Moffitt Cancer Center

Cheryl Grove Cox

Cell Therapy manufacturing is growing at an exponential rate for both Clinical Trials and Commercial products. The number of cellular treatments for multiple disease indications approved by the Food and Drug Association (FDA) increases yearly. The key to maintaining the manufacturing pipeline of patient products will be the ability of the manufacturing facility to reliably produce safe quality products within a defined effectiveness criterion.The development of potency assays to establish mechanisms to measure efficiency is critical for product advancement and patient treatment.

Preliminary clinical evidence for a breakthrough therapy designation requires preliminary clinical support of a treatment effect that may represent substantial improvement over available therapies for the treatment of a serious condition. For purposes of breakthrough therapy designation, preliminary clinical evidence means evidence that is sufficient to indicate that the drug may demonstrate substantial improvement in effectiveness or safety over available therapies, but in most cases is not sufficient to establish safety and effectiveness for purposes of approval. FDA expects that such evidence generally would be derived from phase 1 or 2 trials. Nonclinical information could support the clinical evidence of drug activity. In all cases, preliminary clinical evidence demonstrating that the drug may represent a substantial improvement over available therapy should involve enough patients to be considered credible.

However, FDA recognizes that the data cannot be expected to be definitive at the time of designation. Ideally, preliminary clinical evidence indicating a substantial improvement over available therapies would be derived from a study that compares the investigational drug to an available therapy (or placebo if there is no available therapy) in clinical testing or from a study that compares the new treatment plus SOC to the SOC alone. FDA encourages sponsors to obtain some preliminary comparative data of this type early in development. Other types of clinical data that also could be persuasive include single-arm studies comparing the new treatment with well-documented historical experience. Generally, FDA expects that such historically controlled data would be persuasive only if there is a large difference between the new treatment and historical experience. Data demonstrating that a drug substantially increases overall response rate compared with historical controls (e.g., historical response rate with available therapy), with consideration of duration of the response, also could be persuasive.

Potency assays can be applied to several different areas of Cell Therapy production including product characterization, comparability testing, assessing manufacturing changes, stability studies and lot release testing. By the time the product has reached BLA, the potency assay must be fully vetted and measure the mechanism of action of the product in a quantitative manner using the appropriate reference standards and/or controls. The accuracy, sensitivity, specificity, and reproducibility of the assay must be established.

" The key to maintaining the manufacturing pipeline of patient products will be the ability of the manufacturing facility to reliably produce safe quality products within a defined effectiveness criterion "

Potency in early phase cell therapy product development under preclinical or IND work is not as stringent. In early phase product development, all assays used to measure potency should be described and justified. Quantitative assays are recommended; however, if none are available, a qualitative assay can be paired with an appropriate correlating quantitative physical assay. By the end of Phase 2, the FDA recommends that the potency assay consist of in vivo or in vitro tests that measure an appropriate biological activity. If the product is gene modified, an assay to quantify the expression of the gene therapy vector is recommended.

A validation plan must be written to effectively establish the performance characteristics of the procedure being validated.

The written validation plan must include at a minimum:

• The number and types of samples to be studied

• The study designs

• Acceptance criteria for each parameter

• Data analysis plan

The study design for the validation plan must include an assessment of the potency assay accuracy, precision, range, and specificity. Although not specifically required by the USP, in some cases, sensitivity and robustness may also be applicable.

In the early clinical trial stages, performing multiple potency test can be beneficial. The test results can be aligned with the clinical outcomes to determine which testing platform or platforms are most reliable, robust, feasible for routine use, and provide applicable data. As the trials move into late phase 2 or phase three, the potency test should be limited to one or a small panel that can be formally incorporated into the product release process.

The potency data is another important criterion to evaluate for the release of a cell therapy product in conjunction with purity and identity. However, always to be considered is the variability in the (patient-specific) starting material and the impact to the potency results, making specifications setting challenging. Many studies have already been performed to start unraveling the complex interaction of immune cells with and within the human body environment. With increased in vivo knowledge, improved and adapted manufacturing processes for cell-based products are expected to be established leading to improvements in quality control testing and guidance for potency assay development. A potent in vitro response may not always correlate with prolonged time to progression or patient survival. The final objective of a potency assay validation is to provide an assay or set of assays which are accurate, sensitive, specific, and reproducible in addition to producing reliable data on the quality of each product.