For gene therapies, FDA drafts trial guidance, finalizes "sameness" for orphan exclusivity

Regulatory NewsRegulatory News | 30 September 2021 |  By 

A new draft guidance from the US Food and Drug Administration (FDA) gives cell and gene therapy developers a detailed framework for the conduct of umbrella trials, offering the potential for enhanced speed and efficiency in early-stage clinical trials.
In the umbrella trials envisioned under the draft guidance, two or more versions of a cellular or gene therapy product would be studied for one specific disease using just one trial design, shared infrastructure, and a master protocol. Each individual candidate within the umbrella trial would ordinarily have a unique investigational new drug (IND) application, but the applications can cross-reference each other.
“The potential benefits of this type of umbrella trial include flexibility and efficiency in product development,” explained FDA in the background it provided for the draft guidance. “Instead of an iterative approach to clinical studies, multiple versions of a cellular or gene therapy product can be studied in parallel, which may expedite early clinical development by expeditiously identifying alternative versions of a product that may be safer or more effective.”
FDA enumerated these and other potential efficiencies in the use of umbrella trials for cell and gene therapies, noting that the scope of the draft guidance is limited to early-phase studies of these products for a single disease. “Basket” trials that evaluate one therapy in a number of different populations are excluded from the scope of the guidance; sponsors must also have “complete access to proprietary information” for the products being considered in order to avail themselves of the conditions of the guidance.
The framework set forth in the draft guidance is designed to minimize repetition of effort in the submission of INDs; one “primary” IND will contain most clinical information about the umbrella trial, while “secondary” INDs need not include the clinical information, although they should cross-reference the primary submission.
On the other hand, chemistry, manufacturing and controls (CMC) and pharmacology and toxicology (P/T) information and other data specific to the sub-products in the umbrella trial should each be included in the respective INDs, since they will be unique to the version being studied under that IND.
When study arms are added that include a new version of the investigational product, sponsors can submit a new secondary IND that includes CMC and P/T information pertinent to that new version, while cross-referencing the primary IND for clinical information.
The draft guidance also walks sponsors through the suggested procedure for submitting other changes or new information such as new P/T reports or changes to CMC information for one version of the investigational product.
In each case, recommended procedures flow from the basic premise that changes that apply to one version of the investigational product should be submitted in relation to that individual IND, whether it’s a primary or secondary IND. On the other hand, a proposed change to the umbrella trial clinical protocol — i.e., a change that would affect all products being studied under the umbrella — should be submitted to the primary IND and need not also be submitted to the secondary INDs.
FDA may have occasion to place a clinical hold on the entire umbrella trial, or just to individual study arms; the guidance outlines the actions sponsors should take for each study arm in various possible clinical hold scenarios.
Safety reporting, “at a minimum,” should be submitted for the Primary IND and for the secondary IND that is affected by the safety report. However, if a safety report could affect multiple products within the umbrella trial, safety reports should be filed for the INDs of all products that could potentially be affected.
An integrated annual report can be submitted to the primary IND and each secondary IND, but an annual report is mandated for each IND under 21 CFR 312.33, notes FDA in the draft guidance.
When a study arm is being discontinued for any reason, FDA notes in the guidance that “we do not recommend that the sponsor withdraw [the] Primary IND…because it contains the relevant clinical information.” Instead, advises the agency, the sponsor should submit an updated protocol to the primary IND that does not include the discontinued product.
In the case that a primary IND is withdrawn while other products are still being studied, sponsors should designate another product to have the primary IND, and update and transfer clinical protocol information to the now-primary IND. All cross-referencing for all INDs in the umbrella trial will also need updating.
When moving a product along to a Phase 3 trial, the protocol should be submitted to the IND that contains CMC and P/T information for the product that is being advanced.
The draft guidance closes by noting that alternative trial structures may be acceptable to FDA; sponsors should plan early communication the agency’s Office of Tissues and Advanced Therapies at the Center for Biologics Evaluation and Research to discuss these approaches.
FDA’s finalized gene therapy “sameness” guidance
FDA has also issued a final version of a guidance that tells developers how the agency will interpret “sameness” of gene therapies when making decisions about orphan exclusivity. The final version offers some clarification and further examples but leaves the meat of the January 2020 draft largely unchanged. (RELATED: FDA finalizes six gene therapy guidances, unveils a new draft, Regulatory Focus 28 January 2020)
Industry’s reaction to the draft guidance asked for some of this clarification; the Biotechnology Innovation Organization (BIO) asked for more clarify in what the agency would consider to be a principal molecular structural feature, as well as how the agency would address two gene therapy products that shared both transgene expression and viral vector.
BIO, along with the American Society of Gene and Cell Therapy, also queried the agency on the factors it would use in case-by-case determination of sameness. (RELATED: Gene therapies: Industry asks for clarification on FDA’s sameness guidance, Regulatory Focus 27 July 2020)
Orphan drug regulations that define when drugs are the “same drug” do not address how that definition would apply to gene therapy products, so FDA drafted the guidance to clarify its stance.
The final guidance leaves intact the general framework of the draft, where gene therapies expressing different transgenes are considered different drugs for orphan exclusivity purposes, regardless of which vectors are used.
Similarly, gene therapy products that use different vectors are generally considered different drugs, even if they express the same transgene. However, for both vectors and transgenes, mere polymorphism or another minor difference will probably not be sufficient for FDA to consider the two variations as different drugs for the purposes of orphan exclusivity.
However, even two vectors that lie within the same viral group, such as a gammaretrovirus and a lentivirus, will generally be considered different “when the differences between the vectors impact factors such as tropism, immune response avoidance, or potential insertional mutagenesis.” In these cases, though, sameness of difference of variants of a vector from the same viral group will be judged by FDA on a case-by-case basis.
Additional regulatory elements such as promotors or splicing elements, or the type of cell being transduced, may also influence FDA’s decision-making about sameness, notes the agency in the guidance.
Studying Multiple Versions of a Cellular or Gene Therapy Product in an Early-Phase Clinical Trial
Interpreting Sameness of Gene Therapy Products Under the Orphan Drug Regulations


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