Are you developing an investigational advanced therapy medicinal products (ATMPs) including a gene therapy medicinal product (GTMP), a somatic cell therapy medicinal product (sCTMP) or a tissue engineered product (TEP) or a combined ATMP and planning to initiate first-in-human (FIH) studies? You would need a specific nonclinical data package to support the initiation of the FIH studies.
The nonclinical development of ATMPs follows a distinct path compared to other medicinal products. The sequential nonclinical development in which the amount of data required and the duration of dosing increase by the phase of clinical development is not generally applicable for ATMPs. ATMPs often require most nonclinical data to be available before FIH exposure. At a minimum, the following information should be available before human exposure:
- support for the proof-of-concept in a relevant nonclinical model
- support for the use of administration route, application procedure and application devices
- support of the selection of safe and biologically effective starting dose
- appropriate safety data
Proof-of-concept
Proof-of-concept studies may involve in vivo models mimicking the target disease or condition, as well as in vitro and ex vivo studies to confirm the mode of action, cell functionality, and/or transgene expression.
Safety pharmacology
Safety pharmacology data are not typically required for investigational ATMPs. When there is a potential impact on critical physiological functions—such as cardiovascular, central nervous, or respiratory systems—relevant safety pharmacology data should be available before FIH studies. These assessments may be integrated into proof-of-concept or toxicity studies.
Pharmacokinetics
Biodistribution data should include information on persistence, clearance, duration of effect, and target organ distribution to guide the design and duration of safety studies.
Safety/toxicity
General safety and toxicity studies should help determine a safe starting dose, dosing regimen, and potential safety risks relevant to the intended clinical use. Well-designed proof-of-concept studies with appropriate safety endpoints may be sufficient to support first-in-human trials. If multiple dosing is planned in the first-in-human study, repeat-dose toxicity studies should be conducted.
Genotoxicity
Standard genotoxicity assays are typically not applicable to ATMPs. Instead, concerns such as insertional mutagenesis for integrating viral vectors, off-target effects, and genome modifications for gene-editing products should be addressed. Additionally, genotoxicity risks related to specific impurities or components of the delivery system should also be considered.
Tumorigenicity
Standard lifetime rodent carcinogenicity studies are generally not required. Depending on the product type, the tumorigenic and oncogenic potential may still need to be evaluated using relevant in vitro and in vivo models to assess neoplastic signals, oncogene activation, or cell proliferation rates.
Immunogenicity and immunotoxicity
The delivery of investigational ATMPs may trigger both the innate and adaptive immune systems. These factors should be considered during nonclinical development as part of the overall toxicology assessment. Depending on the product’s mode of action, immunogenicity and/or immunotoxicity evaluations may be required on a case-by-case basis.
Would you like to have our support in your nonclinical strategy and program? Our team has the extensive experience and expertise to support you in all stages in nonclinical development and the regulatory approval process. Please contact us at [email protected]
