Report on the use of non‐clinical studies in the regulatory evaluation of oncology drugs

Hayakawa, Yoshihiro; Kawada, Manabu; Nishikawa, Hiroyoshi; Ochiya, Takahiro; Saya, Hideyuki; Seimiya, Hiroyuki; Yao, Ryoji; Hayashi, Masahiro; Kai, Chieko; Matsuda, Akira; Naoe, Tomoki; Ohtsu, Atsushi; Okazaki, Taku; Saji, Hideo; Sata, Masataka; Sugimura, Haruhiko; Sugiyama, Yuichi; Toi, Masakazu; Irimura, Tatsuro

doi:10.1111/cas.12857

Cited by 5 publications

(5 citation statements)

References 89 publications

(111 reference statements)

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“…In vivo studies using target tumour cell lines were not conducted for histone deacetylase (HDAC) inhibitors, such as romidepsin (indication: PTCL) and vorinostat (indication: CTCL), which showed tumour growth inhibitory activity using other tumour cell lines. It is reported that HDAC inhibitors are effective against cancer types which expressed high level of HDAC, other than the clinically indicated cancers [ 13 , 45 , 46 ].…”

Section: Discussionmentioning

confidence: 99%

Implementation status of pharmacological studies in the development of orphan drugs

Yokoshiki,

Arato

2024

Orphanet J Rare Dis

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Background The nonclinical as well as clinical development of orphan drugs is difficult, owing to unknown pathophysiology and the absence of animal models. Both, the U.S. Food and Drug Administration (FDA) Guidance and European Medicines Agency (EMA) Guidelines, for orphan drug development describe non-clinical studies, but lack specific information, such as animal species and study design. Against this background, this study aimed to elucidate efficient methods for evaluating nonclinical efficacy based on a review report of orphan drugs approved in Japan. Results A total of 184 orphan drugs, including 84 anticancer and 100 non-anticancer drugs, approved in Japan from January 2010 to December 2019 were investigated. Some anticancer drugs progressed to clinical development without distinct efficacy data in nonclinical studies. Patient-derived cells have been used for some drugs due to a lack of established cell lines. Cells used for non-clinical studies were devised for drugs indicated for cancers resistant to prior therapies, tumours with specific amino acid mutations in the target molecules, and solid tumours with specific biomarkers. For some non-anticancer drugs, similar disease animal models and normal animals were used for evaluation, since animal models did not exist. Biomarkers have been used specifically for evaluation in normal animals and as endpoints in some clinical trials. Conclusions It was possible to evaluate drug efficacy by flexibly designing nonclinical studies according to disease characteristics for potentials orphan drugs. These approaches, which are not described in detail in the EMA Guideline or FDA Guidance, may thus lead to approval.

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Section: Discussionmentioning

confidence: 99%

Implementation status of pharmacological studies in the development of orphan drugs

Yokoshiki,

Arato

2024

Orphanet J Rare Dis

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“…Histone deacetylase (HDAC) inhibitors, such as romidepsin (PTCL) and vorinostat (CTCL), were ineffective during in vivo studies using target carcinomas, but showed tumour growth inhibitory activity using other tumour cell lines. HDAC inhibitors are effective against cancer types other than the clinically indicated cancers (13,45). For vorinostat, the PMDA considered that the suppression of CTCL cell proliferation by the same mechanism as that for colon cancer-derived cells, untargeted cancer, was unclear and required additional in vivo studies using CTCL-derived cell lines; however, there was no discussion of its e cacy in CTCL-derived cells in Europe and the United States.…”

Section: Discussionmentioning

confidence: 99%

Implementation status of pharmacological studies in the development of orphan drugs

Yokoshiki,

Arato

2023

Preprint

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Background: The nonclinical as well as clinical development of orphan drugs is difficult, owing to unknown pathophysiology and the absence of model animals. Both, the U.S. Food and Drug Administration (FDA) Guidance and European Medicines Agency (EMA) Guidelines, for orphan drug development describe non-clinical studies, but lack specific information, such as animal species and study design. Against this background, this study aimed to elucidate efficient methods for evaluating nonclinical efficacy based on a review report of orphan drugs approved in Japan. Results: A total of 184 orphan drugs, including 84 anticancer and 100 non-anticancer drugs, approved in Japan from January 2010 to December 2019 were investigated. Some anticancer drugs progressed to clinical development without distinct efficacy data in nonclinical studies. Patient-derived cells have been used for some drugs due to a lack of established cell lines. Cells used for non-clinical studies were devised for drugs indicated for cancers resistant to prior therapies, tumours with specific amino acid mutations in the target molecules, and solid tumours with specific biomarkers. For some non-anticancer drugs, similar disease model animals and normal animals were used for evaluation, since model animals did not exist. Biomarkers have been used specifically for evaluation in normal animals and as endpoints in some clinical trials. Conclusions: It was possible to evaluate drug efficacy by flexibly designing nonclinical studies according to disease characteristics for potentials orphan drugs. These approaches, which are not described in detail in the EMA Guideline or FDA Guidance, may thus allow lead approval.

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“…FDA and EMA have distinct guidelines, whereas there are distinct guidelines in other parts such as Australia, Brazil, Japan, Korea, Singapore, and Taiwan just to give a flavor of the unique differences that pose constraints in the current clinical development of ATMP cell therapy. While such efforts to converge on an unified regulatory process are underway through engagements, two critical issues have been identified to be addressed, the concept of potency assessment as well as in vivo tumorigenicity studies [96].…”

Section: Current Advances and Future Prospectsmentioning

confidence: 99%

Landscape of Manufacturing Process of ATMP Cell Therapy Products for Unmet Clinical Needs

Pörtner¹,

Parida²,

Schaffer³

et al. 2018

Stem Cells in Clinical Practice and Tissue Engineering

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Immune cell therapies have been studied in numerous clinical trials using Advanced Therapy Medicinal Products (ATMP) against a number of diseases having no or inadequate alternative therapies available, for example, various cancer types, cerebral stroke, cardiac infarction, severe autoimmune disorders, or chronic infections. Despite the enormous number of positive observation in ex vivo or animal studies, convincing results in clinical studies remain scanty. The chapter presents a survey and reveals that the manufacturing of immune cells especially for clinical trials is until today primarily performed using archaic, scarcely controlled, and incomparable processes and methods. A deeper characterization of ex vivo expanded immune cells is urgently needed not only on the level of a few receptors and ligands on the cell surface but also with respect to the ever-contained subtypes in an expanded immune cell population, the pattern of secreted effector molecules, and their amounts over time and influences from in vivo components on them.

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Report on the use of non‐clinical studies in the regulatory evaluation of oncology drugs

Cited by 5 publications

References 89 publications

Implementation status of pharmacological studies in the development of orphan drugs

Implementation status of pharmacological studies in the development of orphan drugs

Implementation status of pharmacological studies in the development of orphan drugs

Landscape of Manufacturing Process of ATMP Cell Therapy Products for Unmet Clinical Needs

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