CGT Initial Trials: Latest FDA Recommendations

The development of cell and gene treatments necessitates the rigorous screening of numerous product variants. To assist with this initial process and to ensure that appropriate evidence is gathered so that effective variants of the product are taken through to later-stage trials, the FDA has issued a finalized guidance, Studying Multiple Versions of a Cellular or Gene Therapy Product in an Early-Phase Clinical Trial. This publication mixes cell and gene therapy products, ostensibly because they are overlapping fields of biopharmaceutical research with similar therapeutic goals, such as targeting DNA or RNA inside or outside the human body.

The purpose of the recommendations is to provide an overview of key safety considerations and data verifications to support efficacy claims for studies using numerous iterations of a cellular or gene therapy product in an early-phase clinical trial for a single disease within a single clinical trial. The purpose of these studies is to select the version(s) of the product to move forward with for later-stage trials and a potential IND application, not to offer primary proof of efficacy to support a marketing application.

In September 2021, the guidance was released in draft form. Since then, it has changed to clarify the statistically significant differences between test versions of a product.

Initial Phase Trials’ Aim

The need for the guidelines was brought on by clinical trial sponsors who wanted to use various iterations of a cellular or gene therapy product in a single clinical study to acquire preliminary data on activity and safety. Given the price and complexity of later-stage trials, these methods, also referred to as “umbrella studies,” must be carefully planned. Early-stage trials need to gather data that will be useful for making decisions about which product variants to pursue, but they do not need to collect statistically significant data on efficacy; rather, they only need to meet the safety requirements. For each product variation, specifics on the formulation, manufacturing safeguards, and toxicological data for the variant product must be presented in order to establish safety.

Each product version must submit a new IND to the FDA for each stage of the clinical trial procedure after the initial one. As a result, every iteration of a cell or gene therapy product that is developed is viewed as a separate product. The guidance makes clear the kinds of modifications to product design that qualify as “different versions” to guarantee that there is no doubt regarding this.

Trial Protocol Development

The guidelines for developing a master protocol to review many iterations of a cell or gene therapy product, with an emphasis on both the product’s safety and an evaluation of the bioactivity of each version of the trial product, are very significant for biopharmaceutical companies. This is done to make sure that there is a suitable level of scientific and clinical knowledge before Phase 1 studies involving patients and analyzing responses to dose escalation are conducted. The FDA’s master protocol guideline, released in March 2022, is connected to the guidance in this area. Avoiding any excessive interpretation of the results is crucial to keep in mind when developing a master protocol.

Characterizing and recognizing risk is a crucial component of protocol development. The role of the genetic material’s carrier, or “vector,” in gene therapy carries the possibility of harm. Most vectors are genetically modified viruses. The risks that must be managed include preventing an unwelcome immune response and the ensuing inflammation; a lack of precision, where the vector targets the incorrect cells and causes damage to healthy cells; direct infection brought on by the carrier virus; and tumorigenesis, should the genes carried by the vector be introduced in the incorrect place along the target DNA.

According to the guidance’s definition, any modification to the genetic sequence of a vector, promoter or enhancer, or transgene results in a “new version” of the product.

Getting Ready for Later Cycles

The updated guideline is particularly helpful for trial sponsors since it outlines the key requirements for designing and organizing INDs, submitting new material, and capturing and reporting adverse events. To prevent needless duplication of effort, the guidance explains how a sponsor can designate a primary IND (an IND that holds details about the master trial protocol, attributed to as “IND A”) and how to assign one or more ancillary INDs (these will contain precise details about a chosen product version, but they are not required to replicate the data about the umbrella trial provided in the “Primary IND,” and these are regarded to as “IND Bs”). This nomenclature serves to distinguish between INDs that are obliged to encompass clinical information about the overarching study (principal INDs) and those that are not (secondary INDs).

The recommendation suggests adding a tertiary IND (known as a “IND C”) whenever a “arm”—a specific intervention employing a novel variation of the investigational cellular or gene therapy—is added to the trial. Cross-referencing each additional research arm necessitates updating both the secondary and primary INDs. The primary IND should be revised to incorporate the chemistry, manufacturing, and controls, along with the pharmacology/toxicology parameters, for product C. The FDA requires that sponsors provide a letter for the amendment to the primary IND, detailing the secondary IND number(s), comprising IND C.

The Partial Hold Phase

The guidance highlights safety by stressing that if one arm is put on hold, the Primary IND must transition to a partial hold phase. The FDA might demand that this be placed on indefinite pause. When a partial hold is in effect, the trial sponsor is obligated to send the agency a reply to each IND that was put on hold. The details offered should be focused on the specific IND phase that prompted the delay.

Issuance of FDA Guidelines-Adherent Safety Reports

Safety reports must be issued for an experimental drug with respect to all of the sponsor’s INDs that are pertinent to that product, and reporting requirements must adhere to previous FDA guidelines (including all versions of the product). The necessity to submit an annual report for all ongoing studies is still in place, just like it is for other trials.

The revised guidance does not rule out the consideration of alternate ways for structuring and arranging INDs for studies involving several versions of an investigational product or trials in a single disease, so long as these are well-planned and supported by science. This is consistent with the guidance’s main goal, which is to organize trials for the next generation of life-saving medications in a manner that makes sense.

The FDA welcomes your feedback at any time. The docket number FDA-2021-D-0776 should be included in the header of all written comments.

Engr. Dex Marco Tiu Guibelondo, BS Pharm, RPh, BS CpE

Editor-in-Chief, PharmaFEATURES