Studying Multiple Versions of a Cellular or Gene Therapy Product in an Early-Phase Clinical Trial: Guidance for Industry

Administrative guidance, not enacted legislation. This captured publisher edition preserves the listed document and attachments; later developments are not independently consolidated.

Studying Multiple Versions of a
Cellular or Gene Therapy Product in
an Early-Phase Clinical Trial
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
November 2022

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Table of Contents
I. 	INTRODUCTION............................................................................................................. 1
II. 	BACKGROUND ............................................................................................................... 2
III. 	SCOPE ............................................................................................................................... 2
IV. 	SUBMISSION OF INFORMATION TO INDS ............................................................. 3
A. 	Overview ................................................................................................................ 3
B. 	Adding Arms to the Study.................................................................................... 5
C. 	Submitting Other Types of Changes or New Information ................................ 6
D. 	Clinical Holds and Responses to Hold ................................................................ 6
E. 	Reporting ............................................................................................................... 6
F. 	Completion of Study or Arm(s) ........................................................................... 7
V. 	ALTERNATIVE APPROACHES................................................................................... 8
APPENDIX .................................................................................................................................... 9

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Studying Multiple Versions of a Cellular or Gene Therapy Product
in an Early-Phase Clinical Trial
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
The purpose of this guidance is to provide recommendations to sponsors interested in studying
multiple versions of a cellular or gene therapy1 product in an early-phase clinical trial2 for a
single disease. Sponsors have expressed interest in gathering preliminary evidence of safety and
activity using multiple versions of a cellular or gene therapy product in a single clinical trial.
Although multiple versions of a product can be studied together in a single clinical trial, each
version of the product is distinct and is generally submitted to FDA in a separate investigational
new drug application (IND). The objective of these early-phase clinical studies is to guide which
version(s) of the product to pursue for further development in later-phase studies. Thus, these
studies are not intended to provide primary evidence of effectiveness to support a marketing
application and generally are not adequately powered to demonstrate a statistically significant
difference in efficacy between the study arms. In this guidance, we, FDA, provide
recommendations for studies that evaluate multiple versions of a cellular or gene therapy
product, including how to organize and structure the INDs, submit new information, and report
adverse events. This guidance finalizes the draft guidance of the same title dated September
2021.
In general, FDA’s guidance documents do not establish legally enforceable responsibilities.
Instead, guidances describe the Agency’s current thinking on a topic and should be viewed only
as recommendations, unless specific regulatory or statutory requirements are cited. The use of
1 This guidance does not apply to vaccines intended to prevent infectious diseases, bacteriophage products, live
biotherapeutic products, fecal microbiota for transplantation (FMT) products and allergenic products.
2 This guidance applies only to early-phase clinical trials of cellular or gene therapy products. Later-phase clinical
trials raise different and additional considerations, including those pertaining to subject selection, safety monitoring,
and effectiveness evaluation. For additional information on early-phase clinical trials of cellular and gene therapy
products, see Considerations for the Design of Early-Phase Clinical Trials of Cellular and Gene Therapy Products;
Guidance for Industry, June 2015, https://www.fda.gov/media/106369/download.

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the word should in Agency guidances means that something is suggested or recommended, but
not required.
II. 	BACKGROUND
Clinical trials that study multiple products in parallel for a particular disease or condition under a
master protocol are commonly referred to as “umbrella” trials. In contrast to traditional trial
designs where only one product is evaluated in a single clinical trial, umbrella trials use a single-
trial infrastructure, design, and master protocol to simultaneously evaluate multiple products for
a specific disease or condition, allowing for more efficient product development.
This guidance focuses on a certain type of umbrella trial, where the products are multiple
versions of a cellular or gene therapy product being studied in a single disease. The differences
between the product versions are intended to yield differences in safety or activity, and therefore
the product versions are generally submitted in separate INDs that are cross-referenced among
each other. For example, a sponsor investigating an autologous chimeric antigen receptor (CAR)
T cell product may wish to also investigate a different version of the product (e.g., an altered
CAR protein domain to increase CAR activity, or a new cell source such as an allogeneic donor).
In this situation, the different product versions are considered individual investigational drugs,
but they could be simultaneously evaluated within the same overall trial, as described further in
this guidance. Refer to the Appendix for additional examples of versions of a cellular or gene
therapy product that would be within the scope of this guidance.
The potential benefits of this type of umbrella trial include flexibility and efficiency in product
development. Instead of an iterative approach to clinical studies, multiple versions of a cellular
or gene therapy product can be studied in parallel, which may streamline early clinical
development by expeditiously identifying alternative versions of a product that may be safer or
more effective. Such comparisons can be facilitated by randomization between the study arms, if
feasible. Additionally, this trial design may facilitate sharing of the control group, potentially
facilitating investigator participation and subject enrollment, and may simplify study
management, relative to conducting a separate clinical trial for each product version.
III. 	SCOPE
The scope of this guidance is limited to early-phase studies of multiple versions of a cellular or
gene therapy product being studied in a single disease. We recommend that sponsors contact the
Center for Biologics Evaluations and Research (CBER) if they wish to apply this framework to
other types of products.
This guidance applies to studies where the IND sponsor is responsible for manufacturing all
versions of the cellular or gene therapy product (either directly or through a contract
manufacturer) and the IND sponsor is able to provide the required chemistry, manufacturing, and
controls (CMC) and pharmacology/toxicology (P/T) information for those products either in the
IND submissions or through cross-reference. Situations where the IND sponsor does not have

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complete access to proprietary information for those products being studied raise additional
considerations beyond those described in this guidance.
This guidance does not apply to sponsors conducting studies that are outside the scope of this
guidance (e.g., a trial designed to evaluate a single cell or gene therapy product in different
populations, otherwise known as a “basket” trial). If a sponsor is interested in conducting a
study that is outside the scope of this guidance, we recommend that the sponsor request a pre-
IND meeting with the Office of Tissues and Advanced Therapies (OTAT), CBER, to discuss
their proposed clinical trial design.
IV. 	SUBMISSION OF INFORMATION TO INDS
As noted in sections I and II of this guidance, the purpose of this guidance is to recommend a
more efficient and flexible model to evaluate multiple versions of an investigational product that
would otherwise be evaluated in separate clinical studies. For a single clinical study of different
versions of an investigational product where each version is submitted in a separate IND, it may
be challenging to determine how to structure and organize the INDs, and how to submit changes
or new information as the study progresses. The framework described here is intended to
provide clarity on these topics and, as feasible, to minimize submission of the same information
to multiple INDs by facilitating cross-referencing to shared information in the INDs. Sponsors
may discuss their specific clinical study and planned submission approach with OTAT, CBER
prior to submitting an IND (e.g., by requesting an INitial Targeted Engagement for Regulatory
Advice on CBER producTs (INTERACT)3 or pre-IND meeting4).
A. 	Overview
• 	For purposes of the framework outlined in this guidance, we refer to INDs either as
“Primary” or “Secondary”. The purpose of this nomenclature is to distinguish which
INDs will include clinical information about the umbrella trial (Primary INDs) and
which INDs will not include clinical information about the umbrella trial (Secondary
INDs). For example, an IND amendment that contains only clinical information
about the umbrella trial (e.g., no CMC or P/T information) would only need to be
submitted to the Primary IND.
• 	For a clinical study with two different versions of the investigational product (Product
A and Product B), we recommend that the sponsor submit two separate INDs, IND A
and IND B. One of the INDs, IND A, will be considered the “Primary” IND, and
should include CMC and P/T information for Product A. IND B will be considered a
“Secondary” IND, and will include CMC and P/T information for Product B.
Primary IND A should also include complete clinical information for the umbrella
3 For additional information about INTERACT meetings, please see https://www.fda.gov/vaccines-blood-
biologics/industry-biologics/interact-meetings.
4 See Formal Meetings Between the FDA and Sponsors or Applicants of PDUFA Products, Draft Guidance for
Industry, December 2017, https://www.fda.gov/media/109951/download. When finalized, this guidance will
represent FDA’s current thinking on this topic.

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trial, including the clinical protocol and supporting documents (e.g., investigator
brochure, informed consent form, Form FDA 1572), and a summary of the
similarities and differences between the product versions. This framework can be
further extended to additional versions of the product; if the clinical study includes
three different products (Products A, B, and C), then the CMC and P/T information
for Product C should be provided in Secondary IND C.
• 	Sponsors should consult FDA’s Guidance for Industry: Providing Regulatory
Submissions in Electronic Format – Certain Human Pharmaceutical Product
Applications and Related Submissions Using the eCTD Specifications, February
2020,5 for information regarding electronic common technical document (eCTD)
format for IND submissions.
Figure 1: Schematic Representation of the Primary and Secondary IND Framework6
• 	For the Primary IND (including any amendments), we recommend that the cover
letter clearly state that the IND is a Primary IND and specify the Secondary IND
number(s). For any Secondary IND (including any amendments), we recommend
that the cover letter clearly state that the IND is a Secondary IND and specify the
Primary IND number. We recommend that sponsors request pre-assigned IND
numbers prior to submitting the INDs, so that the cover letter and cross-references for
each IND can include the IND numbers for the other INDs that support the study.
• 	For sponsors adopting the approach described in this guidance, the Primary IND
should cross-reference the Secondary IND(s) for the CMC and P/T information
contained in those INDs. The Secondary IND(s) should cross-reference the Primary
IND for clinical information. If desired, CMC or P/T information that is identical
5 Available at: https://www.fda.gov/media/135373/download.
6 In Figure 1, “Xref” is an abbreviation for cross-reference.

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between the product versions may be submitted solely to the Primary IND and
incorporated into the Secondary IND(s) by cross-reference.
• 	In some cases, sponsors may decide to develop additional versions of a product after
an IND has already been submitted. If the sponsor wishes to evaluate the original and
additional versions of a product together in an umbrella trial, we recommend that
sponsors submit an amendment to the existing IND specifying that it is a Primary
IND and follow the steps in the section IV.B of this guidance to submit Secondary
IND(s) and add arm(s) to the study.
B. 	Adding Arms to the Study
• 	If the arm to be added includes a new version of the investigational cellular or gene
therapy product, (e.g., Product C), we recommend that the sponsor submit:
- 	IND C with CMC and P/T information for Product C. IND C will be considered a
Secondary IND. We recommend that the cover letter for a Secondary IND clearly
state that the IND is a Secondary IND and specify the Primary IND number. The
Secondary IND should cross-reference the Primary IND for clinical information.
- 	An amendment to IND A with the updated clinical protocol, which now includes
an arm for Product C. We recommend that the cover letter for the amendment to
IND A clearly state that the IND is a Primary IND and specify the Secondary IND
number(s), including IND C. We recommend that the Primary IND also be
updated to include a cross-reference to the Secondary IND for CMC and P/T
information related to Product C. It should be noted that the new Secondary IND
C cannot go into effect until 30 days after FDA receives the new IND (21 CFR
312.40(b)(1)), unless FDA provides earlier notification that the clinical
investigations in the IND may begin (21 CFR 312.40(b)(2)). Administration of
Product C cannot begin until IND C goes into effect and IRB approval of the
modified protocol has been granted (21 CFR 56.103).
• 	If the arm to be added does not include a new version of the investigational cellular or
gene therapy (e.g., a new arm that will study Product B in combination with a
marketed product, or a new arm that will study investigational Products A and B
together), then we recommend that the sponsor submit:
- 	An amendment to the Primary IND with the updated clinical protocol (i.e., with
the new arm); and
- 	Any additional P/T information supporting the new arm, if applicable, submitted
to the relevant IND(s).

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C. 	Submitting Other Types of Changes or New Information
• 	For revisions to the umbrella trial clinical protocol that do not add a new arm or for
other types of new clinical information, the sponsor should submit the revised
protocol or new clinical information to the Primary IND. The sponsor does not need
to submit any information to the Secondary INDs.
• 	For new CMC or P/T information (e.g., changes to the CMC information, new P/T
study report): if the new information is specific to one product (e.g., Product B), then
that information should be submitted to IND B only. If the new information is for
multiple products (e.g., Products A and B), then the new information should be
submitted to INDs A and B (or submitted to IND A and cross-referenced by IND B,
as mentioned previously). For new P/T information, the sponsor should also submit
an updated investigator brochure to the Primary IND.
D. 	Clinical Holds and Responses to Hold
• 	If only one arm (e.g., arm studying Product B) will be placed on hold, then the
Primary IND would be placed on partial hold and the relevant Secondary IND would
be placed on hold (or partial hold, if appropriate).
• 	In the event that FDA issues an order placing the entire study on clinical hold (e.g.,
due to a safety issue that applies to all product versions), then all Primary and
Secondary INDs would be placed on hold (or partial hold, if appropriate). 21 CFR
312.42(a).
• 	To respond to a clinical hold, the sponsor will need to submit a response to each IND
that was placed on hold. However, detailed information responding to each hold
comment does not need to be submitted to multiple INDs. For example, if the
Primary IND was placed on partial hold due to CMC concerns with a product in a
Secondary IND, the sponsor should submit the CMC information responding to the
hold comments to the Secondary IND. The response to hold for the Primary IND can
refer to the Secondary IND for detailed information.
E. 	Reporting
• 	IND safety reporting must be performed in accordance with 21 CFR 312.32.7 The
sponsor must submit safety reports for an investigational product to all of the
sponsor’s INDs that are relevant to that product. At a minimum, safety reports must
be submitted to both the Primary IND and any Secondary IND that contains the CMC
and P/T information for that product. In cases where a safety report for one product
is relevant to the safety of multiple related products, the safety report must be
submitted to all of the relevant INDs (21 CFR 312.32(c)). The report submitted to the
7 See Guidance for Industry and Investigators: Safety Reporting Requirements for INDs and BA/BE Studies,
December 2012, https://www.fda.gov/media/79394/download.

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Primary IND should be considered the original report, and reports submitted to the
Secondary IND(s) should be clearly identified as duplicates to ensure that the same
adverse event is not counted more than once. If a report is submitted to multiple
INDs, each IND safety report should identify all INDs to which the report is
submitted.
• 	Sponsors must submit Annual Reports to each IND (21 CFR 312.33).8 If desired, the
sponsor can submit an integrated Annual Report that includes the clinical information
and the CMC and P/T information for all products to the Primary IND, and
simultaneously submit an amendment to each of the Secondary INDs cross-
referencing the integrated Annual Report in the Primary IND.
F. 	Completion of Study or Arm(s)
• 	The Primary IND (e.g., IND A) includes CMC and P/T information for Product A
along with the clinical information for the umbrella trial. If the sponsor would like to
discontinue studying Product A, we do not recommend that the sponsor withdraw
Primary IND A because it contains the relevant clinical information. Instead, we
recommend that the sponsor submit an updated protocol to Primary IND A that no
longer includes the arm with Product A.
• 	If the Primary IND A is withdrawn for any reason, but the sponsor intends to continue
studying products other than Product A under the clinical protocol, then the sponsor
would need to do the following:
- 	Designate another IND (e.g., IND B or IND C) as the new Primary IND;
- 	Submit complete, up-to-date clinical information to the new Primary IND;
- 	Submit any essential CMC or P/T information from the old Primary IND to the
new Primary IND; and
- 	Update all cross-references so that the Secondary INDs now cross-reference the
new Primary IND, and the new Primary IND cross-references the Secondary
INDs. We recommend that the cover letters for each IND amendment clearly
specify the new Primary IND and Secondary INDs.
• 	If the sponsor decides to study one of the products (e.g., Product C) in a later-phase
study (e.g., a Phase 3 study), then the sponsor should submit the Phase 3 protocol to
the IND that contains the CMC and P/T information for Product C (i.e., IND C),
along with any updates to the CMC information for the Phase 3 study. If the sponsor
is interested in continuing the umbrella trial with the remaining product versions (e.g.,
Products A and B), the sponsor may do this by removing the cross-reference from the
Primary IND to IND C and by updating the clinical protocol in the Primary IND to no
8 See Guidance for Industry: E2F Development Safety Update Report, August 2011,
https://www.fda.gov/media/71255/download.

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longer include the Product C arm. Once these changes have been made, IND C will
no longer be considered a Secondary IND and will no longer be part of the umbrella
trial.
V. 	ALTERNATIVE APPROACHES
There may be alternative approaches to structuring and organizing INDs for studies in a single
disease of multiple versions of an investigational product. For example, sponsors may choose to
submit a stand-alone IND that includes only clinical information, with CMC and P/T information
from other INDs incorporated by cross-reference. In this case, the Primary IND would still
include the clinical information for the umbrella trial (including the clinical protocol), but the
Primary IND would cross-reference the Secondary INDs for CMC and P/T information for all
the products studied under the umbrella trial protocol. We recommend that sponsors considering
alternative approaches contact OTAT, CBER to discuss the proposed IND organization and
clinical study.

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APPENDIX: CLARIFICATION ON “VERSIONS OF A CELLULAR OR GENE
THERAPY PRODUCT”
A. 	Changes that Result in “Versions of a Cellular or Gene Therapy Product” (i.e.,
within the scope of this guidance)
The following are examples of changes that result in “versions of a cellular or gene therapy
product.” 9 The different product versions would generally be submitted to separate INDs,
even when they are being studied in the same clinical trial for a single disease.
• 	Changing a cellular product from bulk tumor-infiltrating lymphocytes (TILs) to
purified CD8+ TILs.
• 	Changing from dendritic cells (DCs) pulsed with a recombinant tumor antigen to DCs
pulsed with immunodominant peptides from the same antigen.
• 	Altering the differentiation state of a stem cell product to a more mature cell type
along the same lineage (e.g., neural progenitor cells vs. neurons).
• 	Changing the cell source (e.g., allogeneic vs. autologous, or cord blood vs. bone
marrow) for a mesenchymal stromal cell product.
• 	Changing from an embryonic stem cell bank to an induced pluripotent stem cell
(iPSC) bank to produce the same cell type (e.g., retinal pigment epithelial cells).
• 	Replacing the CAR transgene of a CAR T cell product with a new CAR transgene.
• 	Modifying a CAR T cell product by adding a second transgene that expresses a
costimulatory protein.
• 	Modifying a gene therapy vector to express the same transgene with a different codon
usage, promoter, enhancer, microRNA (miRNA) target or other control element.
• 	Deleting one or more genes from a viral-based or bacterial-based gene therapy vector.
• 	Modifying the transgene sequence in a gene therapy vector, resulting in a change to
the amino acid sequence of the encoded protein.
• 	Changing a capsid protein of a viral-based gene therapy vector.
B. 	Changes that Do Not Result in “Versions of a Cellular or Gene Therapy
Product” (i.e., not within the scope of this guidance)
Changes to the manufacturing process may occur as product development proceeds. In many
cases, these changes can be submitted as an amendment to the existing IND. These changes
are often made in the course of manufacturing process improvement and optimization and/or
preparation for commercial manufacturing and are generally not expected to impact product
safety or effectiveness. Products with these types of manufacturing process changes are not
typically studied in an umbrella trial. Examples may include:
• 	Changing from serum-containing media to serum-free media during cell expansion.
• 	Changing from adherent to suspension cell culture.
• 	Scaling up or scaling out the manufacturing process (e.g., increasing the capacity
and/or number of cell culture containers).
• 	Adding a new manufacturing site.
9 This is not intended to be an all-inclusive list of examples.

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C. 	Unrelated Products
Unrelated products (e.g., TILs versus CAR T cells) are not “versions of a cellular or gene
therapy product,” and umbrella trials that include unrelated products are not within the scope
of this guidance. These trials may be considered on a case-by-case basis; we recommend that
sponsors contact OTAT, CBER to discuss the appropriate regulatory path for such a
proposed trial.