Consideration on Food Effect Studies for Anticancer Drugs Approved in Japan Between 2001 and 2022.

Summary

What is the current knowledge on the topic? ○ To date, there is little knowledge available for comprehensive studies on food effect (FE) studies of anticancer drugs approved in Japan.

What question did this study address? ○ It was hypothesized that because many anticancer drugs have compounds with many adverse effects, FE studies could not be conducted in healthy subjects, and many FE studies had been conducted in patients. In reality, however, many drugs had been subjected to FE studies involving healthy subjects, and many drugs were subjected to FE studies outside of Japan.

What does this study add to our knowledge? ○ It was demonstrated that for new oral anticancer drugs approved in Japan, drugs using ex‐Japan clinical data, drugs other than cytotoxic anticancer drugs, and drugs developed ex‐Japan were more likely to be subjected to FE studies.

How might this change clinical pharmacology or translational science? ○ It was inferred that in FE studies, clinical trials in healthy subjects have already been conducted in response to changes in the modality of anticancer drugs.

Introduction

For a drug to exert its medicinal effects after oral administration, the active pharmaceutical ingredient (API) must be absorbed from the gastrointestinal tract and transferred into the systemic blood circulation [ 1 ]. The stages of API absorption include API release from the formulation, maintenance of the dissolved state in the gastrointestinal tract, and permeation of API molecules through the gastrointestinal membrane into the hepatic circulation [ 2 ], and these are examined based on information on dissolution from the formulation, solubility of the drug substance, and membrane permeability [ 3 ]. In addition, for some drugs, ingestion of food inhibits the absorption of the drug when administered orally, resulting in a decrease in blood concentration, while for others, absorption is promoted, resulting in an increase in blood concentration [ 4 ]. Therefore, in the development of a new drug, studies to evaluate the food effect (FE) on the pharmacokinetics of the drug (FE studies) are generally often conducted in healthy subjects in the early stages of clinical development [ 5 ].

The United States Food and Drug Administration (U.S. FDA) Guidance published in 2022 provides recommendations and considerations for the design of FE studies. It recommends that FE studies be conducted on a “high‐calorie, high‐fat diet” as this is the dietary condition under which the greatest effect on the physiological environment of the gastrointestinal tract can be evaluated. It also mentions instances in which FE studies are unnecessary [ 6 ]. In Japan, the “Clinical Pharmacology Studies of Drugs” issued in 2001 mentions that FE on gastrointestinal absorption of oral drugs should be examined in the early stages of clinical development and that FE should be examined in the final formulation [ 7 ]. However, no regulatory documents on FE studies have been published in Japan since 2001.

Meanwhile, the number of approved anticancer drugs is increasing in Japan [ 8 ]. It is also necessary to promote the popularization of outpatient chemotherapy with anticancer drugs from the perspectives of patient quality of life and healthcare finance reduction. Therefore, treatment with orally administered anticancer drugs is expected to continue to increase in the future. The development of anticancer drugs involves patients from Phase I trials [ 9 ] and requires different nonclinical toxicity studies [ 10 ], and the background information related to planning and conducting clinical pharmacology studies is different from that for noncancer drugs. Additionally, some clinical pharmacology studies are conducted post marketing for some drugs, and the minimum package required to obtain approval may differ from that in noncancer areas [ 11 ]. Furthermore, for anticancer drugs, which are known to have many adverse effects, it is assumed that FE studies cannot be conducted in healthy subjects [ 12 , 13 , 14 ]. However, many unknowns exist about how FE on oral anticancer drugs is examined during clinical development. Therefore, in this study, we aimed to examine whether, how, and where FE studies of anticancer drugs approved in Japan from 2001 to 2022 were conducted, their relationship to the development strategies, and the factors influencing their implementation.

Materials and Methods

Selection of Drug and Database

In this study, out of all anticancer drugs approved in Japan within the 22 years from January 2001 to December 2022, we investigated all anticancer drugs intended for systemic administration by oral administration submitted for investigational new drug application as new molecular entities (NMEs). However, drugs targeting benign tumors or precancerous lesions, drugs intended to provide palliative care, and drugs for pretreatment of stem cell transplantation were excluded.

Data Collection

Information regarding the documents provided at the time of application and background of each drug was obtained from the PMDA website ( https://www.pmda.go.jp/PmdaSearch/iyakuSearch/ ). In addition, information on the U.S. FDA approvals was obtained from Drugs@FDA ( https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm ).

Data Extraction

We investigated the background information of the compounds in each drug, pharmaceutical background information, whether or not FE studies were conducted, and the design of the studies. This study was prepared in accordance with Strengthening the Reporting of Observational Studies in Epidemiology reporting guidelines [ 15 ] for cross‐sectional studies.

Statistical Analysis

JMP Pro15 was used for statistical analysis, with a statistical significance level of 5% (two‐sided). Descriptive statistics were used to characterize the samples of the new drugs and their indications.

Results

765NMEs were approved in Japan between 2001 and 2022. Of these, 620 (81.0%) were nonanticancer drugs and 145 (19.0%) were anticancer drugs. Of the 145 anticancer drugs, 70 (48.3%) were oral drugs, 74 (51.0%) were injections, and 1 (0.7%) was administered via another route (Figure 1 ).

We investigated the number of approvals by year for the 70 approved oral anticancer drugs and found that the number of oral anticancer drug approvals had been increasing over time, and especially since 2014, more anticancer drugs had been approved compared to 2013 and before (Figure 2 ).

Table 1 shows the pharmaceutical background of the 70 anticancer drugs included in this study. Molecularly targeted drugs were the most common (55 drugs; 78.6%), followed by cytotoxic drugs (8 drugs; 11.4%) and hormone drugs (7 drugs; 10.0%). 45 drugs (64.3%) were indicated for solid tumors, 25 (35.7%) for hematopoietic cancers, 22 (31.4%) for major cancers (nonsmall cell lung, breast, colorectal, and gastric cancers), and 48 (68.6%) for other cancers (minor cancers). Additionally, ex‐Japan data were used at the time of application for 64 drugs (91.4%), 36 (51.4%) underwent multiregional clinical trials, and 28 (40.0%) adopted the bridging strategy. 21 drugs (30.0%) included compounds from Japanese pharmaceutical companies, while 49 (70.0%) included compounds from foreign pharmaceutical companies.

We investigated whether or not FE studies were conducted for the 70 drugs, and it was found that 67 drugs (95.7%) were subjected to FE studies while 3 (4.3%) were not (Table 2 ).

The content and design of the FE studies are shown in Table 3 . For the 67 oral anticancer drugs that were subjected to FE studies, 95 FE studies were conducted. The number of FE studies in the application data package for one drug ranged from 1 to 4 studies, with 1 study being the most common in 44 studies (62.9%). Additionally, 82 (86.3%) FE studies were conducted in Phase 1, and 9 (9.5%) were in Phase 3, while 80 (84.2%) were conducted ex‐Japan. With regard to the diet for examining FE, 68 studies (71.6%) had some kind of restriction, high‐fat diet was consumed in 51 studies (53.7%), and both high‐fat and low‐fat diets were consumed in 13 studies (13.7%). Additionally, 60 studies (63.2%) included the definition of fasting. Based on Table 3 , the most common designs for FE studies were healthy subjects (63 studies; 66.3%), single‐dose (79 studies; 83.2%), single‐dosage arm (81 studies; 85.3%), nonrandomized (92 studies; 96.8%), crossover (69 studies; 72.6%), and a sample size of 11–30 cases (61 studies; 64.2%).

A univariate analysis (Chi‐square test) was performed to determine whether or not FE studies were conducted based on differences in pharmaceutical background. As a result, pharmaceutical background with significant differences ( p < 0 .05) is shown in Table 4 .

FE studies were conducted significantly more for drugs using ex‐Japan clinical data, drugs other than cytotoxic anticancer drugs, drugs developed ex‐Japan, and drugs with > 100 cases in pivotal trials.

Discussion

Several comprehensive studies on FE studies of anticancer drugs have been reported ex‐Japan [ 12 , 16 , 17 ]. In Japan, there is also a study on FE studies targeting drugs in all fields [ 18 ]. However, this study spanned a relatively short period of < 10 years and was submitted to a Japanese journal. Therefore, to the best of our knowledge, this is the first report of a long‐term study involving anticancer drugs approved in Japan that was published in an international English‐language journal.

In this study, oral anticancer drugs approved in Japan from 2001 to 2022 were investigated. The most common mechanism of action of the anticancer drugs investigated was molecular targeting. Additionally, many of the drugs underwent multiregional clinical trials and used foreign data. The results are consistent with our previous studies on all anticancer drugs approved in Japan, including injections and additional indications [ 8 , 19 ]. In addition, this study showed that FE studies were conducted for as many as 67 (95.7%) of the 70 oral anticancer drugs. Furthermore, 95 FE studies were conducted on the 67 drugs, and about 2/3 of them (63 studies; 66.3%) were conducted in healthy subjects. Moreover, > 80% of the studies were conducted ex‐Japan, not in Japan. In 2020, a biowaiver notice based on the Biopharmaceutics Classification System was issued, and it is expected that the results of FE studies conducted ex‐Japan will be used even more, and fewer FE studies will be conducted in Japan in the future [ 20 ].

According to the univariate analysis of the relationship between pharmaceutical background and whether or not FE studies were conducted, drugs using ex‐Japan clinical data, drugs other than cytotoxic anticancer drugs, drugs developed ex‐Japan, and drugs with > 100 cases in pivotal trials were more likely to be subjected to FE studies. In general, Western countries do not have region‐specific requirements for application data packages, but in the past, Japan's practice tended to have Japanese people make such requests. However, this study was conducted ex‐Japan; therefore, the results were contrary to practice. This is similar to the review of the necessity of Japanese people undergoing Phase I clinical trials when participating in multiregional clinical trials published in 2024 [ 21 ]. Of the 70 oral anticancer drugs, 3 (4.3%) were not subjected to FE studies. We examined the characteristics of these drugs that were not subjected to FE studies, and while there were no significant characteristics, they had been approved relatively earlier, with all three approved in the 2000s.

Based on a review of the design of the 95 FE studies, the most common FE study designs were healthy subjects, single‐dose, single‐dosage arm, nonrandomized, crossover, and a sample size of 11–30 cases. This result is somewhat similar to that of a study on typical FE studies of all orally administered drugs approved in Japan [ 18 ], and it was believed that no anticancer drug‐specific FE studies have been conducted. Our hypothesis prior to the start of our study was that FE studies could not be conducted in healthy subjects because many anticancer drugs have compounds with many adverse effects and that many FE studies had been conducted in patients. In reality, however, unlike our hypothesis, many drugs had been subjected to FE studies involving healthy subjects. We infer that this is due to the large number of molecularly targeted drugs as anticancer drugs, as shown in the results of this study. In other words, molecularly targeted drugs do not necessarily have unacceptable side effects in healthy subjects and may be actively tested in healthy subjects if they are deemed safe to be administered to healthy subjects [ 16 , 22 ]. In 2021, the FDA launched Project Optimus, an approach to dose‐setting for anticancer drugs, and the concept of P‐1 and dose‐setting studies for anticancer drugs has recently been changing [ 23 ]. This is a movement to revisit dose‐setting studies by MTD Phase 1 studies of anticancer drugs, which have been conducted based on the premise of developing cytotoxic drugs. We examined FE studies in our present study and could infer that in FE studies of anticancer drugs, clinical trials have already been conducted in healthy subjects in response to changes in the modality of anticancer drugs.

Our study has several limitations. First, it was based solely on publicly available information, and we could not access internally held information within companies or regulatory agencies. Second, this study only targeted approved drugs; discontinued and disapproved drugs were excluded. Third, we have not investigated the positioning of the FE study within the clinical development plan, the timing, or the conducting country.

Author Contributions

M.S. and H.K. wrote the manuscript; M.S. and H.M. designed the research; M.S., H.K., and H.M. performed the research; M.S. and H.K. analyzed the data.

Conflicts of Interest

The authors declare no conflicts of interest.

Acknowledgments

We would like to thank Ulatus ( https://www.ulatus.jp/ ) and Enago ( https://www.enago.jp/ ) for English editing and proofreading of the manuscript.

Shibuya M., Kubota H., and Maeda H., “Consideration on Food Effect Studies for Anticancer Drugs Approved in Japan Between 2001 and 2022,” Clinical and Translational Science 18, no. 7 (2025): e70304, 10.1111/cts.70304.

Funding: The authors received no specific funding for this work.

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