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28 June 2025

PhotoChem Reference Chemical Database for the Development of New Alternative Photosafety Test Methods

,
,
,
and
1
College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, Republic of Korea
2
Graduate Program in Innovative Biomaterials Convergence, Ewha Womans University, Seoul 03760, Republic of Korea
*
Authors to whom correspondence should be addressed.
Toxics2025, 13(7), 545;https://doi.org/10.3390/toxics13070545
This article belongs to the Special Issue New Approach Methodologies for Agrochemicals and Food Toxicology
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Abstract

Photosafety assessments are a key requirement for the safe development of pharmaceuticals, cosmetics, and agrochemicals. Although in vitro methods are widely used for phototoxicity and photoallergy testing, their limited applicability and predictive power often necessitate supplemental in vivo studies. To address this, we developed the PhotoChem Reference Chemical Database, comprising 251 reference compounds with curated data from in vitro, in vivo, and human studies. Using this database, we evaluated the predictive capacity of three OECD in vitro test guidelines—TG 432 (3T3 NRU), TG 495 (ROS assay), and TG 498 (reconstructed human epidermis)—by comparing the results against human and animal data. Against human reference data, all three test methods showed high sensitivity (≥82.6%) and strong overall accuracy: TG 432 (accuracy: 94.2% (49/52)), TG 495 (100% (27/27)), and TG 498 (86.7% (26/30)). In comparison with animal data, sensitivity remained high for all tests (≥92.0%), while specificity varied: TG 432 (54.3% (19/35)), TG 495 (63.6% (7/11)), and TG 498 (90.5% (19/21)). TG 498 demonstrated the most balanced performance in both sensitivity and specificity across datasets. We also analyzed 106 drug approvals from major regulatory agencies to assess real-world application of photosafety testing. Since the mid-2000s, the use of in vitro phototoxicity assays has steadily increased in Korea, particularly following the 2021 revision of the MFDS regulations. Test method preferences varied by region, with 3T3 NRU and ROS assays most widely used to evaluate phototoxicity, while photo-LLNA and guinea pig tests were frequently employed for photoallergy assay. Collectively, this study provides a valuable reference for optimizing test method selection and supports the broader adoption of validated, human-relevant non-animal photosafety assessment strategies.

1. Introduction

Photosafety testing primarily aims to evaluate two major aspects: phototoxicity and photoallergy. In pharmaceuticals, photosafety assessment refers to an integrated process that includes photochemical characterization, nonclinical testing, and human safety information, as outlined in the ICH S10 guideline (Photosafety Evaluation of Pharmaceuticals) [1]. The objective of a photosafety evaluation is to minimize the potential risks of chemicals caused by concomitant light exposure to humans. Phototoxicity is defined as a nonimmunologic skin reaction that occurs when reactive chemicals and sunlight interact simultaneously. Such reactions occur shortly after concomitant exposure to photoreactive chemicals and light and often resemble moderate to severe sunburns. In contrast, photoallergy is an acquired immune-mediated reaction in which a photoactive substance activated by sunlight forms an allergenic hapten. This reaction is triggered by either antibody-mediated (immediate) or cell-mediated (delayed) immune responses. Unlike phototoxicity, photoallergy can occur with significantly lower energy exposure. When induced by exogenous substances, it almost exclusively manifests as delayed-type hypersensitivity (type IV). Additionally, this reaction requires an induction period before clinical symptoms appear [2]. This reaction requires a sensitization phase before clinical symptoms manifest [3]. Clinically, photoallergic reactions commonly present as erythema, pruritus, and vesicular lesions, often accompanied by skin lichenification or desquamation. These responses may resemble urticarial or lichenoid eruptions. In particular, flat-topped, keratinized lesions are a characteristic feature of such reactions.
The photoreactive potential of a chemical can be identified by evaluating its absorption in the ultraviolet (UV) spectrum. To elicit a phototoxic or photoallergic response, a chemical must exhibit sufficient light absorption (≥1000 L/mol·cm) within natural sunlight (290–700 nm) [1].
The term photosensitization is often used as a general descriptor for all light-induced tissue responses. However, to ensure clarity between phototoxicity and photoallergy, ICH S10 discourages the use of this term. Accordingly, this study will exclusively focus on the evaluation of phototoxic and photoallergic responses. When a chemical is identified as photoreactive, it is assessed using specific toxicological test methods designed to evaluate both phototoxicity and photoallergy. Key considerations for identifying a photosafety hazard include (1) light absorption within the natural sunlight spectrum (290–700 nm), (2) the generation of reactive oxygen species upon UV–visible light exposure, and (3) adequate distribution to light-exposed tissues (e.g., skin and eyes). If a compound does not meet at least one of these criteria, it is unlikely to pose a direct photosafety concern. Although indirect mechanisms may increase photosensitivity (e.g., metabolic activation), they are not currently addressed due to the lack of established test methods [3]. Currently, in vitro photosafety assessments are primarily focused on phototoxicity and ROS evaluations as specified in OECD and ICH guidelines replacing in vivo phototoxicity tests. However, photoallergy evaluation still requires in vivo experiments, as summarized in Table 1.
Table 1. Phototoxicity and Photoallergy test methods.
While in vitro photosafety tests considerably reduced the use of in vivo tests, comprehensive photosafety assessments still need in vivo tests due to the limitation of in vitro tests in the applicability domain and predictive capacity, demanding novel photosafety testing methods capable of accurately identifying chemicals that induce phototoxic or photoallergic reactions. Here, we compiled a comprehensive reference chemical database of 251 reference chemicals, including 59 phototoxic, 26 non-phototoxic, and 4 photoallergenic substances verified in humans, for the development and evaluation of alternative methods for phototoxic and photoallergy tests.

2. Materials and Methods

2.1. Construction of Phototoxicity Reference Substance Database

To support the research and validation of new phototoxicity test methods, a phototoxic reference chemical database was established. Each chemical was documented with key identifiers such as CAS numbers, physicochemical properties, and UV absorption parameters. To facilitate the development of testing methods across diverse chemical categories, information on their usage classification—pharmaceuticals, cosmetics, industrial chemicals, and agrochemicals—was also included. Both in vitro and in vivo data were collected. Importantly, test results from the OECD Test Guidelines (TGs) and human patch tests were incorporated to evaluate the predictive power and consistency between testing methodologies.

2.2. Phototoxicity Testing Methods Used for Pharmaceuticals

The phototoxicity testing methods used in the nonclinical stages of pharmaceutical development were investigated through searching regulatory approval documents and assessment reports from the U.S. FDA, Japan’s PMDA, the EMA, and South Korea’s MFDS.

2.3. Comparison of In Vivo and In Vitro Data of Phototoxicity Reference Chemicals

To evaluate the predictive performance and reliability of in vitro phototoxicity test methods, a comparative analysis was conducted using 252 reference chemicals with available in vivo or human data. The in vitro test methods were based on three internationally validated OECD guidelines (Table 2).
Table 2. Criteria for phototoxicity prediction according to OECD Test Guidelines.
Only chemicals for which both in vitro and in vivo test results were available were included in the comparative analysis. Each compound was classified as either phototoxic (PT) or non-phototoxic (NPT) based on the outcomes of both test types. The sensitivity, specificity, and accuracy were calculated to assess the performance of each in vitro method.

2.4. Photochemical Properties

To evaluate the potential for light-induced reactivity, the primary criterion was whether the chemical absorbs light within the 290–700 nm wavelength range. A chemical was considered unlikely to cause direct phototoxicity if it exhibited a molar extinction coefficient (MEC) of less than 1000 L/mol·cm in this range. That is, if the chemical had an MEC value below 1000 L/mol·cm between 290 and 700 nm and lacked additional supportive data, it was deemed not to pose a photosafety concern in humans, according to ICH S10 guidelines [1].

3. Results

3.1. Analysis of Reference Chemicals in the PhotoChem Database

A total of 251 reference chemicals were collected and classified based on their photo-toxicity and photosensitization profiles. These compounds are widely used in various industries, including pharmaceuticals, cosmetics, and agriculture, where photoreactivity under ultraviolet (UV) exposure plays a significant role in safety evaluation.
For each chemical, various physical properties were recorded, including physical state; molar absorbance (ε); maximum UV absorption wavelength (λmax); and test results across human, animal, and in vitro models.
To better understand the material characteristics, the physical states of all 251 chemicals were analyzed. As shown in Table 3, the majority of the chemicals were in solid form (n = 218, 86.9%), followed by liquids (n = 26, 10.4%). Gels accounted for two chemicals, and viscous or oil-based chemicals, categorized as “Other,” also accounted for two chemicals (0.8%), while three chemicals were labeled as “Unknown” due to the absence of a definitive classification (1.2%).
Table 3. List of reference chemicals in the PhotoChem DB.

3.2. Human vs. Animal Test Results for Reference Test Chemicals

To assess the phototoxic potential of the reference chemicals in human models, available in vivo test data were categorized by their respective outcomes. Figure 1 illustrates the comparative distribution of test results from human and animal studies for 251 chemicals.
Figure 1. Comparison of photosafety results from human and animal tests in the PhotoChem DB. This figure shows the photosafety results for reference chemicals based on human and animal test data. In animal studies, most compounds were clearly categorized as either non-phototoxic (NPT) or phototoxic (PT). In contrast, human data included a broader range of outcomes such as inconclusive results, mild reactions, or photosensitization (photopatch), reflecting the complexity of clinical assessments.
A total of 103 chemicals out of the PhotoChem DB have human test results: 59 chemicals were identified as phototoxic (PT); 26 chemicals were categorized as non-phototoxic (NPT); 8 chemicals were reported as inconclusive; 4 chemicals were given a PT/NPT; 3 chemicals were labeled as photosensitive (PS); and a single case each was observed for mild phototoxicity (mild PT), non-photosensitization (NPS), and PS (photo patch) testing, with each indication a specialized or rare response type.
Animal model studies were also reviewed to evaluate the phototoxicity potential of the 251 reference chemicals. These models provide complementary data for human studies and are particularly important when human testing is ethically or practically limited.
As depicted in Figure 1, the animal testing results reveal the following distribution: 70 chemicals were classified as non-phototoxic (NPT), 60 chemicals showed a positive phototoxicity (PT), 12 chemicals received mixed classifications (NPT/NPS), 4 chemicals were marked as non-photosensitive (NPS), 3 chemicals were classified as PT/NPT, 2 chemicals were classified as PT/PS, and 1 chemical was confirmed as photosensitive (PS).

3.3. Correlation of Human Test Data with In Vivo or In Vitro Tests

The classification results for phototoxicity and photosensitization from human and animal studies showed substantial agreement, although some variation in sensitivity was observed. Out of 251 total chemicals, those lacking paired results across test types were excluded from the analysis. Sensitivity, specificity, precision, and accuracy were evaluated accordingly (Table 4 and Table 5).
Table 4. Predictive performance of in vivo phototoxicity tests compared with human patch tests.
Table 5. Predictive performance of in vitro phototoxicity tests compared with human test results.
Table 5 presents the predictive performance of three OECD test methods (TG 432 (3T3 Neutral Red Uptake phototoxicity test), TG 495 (Reactive Oxygen Species assay), and TG 498 (Reconstructed Human Epidermis model)) against human or animal tests. These results indicate that while the classification of non-phototoxic chemicals aligns with some in vivo data, inconsistencies across untested or conflicting chemicals (e.g., PT and PT/NPT) highlight the need for comprehensive and standardized in vivo testing to improve the reliability of non-phototoxic classifications.
Overall, the findings emphasize the importance of integrating both human and animal data to achieve more accurate and reliable assessments of phototoxicity and photosensitization. Leveraging the strengths of each model can enhance predictive performance and improve overall safety evaluation strategies.

3.4. Analysis of Photosafety Testing Used in Drug Approvals

In recent decades, phototoxicity and photosensitization testing have gained increasing importance in pharmaceutical safety assessments. To examine how these tests are implemented in regulatory practice, we analyzed drug approvals from major regulatory agencies including the United States Food and Drug Administration (U.S. FDA), Japan’s Pharmaceuticals and Medical Devices Agency (PMDA), the European Medicines Agency (EMA), and South Korea’s Ministry of Food and Drug Safety (MFDS). Based on compiled data from approved drug dossiers, we assessed the frequency, testing strategies, and adoption trends of photosafety evaluations.
The analysis revealed a growing adoption of photosafety testing across all agencies. In particular, data from Korea’s MFDS showed that photosafety test results were not consistently included in approval documents prior to the revision of its regulatory guidelines on 11 November 2021. At that time, certain nonclinical safety assessments, including photosafety tests, were exempted for specific categories of drugs. However, following the regulatory revision, phototoxicity and photosensitization testing became mandatory components of nonclinical safety evaluations. This regulatory shift highlights the increasing importance placed on photosafety assessments in Korea and aligns with the global trend toward comprehensive photoreactivity risk management.
Following this, we further analyzed a total of 106 approved pharmaceutical products that included photosafety assessments, focusing on their annual adoption patterns and the specific test methods used. To visualize this trend, we generated a yearly distribution graph showing the implementation of phototoxicity and photosensitization testing over time (Figure 2). In addition, test method utilization was analyzed by regulatory authority, including the FDA, PMDA, EMA, and MFDS, to assess differences in test preferences among countries (Figure 3).
Figure 2. Annual trend of phototoxicity and photosensitization testing among approved pharmaceutical products (n = 106). The graph illustrates the increasing frequency of photosafety testing over the years, particularly for phototoxicity since the mid-2000s.
Figure 3. Number of phototoxicity and photosensitization tests conducted by country and year. The chart displays the test method distribution across four regulatory authorities: the FDA, PMDA, EMA, and MFDS.
The analysis revealed a notable increase in the application of phototoxicity tests beginning in the mid-2000s, followed by a gradual rise in photosensitization testing in more recent years. Regionally, the PMDA and FDA showed the highest number of total test submissions, while MFDS data showed a steep increase post-2021. Across agencies, 3T3 NRU, ROS assays, and RHE-based models were most commonly used for phototoxicity, whereas LLNA and guinea pig-based protocols were predominantly used for photosensitization.
Figure 2 illustrates the annual trend in phototoxicity and photosensitization testing from 1979 to 2024, based on data extracted from 106 approved pharmaceutical products that included photosafety evaluations. During the early years of the dataset, reports of both phototoxicity and photosensitization testing were infrequent or absent, likely due to the absence of standardized regulatory requirements or test guidelines during that time.
A notable shift occurred beginning in the mid-2000s, with a steady increase in phototoxicity test implementation. This upward trend culminated between 2018 and 2021, during which over 18 phototoxicity assessments were recorded in a single year. This surge may be attributed to the widespread regulatory adoption of OECD TG 432 and increased emphasis on nonclinical photosafety data in global drug development and review processes.
In contrast, photosensitization testing exhibited a more gradual increase, with a relatively small number of cases—typically fewer than five per year—reported since 2010. This modest rise suggests that photosensitization assessments are applied more selectively, potentially limited to compounds with specific structural alerts, photoreactive moieties, or UV absorption profiles. The overall pattern reflects a growing awareness of photosafety considerations and regulatory alignment over time, particularly for phototoxicity.
Figure 3 presents a cumulative analysis of photosafety testing conducted by regulatory authority across four countries: the United States (the FDA), Japan (the PMDA), the European Union (the EMA), and South Korea (the MFDS). The data shows a distinct pattern in how each country has adopted and implemented phototoxicity and photosensitization testing in their regulatory processes over time.
The PMDA and FDA demonstrated relatively early adoption, with consistent test submissions reported since the mid-2000s. In contrast, data from the EMA showed a gradual increase, reflecting more selective application based on compound characteristics or risk assessment strategy. The most prominent change was observed in Korea’s MFDS, where a sharp rise in test submissions occurred after 2021, coinciding with the regulatory amendment that made photosafety testing mandatory for new drug applications.
This country-specific breakdown illustrates differing timelines and regulatory emphases in adopting photosafety tests, highlighting the importance of harmonized global guidelines and the evolving role of photoreactivity evaluation in drug approval pathways.
Figure 4 and Figure 5 present a comparative overview of phototoxicity and photosensitization test methods employed by four major regulatory agencies: the EMA, FDA, PMDA, and MFDS. These pie charts illustrate how each country distributes its use of test strategies for photosafety assessments based on approved pharmaceutical dossiers.
Figure 4. Distribution of phototoxicity test methods used in pharmaceutical approvals by country. The chart compares the types of phototoxicity test methods adopted by four major regulatory authorities (the EMA, FDA, PMDA, MFDS), illustrating differences in testing strategies and preferences for alternative versus traditional approaches.
Figure 5. Distribution of photosensitization test methods used in pharmaceutical approvals by country. This figure highlights the diversity of test types adopted for photosensitization assessment across the EMA, FDA, PMDA, and MFDS, indicating variation in clinical, in vivo, and alternative testing practices.
In phototoxicity evaluations (Figure 4), the 3T3 NRU test method was the most frequently applied across all agencies, particularly by the PMDA (58.67%) and EMA (34.40%). The FDA showed more diversified usage, including the clinical test, UV spectrum analysis, and hemoglobin oxidation methods. The MFDS primarily relied on in vivo studies and the 3T3 NRU test, reflecting its recent emphasis on incorporating alternative methods.
In contrast, photosensitization testing (Figure 5) exhibited greater heterogeneity across agencies. The FDA and MFDS predominantly used in vivo tests and clinical tests, while the PMDA applied a wider range of methods, including in vivo tests, Photo-LLNA, and photopatch testing. The EMA utilized a more balanced mix of in vivo, in vitro, and clinical approaches. These results suggest differences in regulatory preferences and test accessibility, as well as varying degrees of reliance on traditional versus alternative methods.
Figure 6 provides a comparative overview of the relative proportion of phototoxicity and photosensitization tests conducted by four regulatory agencies: the EMA, FDA, PMDA, and MFDS. Across all countries, phototoxicity assessments represented the dominant form of photosafety testing, reflecting its broader regulatory adoption and the availability of validated test guidelines such as OECD TG 432.
Figure 6. Distribution of photosafety test types submitted to four regulatory agencies (the EMA, FDA, PMDA, MFDS). Phototoxicity tests accounted for the majority of evaluations across all agencies, with the MFDS showing the highest proportion (86.4%). In contrast, the EMA reported the highest relative use of photosensitization tests (29%), indicating varying emphasis on test types among regulatory bodies.
Among the agencies, the MFDS reported the highest proportion of phototoxicity testing (86.4%), which may reflect its more recent enforcement of standardized safety requirements and a preference for phototoxicity evaluation during initial risk screening. In contrast, the EMA exhibited the greatest use of photosensitization tests (26.7%), indicating a relatively broader application or heightened regulatory interest in photoallergy assessments. The FDA and PMDA showed similar test ratios, with phototoxicity accounting for approximately 77% of their total photosafety submissions. These findings suggest that approaches to photosafety assessment vary among regulatory agencies.

4. Discussion

This study highlights the need for a harmonized and scientifically robust approach to photosafety evaluation by providing a comprehensive overview of current trends and challenges and by establishing a curated database of reference substances with a comparative analysis of validated in vitro methods against in vivo outcomes. Through the development of the PhotoChem Reference Chemical Database, we compiled detailed information on 251 substances, including phototoxic, non-phototoxic, and photosensitization classifications. Our database includes cosmetics [159], pharmaceuticals [48], and industrial and agricultural chemicals [54] for which photosafety assessment is required. It also integrates CAS numbers, physicochemical data, UV absorbance characteristics, and test results from the literature and drug approval dossiers across four major regulatory regions: the United States, Europe, Japan, and South Korea.
An evaluation of three key OECD in vitro test methods, namely TG 432, TG 495, and TG 498, revealed that all three in vitro test methods demonstrated high sensitivity and accuracy when compared to human and animal classifications. These results suggest strong potential for these methods to serve as alternatives to traditional animal-based testing. However, the notably lower specificity observed in TG 432 and TG 495 (54.3% and 63.6%, respectively) compared to TG 498 highlights an important limitation of current cell-based models. These methods are designed to maximize sensitivity to minimize false negatives, but this often leads to an increased incidence of false positives, reducing overall specificity. In contrast, TG 498, which employs reconstructed human epidermis models, demonstrated superior performance in both sensitivity and specificity despite having fewer data points. This suggests that 3D reconstructed human skin-based models may better mimic in vivo conditions, and their use in photosafety testing is likely to expand in future regulatory frameworks. The observed differences in specificity underscore the need for continued refinement and novel photosafety testing methods suited to particular regulatory contexts.
To further address these limitations and enhance the precision of in vitro models, quantitative structure–activity relationship (QSAR) models and artificial intelligence (AI)-based prediction systems may offer promising complementary approaches. QSAR models can prescreen compounds based on structural alerts and physicochemical properties, while AI models trained on multi source data including UV spectrum, historical assay results, and chemical fingerprints can provide integrated, quantitative predictions of phototoxic potential. Importantly, the PhotoChem DB developed in this study provides a robust foundation for building and validating such predictive models, suggesting that our study may contribute to the evolution of more accurate and human relevant non-animal assessment strategies.
An analysis of 106 pharmaceutical approvals from the FDA, PMDA, EMA, and MFDS revealed an increasing emphasis on phototoxicity evaluation across jurisdictions. A notable increase in test submissions to the MFDS was observed following the 2021 revision of its regulatory guidelines. Moreover, the distribution of test method preferences varied by country, with the 3T3 NRU and ROS assays commonly used for phototoxicity evaluation, while photo-LLNA and guinea pig assays were frequently applied for photosensitization.
Together, the curated database and comparative method analysis reinforce the importance of developing scientifically validated and internationally aligned nonanimal testing strategies. These findings also demonstrate the value of integrating physicochemical and UV-reactive properties to enhance predictive toxicology and support regulatory decision making.

5. Conclusions

In this study, we assessed the phototoxic potential of a range of chemical compounds using the 3T3 Neutral Red Uptake Phototoxicity Test (3T3 NRU PT), along with other validated in vitro methods. Several test substances exhibited significant responses upon UVA exposure, underscoring the importance of early stage photosafety screening, particularly for substances likely to be simultaneously exposed to skin and light. The 3T3 NRU PT method proved to be a reliable and reproducible tool for identifying phototoxicity, supporting its continued use in safety assessments. When benchmarked against human and animal data, TG 495 and TG 498 also showed excellent predictive performance, further validating the role of in vitro alternatives in regulatory applications. Furthermore, the PhotoChem Reference Chemical Database developed in this study serves as a valuable platform for advancing research, regulatory alignment, and method innovation. By combining chemical characteristics, UV absorption profiles, and cross-platform results, the database enables an integrated and data-driven analysis of photoreactivity risk.
Future research should aim to improve the precision of in vitro models, deepen mechanistic understanding, and adopt computational tools such as quantitative structure activity relationship (QSAR) models and artificial intelligence-based prediction systems. These approaches will facilitate scientifically rigorous and ethically responsible photosafety evaluation while reducing reliance on animal testing. In addition, the PhotoChem DB is expected to evolve as a dynamic, expandable resource by incorporating newly identified reference compounds, mechanistic data, and test results. Its continued development will also support the creation and validation of QSAR and AI-driven models, contributing to more precise, efficient, and human relevant safety assessments.

Author Contributions

Conceptualization, G.-Y.L., S.B. and K.-M.L.; methodology, G.-Y.L., J.-H.H. (Jee-Hyun Hwang), J.-H.H. (Jeong-Hyun Hong), S.B. and K.-M.L.; formal analysis, G.-Y.L., J.-H.H. (Jee-Hyun Hwang) and J.-H.H. (Jeong-Hyun Hong); investigation, G.-Y.L., J.-H.H. (Jee-Hyun Hwang) and J.-H.H. (Jeong-Hyun Hong); resources, K.-M.L.; data curation, G.-Y.L., J.-H.H. (Jee-Hyun Hwang), J.-H.H. (Jeong-Hyun Hong) and K.-M.L.; writing—original draft preparation, G.-Y.L.; writing—review and editing, S.B. and K.-M.L.; supervision, K.-M.L.; project administration, K.-M.L.; funding acquisition, S.B. and K.-M.L. All authors have read and agreed to the published version of the manuscript.

Funding

This research was supported by grants (RS-2024-00396737 and 24212MFDS250) from the Ministry of Food and Drug Safety Korea.

Institutional Review Board Statement

Not applicable.

Data Availability Statement

The data presented in this study are available from the corresponding author on request.

Conflicts of Interest

The authors declare no conflicts of interest.

Correction Statement

This article has been republished with a minor correction to the Funding statement. This change does not affect the scientific content of the article.

Abbreviations

The following abbreviations are used in this manuscript:
OECDThe Organization for Economic Co-operation and Development
ICHInternational Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use
FDAU.S. Food and Drug Administration
PMDAJapan Pharmaceuticals and Medical Devices Agency
EMAEuropean Medicines Agency

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