Interpreting Sameness of Gene 
Therapy Products Under the Orphan 
Drug Regulations
 
 
 
Guidance for Industry 
 
 
 
 
 
 
 
 
 
 
 
Additional copies of this guidance are available from the Office of Communication, Outreach 
and Development (OCOD), 10903 New Hampshire Ave., Bldg. 71, Rm. 3128, Silver Spring, 
MD 20993-0002, or by calling 1-800-835-4709 or 240-402-8010, or email ocod@fda.hhs.gov, or 
from the Internet at https://www.fda.gov/vaccines-blood-biologics/guidance-compliance-
regulatory-information-biologics/biologics-guidances. 
 
For questions on the content of this guidance, contact OCOD at the phone numbers or email 
address listed above. 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Biologics Evaluation and Research 
Office of Orphan Product Development 
September 2021 
    Contains Nonbinding Recommendations 
 
Table of Contents 
 
 
I.  INTRODUCTION............................................................................................................. 1 
II.   BACKGROUND ............................................................................................................... 2 
III.   INTERPRETING SAMENESS OF GENE THERAPY PRODUCTS ......................... 3 
ii  Contains Nonbinding Recommendations 
 
Interpreting Sameness of Gene Therapy Products Under the 
Orphan Drug Regulations 
 
 
Guidance for Industry 
 
 
This guidance represents the current thinking of the Food and Drug Administration (FDA or 
Agency) on this topic.  It does not establish any rights for any person and is not binding on FDA 
or the public.  You can use an alternative approach if it satisfies the requirements of the 
applicable statutes and regulations.  To discuss an alternative approach, contact the FDA staff 
responsible for this guidance as listed on the title page.  
 
I.  INTRODUCTION 
This guidance provides FDAs current thinking on determining sameness of human gene 
therapy1 products under FDAs 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. 
 
 
1 Human gene therapy seeks to modify or manipulate the expression of a gene or to alter the biological properties of 
living cells for therapeutic use.  FDA generally considers human gene therapy products to include all products that 
mediate their effects by transcription or translation of transferred genetic material, or by specifically altering host 
(human) genetic sequences.  Some examples of gene therapy products include nucleic acids (e.g., plasmids, in vitro 
transcribed ribonucleic acid (RNA)), genetically modified microorganisms (e.g., viruses, bacteria, fungi), engineered 
site-specific nucleases used for human genome editing, and ex vivo genetically modified human cells.  Gene therapy 
products meet the definition of biological product in section 351(i) of the Public Health Service Act (42 
U.S.C. 262(i)) when such products are applicable to the prevention, treatment, or cure of a disease or condition of 
human beings (see Federal Register Notice: Application of Current Statutory Authorities to Human Somatic Cell 
Therapy Products and Gene Therapy Products (58 FR 53248, October 14, 1993)), available at 
https://www.fda.gov/media/76647/download.  For additional information regarding human gene therapies, please 
see, e.g., Chemistry, Manufacturing, and Control (CMC) Information for Human Gene Therapy Investigational New 
Drug Applications (INDs); Guidance for Industry, January 2020, available at 
https://www.fda.gov/media/113760/download.  
1  Contains Nonbinding Recommendations 
 
II.  BACKGROUND 
As with other drugs,2 a human gene therapy product may qualify for orphan-drug designation3 if 
it is intended for the treatment of a rare disease or condition4 and the sponsor provides sufficient 
scientific rationale to establish a medically plausible basis for expecting the drug to be effective 
in the rare disease.5  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,6 and consideration for seven years of 
orphan-drug exclusivity, as long as the eligibility criteria are met.7  
 
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.8  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 drug10 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.11  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.12  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 
 
2 For the purposes of this guidance, the term drug refers to both human drug and biological products. 
3 A public database of orphan-drug designations and approvals is available at 
https://www.accessdata.fda.gov/scripts/opdlisting/oopd/. 
4 Section 526 of the Federal Food, Drug, and Cosmetic Act (FD&C Act), 21 U.S.C. 360bb, generally defines a rare 
disease or condition as any disease or condition that affects fewer than 200,000 persons in the United States. 
5 See section 526 of the FD&C Act, 21 U.S.C. 360bb; see also 21 CFR Part 316, Subpart C. 
6 For more information regarding the fee exemption, please see section V of Prescription Drug User Fee Act 
Waivers, Reductions, and Refunds for Drug and Biological Products; Guidance for Industry, October 2019, 
available at https://www.fda.gov/media/131797/download.   
7 See section 527 of the FD&C Act, 21 U.S.C. 360cc; see also 21 CFR 316.3(b)(12) and 21 CFR Part 316, Subpart 
D. 
8 See Meetings with the Office of Orphan Products Development: Guidance for Industry, Researchers, Patient 
Groups, and Food and Drug Administration Staff, July 2015, available at 
https://www.fda.gov/media/111946/download. 
9 For more information regarding recommendations on formal meetings between FDA and sponsors or applicants 
relating to the development and review of biological products, please see Formal Meetings Between the FDA and 
Sponsors or Applicants of PDUFA Products, Draft Guidance for Industry, December 2017, available at 
https://www.fda.gov/media/109951/download.  When finalized, this guidance will represent FDAs current thinking 
on this topic. 
10 21 CFR 316.3(b)(14). 
11 21 CFR 316.20(a). 
12 21 CFR 316.31. 
2  Contains Nonbinding Recommendations 
 
same use or indication.13  Consideration of clinical superiority is based on greater efficacy, 
greater safety, or a major contribution to patient care.14 
 
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.15  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.16  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 orphan-
drug exclusivity.  This guidance describes FDAs current interpretation of how the regulatory 
sameness criteria apply to gene therapies. 
III.  INTERPRETING SAMENESS OF GENE THERAPY PRODUCTS 
For the purpose of granting orphan-drug designation and determining eligibility for orphan-drug 
exclusivity, assuming that two gene therapy products are intended for the same use or indication, 
FDAs determination of sameness will consider, per 21 CFR 316.3(b)(14)(ii), the principal 
molecular structural features of the gene therapy products.  FDA generally intends to consider 
certain key features such as transgenes and vectors used in gene therapy products to be principal 
molecular structural features under this regulation.17  For example, for two gene therapy 
products intended for the same use or indication: 
 
  If the two gene therapy products express different transgenes (e.g., transgenes that encode 
different enzymes for treatment of the same rare disease), FDA generally intends to 
consider them to be different drugs for purposes of 21 CFR 316.3(b)(14)(ii) because they 
will not contain the same principal molecular structural features.  This applies whether 
the products have or use the same vector or different vectors. 
  If the two gene therapy products have or use different vectors, FDA generally intends to 
consider them to be different drugs for purposes of 21 CFR 316.3(b)(14)(ii) because they 
will not contain the same principal molecular structural features.  This applies whether 
the products express the same transgene or different transgenes.  For example:  
-  FDA generally intends to consider vectors from a different viral group (e.g., 
gammaretrovirus vs. adeno-associated virus (AAV)) to be different for purposes 
of 21 CFR 316.3(b)(14)(ii). 
 
13 Section 527(c) of the FD&C Act; 21 CFR 316.34(c). 
14 21 CFR 316.3(b)(3). 
15 21 CFR 316.3(b)(14)(ii). 
16 21 CFR 316.3(b)(14)(ii)(A)-(D). 
17 For the definitions of and additional information regarding transgenes and vectors, please see, e.g., Long Term 
Follow-Up After Administration of Human Gene Therapy Products; Guidance for Industry, January 2020, available 
at https://www.fda.gov/media/113768/download.   
 
3  Contains Nonbinding Recommendations 
 
-  FDA generally intends to consider vectors from the same viral group (e.g., adeno-
associated virus 2 (AAV2) vs. adeno-associated virus 5 (AAV5), or 
gammaretrovirus vs. lentivirus) to be different for purposes of 21 CFR 
316.3(b)(14)(ii), when the differences between the vectors impact factors such as 
tropism, immune response avoidance, or potential insertional mutagenesis. 
-  FDA generally intends to determine whether variants of a vector from the same 
viral group (e.g., AAV2 vs. a variant of AAV2) are the same or different for 
purposes of 21 CFR 316.3(b)(14)(ii) on a case-by-case basis.  
In the scenarios described in the bullets above, FDA generally does not intend to consider these 
principal molecular structural features to be different for purposes of 21 CFR 316.3(b)(14)(ii) if 
there are only minor differences (e.g., polymorphism) in the transgenes and/or the vectors.  In 
other words, FDA does not intend to consider two gene therapy products to be different drugs 
based solely on minor differences between their transgenes and/or vectors.  FDA generally 
intends to determine whether differences between the transgenes and/or vectors are minor 
differences on a case-by-case basis. 
If two gene therapy products express the same transgene and have or use the same vector, 
determining whether the gene therapy products are the same drug for purposes of 21 CFR 
316.3(b)(14)(ii) may also depend on additional features of the final product that can contribute to 
the therapeutic effect.  These additional features may include regulatory elements (e.g., 
promoters, enhancers, or splicing elements), or for ex vivo genetically modified cells, may 
include the cell type that is transduced.  In these cases, FDA generally intends to determine 
whether the two gene therapy products are different drugs for purposes of 21 CFR 
316.3(b)(14)(ii) on a case-by-case basis. 
4