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  Contains Nonbinding Recommendations 
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 
 
 
i  Contains Nonbinding Recommendations 
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, FDAs guidance documents do not establish legally enforceable responsibilities. 
Instead, guidances describe the Agencys 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.  
 
 
1  Contains Nonbinding Recommendations 
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 
2  Contains Nonbinding Recommendations 
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 FDAs current thinking on this topic. 
3  Contains Nonbinding Recommendations 
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 FDAs 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. 
4  Contains Nonbinding Recommendations 
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). 
   
5  Contains Nonbinding Recommendations 
 
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 
sponsors 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.   
6  Contains Nonbinding Recommendations 
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.  
7  Contains Nonbinding Recommendations 
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. 
   
8  Contains Nonbinding Recommendations 
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. 
9  Contains Nonbinding Recommendations 
 
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. 
10