Clinical trial planning, design and execution: Considerations and best practices

Introduction

The purpose of this section is to provide recommendations regarding selected aspects of the design of early phase clinical trials of gene therapy products, as covered by established FDA guidance for gene therapies. Such trials include most Phase 1 trials, including the initial introduction of an investigational new drug into humans (FIH), and some Phase 2 trials. Note, this section will not provide detailed information about the pre-clinical and CMC components of an IND, as we have previously discussed these in the appropriate IND modules.

The design of early-phase clinical trials of gene therapy products often differs from the design of clinical trials for other types of pharmaceutical products. Differences in trial design are necessitated by the distinctive features of these products and may also reflect previous clinical experience. Early experiences with gene therapy products indicate that some gene therapies may pose substantial risks to subjects. Risks could include multi-organ failure and death, as well as malignancies. These events illustrate that the nature of the risks of cell and gene therapy products can be different from those typically associated with other types of pharmaceuticals.

The design of early-phase clinical trials of gene therapy products often involves consideration of issues related to clinical safety, pre-clinical, and CMC that are more prevalent in gene therapy development compared to other therapies (e.g., biologics and small molecules). Such issues are more prominent in gene therapies because of factors such as novelty of the technology, complex mechanism of action, potential for long-term effects, and manufacturing challenges due to complex processes involving production and purification of viral vectors. Trial design is influenced by the many distinctive features of gene therapy products as it relates to product characteristics, manufacturing considerations, and pre-clinical design. Some of which are unique to gene therapy products and can dictate critical elements of the clinical trial design. The following table describes some of these special features.

Features of gene therapies influencing CT design

Product characteristics	Manufacturing considerations	Preclinical considerations
Lack of clinical experience, resulting in uncertainty about the nature and frequency of safety problems that might be expected Gene therapy products can persist in humans for an extended period after administration – requires prolonged observation of subjects to evaluate safety with evolution Risk of uncontrolled expression of a delivered gene interfering with normal function of a critical enzyme, hormone, or biological process in the recipient	Scientific or logistical complexities of manufacturing may impose practical limits on the dose of the product that can be produced, or may limit the concentration/volume of product that can be delivered – might result in restriction of the range of doses that are feasible in an early-phase trial Some gene therapy products may take several weeks to months to produce – a failure or delay in manufacturing could prevent a subject from being treated as intended	High need to conduct a careful benefit-risk analysis due to the diverse biology and scientific issues associated with gene therapy products – performed in the context of the clinical condition under study Lack of adequate data to guide clinical trial design since traditional PK studies are generally not feasible for gene therapy products Unreliability of extrapolation from a gene therapy product dose administered in animals to a clinical dose due to various issues, such as species specificity and immunogenicity

It is important to ensure proper planning, design, and execution of clinical trials. This is essential for generating reliable, valid, and ethical results. Next, we will look at clinical trial design and the important elements to consider.

Documentation Index

Clinical trial planning, design and execution: Considerations and best practices

Introduction

Features of gene therapies influencing CT design