 [21.8] | 82.2 [38.4] | 0.0001 |
wCDx: anticancer drugs that require the use of CDx; woCDx: anticancer drugs that do not require the use of CDx. Benefit and risk were calculated as the average of objective response rate and incidence rate of CTCAE grade 3 or higher adverse events in available clinical trials for drug approval, respectively. p-Values were analyzed by Mann–Whitney U-test.
In our analysis, we omitted the cost of CDx. The product price of CDx can be as high as 1.8 million Japanese yen per kit, and the reimbursement points vary widely from 690 to 56000. Because laboratory testing can be performed for multiple patients simultaneously, the cost per specimen varies depending on how medical institutions utilize the CDx. In addition, medical institutions may need to cover the cost of laboratory testing depending on the patient’s condition.23) Therefore, a simple comparison of CDx costs would be too complicated to interpret. A relatively high cost of CDx should be considered when using health technology assessment methods together with various cost-effectiveness studies.24,25)
Developing wCDx anticancer drugs often requires pharmaceutical companies to collaborate with medical device and diagnostic drug manufacturers, increasing development complexity and costs. However, previous reports suggest that restricting patient populations via CDx improves the success rate of clinical trials.26) While narrowing the patient population in clinical practice directly reduces market size, the absence of pricing differences between wCDx and woCDx drugs may discourage companies from pursuing CDx development. Nonetheless, our findings suggest that CDx improves treatment outcomes and reduces AE-related burdens, underscoring the need to actively promote CDx development for anticancer drugs that could theoretically benefit from its use. To facilitate this, regulatory support will be critical in overcoming the development hurdles associated with CDx-integrated therapies.
There are limitations in this study. We only used ORR and safety data in the anticancer drug approval process; therefore, the benefit and risk of anticancer drugs in this study were indicated using data from a limited number of patients during clinical trials.
Overall, our study demonstrated that anticancer drugs requiring CDx provide superior treatment outcomes compared with non-CDx drugs, primarily due to a lower incidence of severe AEs. To enhance patient-centered cancer care and alleviate treatment burdens on patients and caregivers, CDx should be actively developed and implemented for APIs with mechanisms of action suitable for biomarker-based selection. Additionally, regulatory policies supporting CDx-integrated anticancer drug development will be essential, given the higher developmental challenges associated with these therapies.
The authors declare no conflict of interest.
This article contains supplementary materials.
