Contains Nonbinding Recommendations
vi. Multiple sacrifice time points to capture potential acute, chronic,
and/or delayed-onset toxicities, as well as the potential for resolution
of toxicities. The time intervals designated for the sacrifice time
points will depend on the animal model used, the investigational
product, the dosing schedule, the pharmacodynamic and
pharmacokinetic response observed, and the proposed patient
population. The POC studies, as well as the GT product tissue
biodistribution profile and the CT product fate post-administration,
should help guide the selection of study duration and sacrifice time
intervals.
vii. Safety endpoints that capture potential toxicities. Standard parameters
monitored include mortality (with cause of death determined, if
possible), clinical observations, body weights, physical examinations,
food consumption/appetite, water consumption (as applicable), clinical
pathology (serum chemistry, hematology, coagulation, urinalysis),
organ weights, gross pathology, and histopathology.
viii. Additional parameters specific to either the investigational CGT
product used and/or specific to the intended patient population.
Examples of product-specific study parameters include humoral or
cellular immune responses, vector biodistribution, CT product fate,
behavioral testing, neurological exams, ophthalmic exams, cardiac
assessments, imaging (i.e., MRI, ultrasound, radiography), presence of
abnormal/ectopic growths (i.e., hyperplasia, tumors), putative
biomarkers, and specialized histopathology (i.e., immunohisto-
chemistry). The data collected should include both morphological and
functional assessment, whenever possible, to determine whether an
association exists between non-terminal and terminal findings.
Reversibility of any findings should also be addressed. Refer to other
sections of this document for guidance that is specific to product class.
These preclinical data will help guide clinical trial design. For example, data
generated from the toxicology studies will potentially establish a No-Observed-
Adverse-Effect-Level (NOAEL), which will help determine selection of the
starting dose level and subsequent dose-escalation scheme for the clinical trial. In
addition, this information will potentially allow for circumvention or mitigation of
significant toxicities in patients.
6. Product Delivery Considerations
The ROA used to deliver the investigational CGT product in the definitive
preclinical studies should mimic the ROA to be employed in the clinical setting to
the greatest degree possible. If it is not possible to replicate the clinical ROA in
the animal model, then alternative routes/methods should be proposed and
scientifically justified as a part of the preclinical development plan.
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