Comparison of international guidelines for early-phase clinical trials of cellular and gene therapy products

Abstract

Cellular and gene therapies (CGT) are promising fields that are bringing significant clinical benefits to patients by directly targeting the underlying cause of disease. In line with this trend, regulatory agencies in every country have been making efforts to accelerate CGT product development. For acceleration, it is necessary to increase the efficiency of clinical trials, thus the early-phase clinical trials for CGT products should be elaborate and productive. The guidelines of international regulatory agencies were compared and analyzed to examine the considerations for the design of early-phase CGT products. The guidelines described a safety evaluation, preliminary evidence of effectiveness gathering, dose exploration, and a feasibility assessment as common objectives of early-phase clinical trials for CGT products. In addition, the considerations for the design of early-phase CGT products included pretreatment effects and problems in the manufacturing and administration process. The guidelines also covered selection of a study population, control group/blinding, and dose/regimen planning. There were differences in the degree of detail, description, and the scope of the content covered by each guideline. The guideline published by FDA was the most specific. However, when compared with the previous guidelines for designing early-phase clinical trials for small molecules and biologics, the current guidelines need to be revised to suggest more detailed and practical principles and rules.

Considerations for Cell and Gene Therapy Programs Entering the Clinical Space

“…The specific risks of CGT and the duration of follow‐up might vary significantly from more traditional therapies, for all the reasons described in the Benefits/Risk section above. The EMA may also have a particular interest in the administration process of the product, product failure, and mandatory concomitant medications, 27 whereas this may be less explicit by the FDA. The IB should include comprehensive information on risks of product, particularly those risks specific to the CGT product (e.g., infections, immunogenicity, immunosuppression, and malignant transformation) in the target population.…”

“…The required elements of early-phase clinical trials are generally similar in the United States and the European Union, although the degree of details in regulatory guidance may differ. 27…”

“…For example, incorporating biomarkers into the first‐in‐human (FIH) trial may be highly valuable to support the rationale for continued evaluation and/or the design of future trials. Both the EMA and FDA look for early trials to evaluate safety and projected efficacious dose range, whereas the FDA may also seek data on feasibility and activity assessments 27 …”

“…Both the EMA and FDA look for early trials to evaluate safety and projected efficacious dose range, whereas the FDA may also seek data on feasibility and activity assessments. 27…”

“…The following section describes features of patient selection, site/investigator expertise, assessments of pharmacokinetics (PKs) and pharmacodynamics (PDs), and study design that arise from the unique operational and regulatory requirements of CGT and that should be considered in a phase I program based on US 25 and European 26 guidance. The required elements of early‐phase clinical trials are generally similar in the United States and the European Union, although the degree of details in regulatory guidance may differ 27 …”