Clinical Trial Design For Early-Phase Trial for Cellular and Gene Therapy Products

Introduction of Early-Phase Trials For Cell and Gene Therapy
All Early-Phase trials are conducted under the IND regulations in 21 CFR Part 312 which emphasize the importance of the assessment of trial risks and the safeguards for trial subjects. For early-phase clinical trials, especially first-in-human trials, the primary objective should be an evaluation of safety (21 CFR 312.21). The FDA has issued guidance on "Consideration for the design of early-phase clinical trials of cellular and Gene Therapy Products." 

Purpose of Early Clinical Trials

1. Dose Exploration: For gene therapy trials, the dose exploration study is useful to determine the range of biologically active or optimal effective doses and maximal therapeutic dose.

2. Feasibility: Assessments Cellular and gene therapy products sometimes require specialized devices or novel procedures for administration, customized preparation of products, special handling of products (e.g., very short expiration time), or adjunctive therapy. The early-phase trials are designed to identify and characterize any technical or logistic issues with manufacturing and administering the product.

3. Activity Assessments: A common secondary objective of early-phase trials is to obtain preliminary assessments of product activity, using either short-term responses or longer-term outcomes that could suggest a potential for efficacy. Such proof-of-concept data can support subsequent clinical development.

Choosing a Study Population
Choice of the subjects to include in the trial depends on the expected risks and potential benefits, recognizing that there will be considerable uncertainty about those expectations in an early-phase trial. Expected risks may be estimated from the nonclinical data, an understanding of the biological mechanisms, and any previous relevant human experience, but the clinical significance of those risks can depend on the population that receives the product.

Control Group and Blinding
The objectives of early-phase trials usually focus on safety, for which rigorous inference regarding comparison to a control (e.g., placebo) is not generally necessary. However, a concurrent control group may be particularly valuable for trials in diseases for which the natural history is not well-characterized or for trials that enroll subjects with a wide range of disease severity.

Dose and Regimen

Dose finding from Preclinical Data
A conventional allometric scaling methods for CGT products may be less precise than for small-molecule drugs, and traditional PK and pharmacodynamic correlations are not possible with cell and gene therapy. But the animal or in vitro data can provide sufficient information to determine if a specific starting dose has an acceptable level of risk.

Dose Escalation and Regimen
Clinical development of CGT products has often included dose escalation in half-log (approximately three-fold) increments. However, the dosing increments used for dose escalation should consider preclinical and any available clinical data regarding the risks and activity associated with changes in dose. Most first-in-human CGT trials are designed as a single administration or one-time dosing regimen to understand the lasting effect (durability) and associated safety risk.

Staggering Administration (Multi-Gated Enrollment)
When there is no previous human experience with a specific CGT product or related product, treating several subjects simultaneously may represent an unreasonable risk. To address this issue, most first-in-human trials of CGT products include staggered treatment to limit the number of subjects who might be exposed to an unanticipated safety risk. With staggered treatment, there is a specified follow-up interval between administration of the product to a subject, or small group of subjects, and administration to the next subject or group of subjects.

Monitoring and Follow-up

General Monitoring Considerations
In Early-phase trials, the assessments are conducted to unearth both expected and unexpected safety issues. General safety monitoring typically includes the recording of symptoms and common clinical measurements, such as physical examinations, chemistry profiles, complete blood counts, and possibly other examinations that are appropriate for the condition being investigated.

Specific monitoring program 
The specific monitoring program depends on multiple factors, such as the nature and mechanism of action of the product, the study population, the results of animal studies, and any related human experience. The monitoring program should continue both safety and pharmacologic activity regardless of whether or not they receive the complete treatment regimen. In early-phase clinical trials, the secondary outcome measure also includes efficacy outcome measures. These data can provide preliminary efficacy or proof-of-concept data to support subsequent clinical development.
For early-phase trials, all adverse events should be documented and reported. The inclusion of Data Monitoring Committee (DMC) could help ensure additional the safety of the participants in the clinical studies. 
Monitoring to look for unanticipated safety issues, evaluations may include assessments targeting specific safety issues that could be anticipated with CGT products. Such product-specific safety issues might include
  • Acute or delayed infusion reactions, autoimmunity, graft failure, GVHD, new malignancies, the transmission of infectious agents from a donor, and viral reactivation.
  • Cellular and humoral immune responses against CGT products
  • Persistence of the product (the presence of cells, vector, or virus in biological fluids or tissues)
  • The activity of CGT product (Physiologic effects, such as gene expression, protein activity or changes in biomarkers)
  • The potential for viral shedding
  • Analysis of integration into the genome

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