This guidance provides FDA’s current thinking on determining sameness of human gene therapy1 products under FDA’s orphan drug regulations for the purpose of orphan-drug designation and orphan-drug exclusivity. This guidance is intended to assist stakeholders, including industry and academic sponsors who seek orphan-drug designation and orphan-drug exclusivity, in the development of gene therapies for rare diseases. This guidance focuses specifically on factors that FDA generally intends to consider when determining sameness for gene therapy products and does not address sameness determinations for other types of products. This guidance finalizes the draft guidance of the same title dated January 2020.
The contents of this document do not have the force and effect of law and are not meant to bind the public in any way, unless specifically incorporated into a contract. This document is intended only to provide clarity to the public regarding existing requirements under the law. FDA guidance documents, including this guidance, should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited. The use of the word should in FDA guidances means that something is suggested or recommended, but not required.
As with other drugs, a human gene therapy product may qualify for orphan-drug designation if it is intended for the treatment of a rare disease or condition and the sponsor provides sufficient scientific rationale to establish a medically plausible basis for expecting the drug to be effective in the rare disease. Orphan-drug designation may provide the sponsor of a gene therapy product with financial incentives, including tax credits for qualified clinical testing and waiver of the human drug application fee for a marketing application, and consideration for seven years of orphan-drug exclusivity, as long as the eligibility criteria are met.
In order to be considered for orphan-drug designation, a sponsor must submit a request for designation for its drug to the Office of Orphan Products Development (OOPD) following the procedures described in 21 CFR 316.20. Sponsors can apply for orphan-drug designation at any point prior to submission of a marketing application. If sponsors have questions regarding orphan-drug designation, we recommend contacting OOPD. If sponsors have questions related to specific gene therapy product development programs, we recommend contacting the Office of Tissues and Advanced Therapies in the Center for Biologics Evaluation and Research (e.g., through an IND amendment requesting advice or through a formal meeting request).9
If a sponsor requests orphan-drug designation for a drug that is the same drug as a drug already approved for the same use or indication, the sponsor is required to provide a plausible hypothesis that its drug is clinically superior to the previously approved drug. When FDA grants marketing approval for a drug for a use or indication within the rare disease or condition for which the drug received orphan-drug designation, FDA will determine if the drug is eligible for orphan-drug exclusivity. If FDA previously approved the same drug for the same use or indication, to be eligible for orphan-drug exclusivity, the sponsor of the new drug will need to demonstrate that its drug is clinically superior to all previously approved same drugs for the same use or indication. Consideration of clinical superiority is based on greater efficacy, greater safety, or a major contribution to patient care.
The orphan drug regulations define “same drug” for a drug composed of large molecules (macromolecules) as a drug that contains the same principal molecular structural features (but not necessarily all of the same structural features) and is intended for the same use or indication as a previously approved drug, except that, if the subsequent drug can be shown to be clinically superior, it will not be considered to be the same drug. The regulations further describe the criteria to be applied for protein drugs, polysaccharide drugs, polynucleotide drugs, and closely related, complex partly definable drugs with similar therapeutic intent, such as two live viral vaccines. However, the regulations do not elaborate on how the “same drug” definition applies specifically to gene therapy products for the purposes of orphan-drug designation and orphandrug exclusivity. This guidance describes FDA’s current interpretation of how the regulatory “sameness” criteria apply to gene therapies.
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