Gene therapy product similarity determination Industry requires more clarification

Developers of the Serin-Bluewood gene therapy product are seeking more explanations from the U.S. FDA to determine when the same class of viral vectors can be considered different enough for the purpose of granting orphan drug identification or franchise.
In addition, stakeholders want the FDA to better define the types of nuances and provide examples that affect the FDA's determination of "similarity" under orphan drug regulations, and to share its lessons when it identifies gene therapy products.
's draft guidelines for interpreting the similarity of gene therapy products in accordance with orphan drug regulations, released in January, the FDA said that if two gene therapy products have the same use or adaptability, certain key characteristics, such as genetically modified and vectors, will be considered "primary molecular structural characteristics" in determining the identity of orphan drugs and the identification of franchises.
if two gene therapy products express different genetically modified and/or use vectors from different virus categories, the FDA usually intends to treat them as different drugs.
, however, the FDA will determine whether two vectors from the same virus category (e.g., adeno-related virus 2 (AAV2) are the same or different from adeno-related virus 5 (AAV5) on a case-by-case basis.
the unnecessary franchise reward for preventing trivial changes between products, the FDA says it will not treat two gene therapy products as different drugs based solely on "small differences" between genetically modified and/or vectors of the two gene therapy products.
If two gene therapy products express the same GM and use the same vector, the determination of whether the two are the same drug may also depend on other characteristics of the product that are helpful for therapeutic effect, including regulatory elements, or cells used for gene modification, which may include the type of cells that are transducted.
two vectors from the same virus category, in their feedback on the draft guidelines, the bidders expressed concern about the ambiguous practice of fda-recommended case-by-case determination of similarity between the two vectors from the same virus category.
BioMarin, "we appreciate the FDA's intention to determine whether two vectors from the same virus category (for example, AAV2 and AAV5) are the same or different on a case-by-case basis."
considering the huge development of gene therapy products using AAV vectors, it would be helpful to further clarify the FDA's thinking on factors that may be considered at the same or different time in determining vectors in the same virus category.
" Pfizer recommends treating two seroslots from the same virus category, such as AAV2 and AAV5, as different.
, "The difference is scientifically supported, " says Mr Pfizer.
evolutionary differences are captured by the classification of the development of small virus systems and are known to affect biological characteristics such as immunogenicity, addiction, and infectiousness.
" similarly, Regeneron asked the FDA to identify two vectors from the same virus category with different serotypes as sufficient to classify two gene therapy products as different.
AAV serotypes may show differences in tissue narcissism, GMO expression and immunogenicity, which are important features that can seriously affect product safety and effectiveness, according to the company.
", we recommend classifying gene therapy products from different genotypes as different products.
a case-by-case approach would lead to uncertainty, controversy and potential controversy, which would hinder innovation in the development of certain types of gene therapy products.
" many commentators urged the FDA to clarify which gmos and vectors may constitute "small differences" and provide specific examples.
, the industry urged the FDA to clarify the meaning of "other characteristics" of gene therapy products and provide examples, such as which "regulatory elements" may be relevant and used to determine similarity.
CSL Behring requires the FDA to include delivery systems and manufacturing technologies as "other characteristics" in determining differences in similarity.
BioMarin requires the FDA to provide examples of information types, such as research and development data or non-clinical data, "which will help the FDA determine whether other characteristics, such as regulatory elements that act as regulators for different promoters, can contribute to the determination of therapeutic effects, so that these other characteristics can be considered as major molecular structural characteristics."
" public meetings and experience sharing, given the limited experience to date in identifying orphan drugs in the field of gene therapy, several feedbacks highlight the need for the FDA to continuously learn and share information with bidders.
Biotech Innovations (BIO) said,
The regulatory discussions surrounding gene therapy products and, of course, the science are still developing, and there may not be enough information to understand all possible scenarios in which gene therapy products may differ."
addition, it is not possible or has not yet been measured for factors that may eventually lead to significant differences in clinical safety and effectiveness.
, as we gain more experience, we emphasize the importance of FDA updating and engaging stakeholders.
" BIO recommends that the FDA hold a public meeting and issue discussion guidelines to gather the views of other stakeholders and consider including them in the draft question-and-answer guide.
discussion guidelines and the draft question-and-answer guidelines should address the FDA's thinking on the following issues: What does the FDA consider to constitute a "major molecular structure feature" in terms of gene therapy guidelines? What factors does the FDA consider on a case-by-case basis when two gene therapy products express the same GM and use vectors of the same virus category? What do the FDA consider to be other "regulatory elements" that may be separated from other gene therapy products? How will the FDA consider other factors when determining similarity? The Alliance for Regenerative Medicine (ARM) says that once the FDA believes it has enough experience, it should share the lessons it has gathered as a general principle as to why orphan drug identification or franchises are granted or not granted.
," arm said, "Based on the FDA's experience in determining similarity, it would be helpful if the FDA could provide more information on relevant considerations."
, for example, unique considerations for different types of gene therapy products to provide more clarity at the product type level.
, the National Organization for Rare Diseases says that as scientific developments and FDA experience accumulate, their thinking should be shared on other characteristics that help or do not contribute to similarity.
NORD said more guidance was needed on the interpretation of "small differences" in GM and vectors, as a lack of clarity could affect how bidders develop their research and development plans and impact investment and innovation.
"As the FDA acquires more knowledge and experience, it is critical for the FDA to clearly communicate what constitutes a nuance, how this decision is made, and how drug developers collect this information to maximize the incentives provided by the Orphan Drug Act."
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