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Navigating Orphan Drug Regulations for Gene Therapy Products

Human gene therapy products, like other medicines, may be eligible for an orphan drug status or designation provided sponsors can demonstrate that the product can treat a rare disease and that they can prove a scientific rationale basis for product’s effectiveness in treating the rare disease. If the eligibility criteria is met, then the orphan drug designation can provide financial incentives, waiver of fee for human drug marketing application, and exclusive marketing rights for up to seven years subject to meeting certain criteria. Regulatory agencies across the globe are enhancing the regulatory framework surrounding orphan drugs to ensure there are treatment options available for rare diseases while also offering sponsors with other benefits. An example is the US FDA’s guidance document for interpreting human gene therapy products as orphan drugs under the principle of equivalence.

How to submit an Orphan Drug Designation Request to the US FDA

Sponsors should submit designation requests to the Office of Orphan Products Development (OOPD) making sure they are in line with the requirements of 21 CFR 316.20: Content and format of a request for orphan-drug designation. They can submit their designation request at any time before submitting a marketing application. The US FDA recommends to communicate with the OOPD for any questions related to orphan drug designation, and Office of Tissues and Advanced Therapies (or Center for Biologics Evaluation and Research) for questions related to particular gene therapy product development programs.

If a sponsor requests an orphan designation for a medicine that is similar to one that has already been approved for the same indication or use, then the sponsor must provide reasonable hypothesis that their drug is superior (from a clinical perspective) to the medicine that has previously been approved. When reviewing and deciding the grant for market approval, the US FDA evaluates whether the drug falls under orphan-drug exclusivity. 

Rationale for Interpreting the Sameness of Gene Therapy Products under Orphan Drug Regulations

According to the US FDA, a “same drug” for a product that constitutes macromolecules is a drug containing the same primary molecular features and is for the same indication and use as the previously approved drug. However, if the sponsor can prove that the proposed product is clinically superior to the approved drug, then these are not considered the same. While orphan drug regulations further highlight which criteria should be applied for other drugs (protein, polysaccharide, polynucleotide, etc) that have the same therapeutic intent, they do not address whether the definition of “same drug” is applicable to gene therapy products especially those that intend to achieve orphan-drug designation and exclusivity. Hence, the US FDA’s guidance document on Interpreting the Sameness of Gene Therapy Products under Orphan Drug Regulations describes how these criteria may apply to human gene therapies. 

Interpreting Sameness of Gene Therapy Products

For orphan-drug designation and exclusivity eligibility, assuming two gene therapy products target the same indication, the FDA assesses sameness based on 21 CFR 316.3(b)(14)(ii), emphasizing principal molecular structural features, notably transgenes and vectors.

  • Transgenes and Vectors:
    • Different transgenes or vectors categorize gene therapy products as distinct drugs, irrespective of vector similarity.
    • Variations in viral groups or within the same group, impacting factors like tropism or immune response, classify vectors as different.
    • Minor differences in transgenes or vectors, like polymorphisms, do not warrant distinct categorization.
  • Additional Features:
    • Additional components contributing to therapeutic effects, such as regulatory elements or transduced cell types, are considered on a case-by-case basis to determine drug sameness.


FDA evaluates sameness primarily based on transgenes and vectors, considering additional product features as necessary. Minor variations do not automatically denote distinct drugs, with each case subject to individual scrutiny. The guidance aims to provide clarity and direction to stakeholders navigating the complex landscape of gene therapy development for rare diseases under FDA oversight.

As part of its pharmaceutical product portfolio, DDReg provides regulatory solutions for biotechnology products throughout the entire product lifecycle. With experience of over 120 regulatory agencies and subject matter expertise, DDReg is the go-to-partner for pharmaceutical regulatory services. Read more from the experts: Harmonization for the Development of Cell and Gene Therapies