Considerations for the Design of 
Early-Phase Clinical Trials of  
Cellular and Gene Therapy Products 
_________________________________
 
 
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 240-402-7800, or email ocod@fda.hhs.gov, or from 
the Internet at 
http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guida
nces/default.htm. 
 
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 
June 2015  Contains Nonbinding Recommendations 
 
Table of Contents 
 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  BACKGROUND ............................................................................................................... 2 
III.  FEATURES OF CGT PRODUCTS THAT INFLUENCE CLINICAL TRIAL 
DESIGN ............................................................................................................................. 3 
A.  Product Characteristics ........................................................................................ 3 
B.  Manufacturing Considerations ............................................................................ 5 
C.  Preclinical Considerations.................................................................................... 5 
IV.  CLINICAL TRIAL DESIGN .......................................................................................... 6 
A.  Early-Phase Trial Objectives ............................................................................... 6 
B.  Choosing a Study Population ............................................................................... 8 
C.  Control Group and Blinding .............................................................................. 12 
D.  Dose and Regimen ............................................................................................... 14 
E.  Treatment Plan.................................................................................................... 15 
F.  Monitoring and Follow-up ................................................................................. 18 
V.  MEETINGS WITH OCTGT ......................................................................................... 22 
VI.  GUIDANCE ON SUBMITTING AN IND .................................................................... 22 
VII.  REFERENCES ................................................................................................................ 24 
i  Contains Nonbinding Recommendations 
 
Considerations for the Design of Early-Phase Clinical Trials of 
Cellular and Gene Therapy Products 
_______________________________________________________ 
 
Guidance for Industry 
 
 
This guidance represents the Food and Drug Administrations (FDAs or Agencys) current 
thinking on this topic.  It does not create or confer any rights for or on any person and does not 
operate to bind FDA or the public.  You can use an alternative approach if the approach satisfies 
the requirements of the applicable statutes and regulations.  If you want to discuss an alternative 
approach, contact the FDA staff responsible for implementing this guidance using the contact 
information on the title page of this guidance. 
 
 
I.  INTRODUCTION 
 
The Center for Biologics Evaluation and Research (CBER)/Office of Cellular, Tissue, and Gene 
Therapies (OCTGT) is issuing this guidance to assist sponsors and investigators in designing 
early-phase clinical trials for cellular therapy (CT) and gene therapy (GT) products.  CT and GT 
products will be referred to collectively as CGT products.  This guidance provides OCTGTs 
current recommendations regarding clinical trials in which the primary objectives are the initial 
assessments of safety, tolerability, or feasibility of administration of investigational products.  
Such trials include most Phase 1 trials, including the initial introduction of an investigational 
new drug into humans, and some Phase 2 trials of CGT products. 
 
The scope of this guidance is limited to products for which OCTGT has regulatory authority.  
CGT products within the scope of this guidance meet the definition of biological product in 
section 351(i) of the Public Health Service (PHS) Act (42 U.S.C. 262(i)) and include CT and GT 
products that are used as therapeutic vaccines.1  This guidance does not apply to those human 
cells, tissues, and cellular- and tissue-based products (HCT/Ps) regulated solely under section 
361 of the PHS Act (42 U.S.C. 264), as described in Title 21 of the Code of Federal Regulations 
(CFR) Part 1271 (21 CFR Part 1271), or to products regulated as medical devices under the 
Federal Food, Drug, and Cosmetic Act, or to therapeutic biological products for which the 
Center for Drug Evaluation and Research (CDER) has regulatory responsibility.  
 
There is increasing interest and activity in the development of CGT products because of their 
potential to address unmet medical needs.  This guidance is intended to facilitate such 
development by providing recommendations regarding selected aspects of the design of early-
phase clinical trials of these products.  This guidance does not provide detailed information about 
the preclinical and chemistry, manufacturing, and controls (CMC) components of an 
                                                 
1 Many of the principles in this guidance may apply to combination products involving a biological product under 
OCTGTs regulatory authority. 
1  Contains Nonbinding Recommendations 
 
investigational new drug application (IND), as we have previously provided recommendations in 
connection with these components (Refs. 1, 2, and 3).  This guidance is intended to complement 
the information in those guidances.  
 
This guidance finalizes the draft guidance of the same title dated July 2013. 
 
FDAs guidance documents, including this guidance, do not establish legally enforceable 
responsibilities.  Instead, guidances describe the FDAs current thinking on a topic and should be 
viewed only as recommendations, unless specific regulatory or statutory requirements are cited.  
The use of the word should in FDAs guidances means that something is suggested or 
recommended, but not required. 
 
 
II.  BACKGROUND 
 
The design of early-phase clinical trials of CGT products often differs from the design of clinical 
trials for other types of pharmaceutical products.  Differences in trial design are necessitated by 
the distinctive features of these products, and also may reflect previous clinical experience.  
 
Early experiences with CGT products indicate that some CGT products may pose substantial 
risks to subjects.  These experiences include multi-organ failure and death of a subject who 
received a GT product for ornithine transcarbamylase deficiency (Ref. 4), late-onset T-cell 
leukemia in subjects who received a GT product for X-linked severe combined 
immunodeficiency (X-SCID) (Ref. 5), and development of tumors in the brain and spinal cord of 
a patient who received intrathecal allogeneic stem cells for ataxia telangiectasia (Ref. 6).  These 
events illustrate that the nature of the risks of CGT products can be different from those typically 
associated with other types of pharmaceuticals. 
 
Features of some CGT products that may contribute to their risks include the potential for 
prolonged biological activity after a single administration, a high potential for immunogenicity, 
or the need for relatively invasive procedures to administer the product.  Unlike many small 
molecule pharmaceuticals, the logistics and feasibility of manufacturing a CGT product 
sometimes influence the design of the clinical trials.  In addition, the preclinical data generated 
for CGT products may not always be as informative as for small molecule pharmaceuticals, 
particularly since it usually is not feasible to conduct traditional preclinical pharmacokinetic 
(PK) studies with CGT products.   
 
Thus, the design of early-phase clinical trials of CGT products often involves consideration of 
clinical safety issues, preclinical issues, and CMC issues that are encountered less commonly or 
not at all in the development of other pharmaceuticals.  Section III of this guidance describes 
some distinctive features of CGT products and their development.  Section IV discusses specific 
aspects of the design of early-phase trials of CGT products, based on consideration of the issues  
presented in Section III.  Therefore, Section IV focuses on elements of trial design that may be 
different for CGT products than for other types of pharmaceuticals.  Finally, Sections V and VI 
offer brief recommendations regarding IND submissions and meetings with OCTGT.  
 
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III.  FEATURES OF CGT PRODUCTS THAT INFLUENCE CLINICAL TRIAL 
DESIGN 
 
The design of early-phase clinical trials of CGT products is influenced by their many distinctive 
features.  These features include product characteristics and manufacturing considerations, some 
of which are unique to CGT products, and can dictate critical elements of the clinical trial design.  
In addition, the preclinical studies conducted in support of the clinical trial design are often 
different from those for other types of products.  This section describes some of these special 
features.  Section IV describes how these special features influence the design of clinical trials 
for CGT products.   
 
A.  Product Characteristics 
 
1.  Characteristics of Both CT and GT Products 
 
In contrast with some well-studied classes of small molecules, there is a relative lack 
of clinical experience with some CGT products.  In the absence of substantial 
experience across a broad population, there can be considerable uncertainty about the 
nature and frequency of safety problems that might be associated with specific types 
of CGT products.   
 
Also, some CGT products can persist in humans for an extended period after 
administration, or have an extended or permanent effect even after the product itself 
is no longer present.  The effects of the product might evolve over time (e.g., stem 
cells that proliferate and differentiate).  Therefore, evaluation of safety and 
pharmacologic activity might require observation of subjects for a substantial period 
of time to understand the safety profile.  Additional information about duration of 
follow-up can be found in Section IV.F.3 of this guidance. 
 
CGT products may require surgery or other invasive procedures for delivery to the 
target site.  The risks added by the use of an invasive procedure might be a substantial 
component of the overall risk of treatment, particularly when the product is 
administered into a relatively sensitive site, such as the heart or central nervous 
system.  In some cases, product delivery may require use of an investigational device.  
The use of an existing, legally marketed device for administering a CGT product also 
may be investigational.  As indicated in Section V of this guidance, it is appropriate 
to discuss clinical issues related to such usage in the pre-IND meeting.  Furthermore, 
when surgery or other invasive procedures are required, the training of those 
responsible for administering the product might affect the safety and reliability of the 
administration procedure (see Section IV.E.3).  
 
Allogeneic CT products, GT vectors, and proteins that might be produced by CGT 
products have the potential to elicit immune responses (immunogenicity).  The 
induction of an immune response may be the desired effect of some products, such as 
therapeutic vaccines.  For other CGT products, immunogenicity may be a risk.  For 
3  Contains Nonbinding Recommendations 
 
example, pre-existing antibodies, or antibodies that develop after administration of 
the product, could reduce or extinguish a beneficial effect, cause an adverse reaction 
(e.g., an autoimmune syndrome), or influence safety or efficacy if there are any 
subsequent administrations.  Also, in patients who have a condition that could be 
treated with a cellular, tissue, or organ transplant in the future, the development of 
antibodies to an allogeneic CGT product might jeopardize the success of the future 
transplant. 
 
2.  Characteristics of CT Products 
 
CT products have unique complexities due to the dynamic nature of living cells.  For 
example, cells may present a variety of molecules on their membranes and express a 
variety of factors.  These molecules and factors may be affected by the 
microenvironment and change over time.  Cells may differentiate in vivo into 
undesired cell types.  Cells might also develop undesired autonomous functions, such 
as cells with the characteristics of cardiomyocytes forming a focus that generates 
electrical activity uncoordinated with the rest of the heart (Ref. 7).  Stem cells, which 
have the potential to develop into a variety of mature tissue types, may undergo 
transformation and begin forming tumors (Ref. 6).  In addition, a CGT product may 
include a variety of cell types, and it may be unclear which cell type or types are 
responsible for any specific toxic or therapeutic effect.   
 
Another distinctive feature of cells is the ability to migrate.  Systemic delivery of CT 
products may result in cells being distributed to a variety of tissues in the body; even 
cells delivered to a specific tissue or organ may migrate to unintended locations (Ref. 
8). 
 
The source (donor) of the cells or tissue may be the subject to be treated (autologous), 
or another individual (allogeneic).  In some cases, the donor may receive a treatment 
prior to the harvest of source material.  If the donor is also the trial subject, such pre-
treatment may add to the overall risk to the subject.   
 
Similarly, some CT products require pre-treatment of the recipient, e.g., with immune 
modification or myeloablative conditioning to facilitate cell survival.  In such cases, 
the risks associated with the pre-treatment should be considered in the overall benefit-
risk assessment. 
 
3.  Characteristics of GT Products  
 
Several characteristics of GT products can influence trial design.  For example, 
expression of a delivered gene may be uncontrolled and interfere with normal 
function of a critical enzyme, hormone, or biological process in the recipient.  Some 
GT products are designed to integrate into the DNA of the recipients cells to allow 
for long-term expression of the integrated genes.  This genomic alteration could cause 
activation or inactivation of neighboring genes and give rise to benign or malignant  
4  Contains Nonbinding Recommendations 
 
tumors (Ref. 5).  In addition, GT products with a viral or bacterial vector present the 
possibility of shedding, i.e., excretion/secretion of viral particles or bacteria that could 
be transmitted to other individuals. 
 
4.  Characteristics of Gene-Modified Cellular Products 
 
Gene-modified cells, or ex vivo GT products, are products in which a gene is 
introduced into cells ex vivo, and then the modified cells are administered to the 
subjects.  Products of this type have features, and potential risks, of both GT and CT 
products.  Therefore, clinical trial design considerations of both GT and CT products 
apply to gene-modified cells. 
 
B.  Manufacturing Considerations 
 
The scientific or logistical complexities of manufacturing CGT products may impose 
practical limits on the dose of the product that can be produced, or may limit the 
concentration or volume of product that can be delivered.  These factors might therefore 
restrict the range of doses that are feasible in an early-phase trial.  The implications of 
these factors for trial design are discussed in Sections IV.A.1 and IV.D. 
 
For autologous products or patient-specific allogeneic donor products, unique product 
lots are manufactured for each subject, and potentially for each dose a subject receives.  
For such products, the inability to control factors such as subject-to-subject variability 
can contribute to product complexity.  Some CGT products may take several weeks to 
months to produce.  A failure or delay in manufacturing could prevent a subject from 
being treated as intended.  For other patient-specific products, cell viability and potency 
may decline rapidly from the time of formulation.  Therefore, fresh cells that are not 
cryopreserved may require administration within hours of manufacturing.  Trial design 
considerations for patient-specific products are discussed in Section IV.E.4. 
 
C.  Preclinical Considerations 
 
Preclinical in vitro and in vivo proof-of-concept, pharmacology, and toxicology studies 
are conducted to establish feasibility and rationale for clinical use of the investigational 
CGT product, as well as characterize the products safety profile.  These studies also 
provide the scientific basis to support the conclusion that it is reasonably safe to conduct 
the proposed clinical investigations (21 CFR 312.23(a)(8)).  Due to the diverse biology 
and scientific issues associated with CGT products, it is important to conduct a careful 
benefit-risk analysis, performed in the context of the particular clinical condition under 
study.  Preclinical data generated from studies conducted in appropriate animal species 
and animal models of disease contribute to defining reasonable risk for the investigational 
CGT product.   
 
Several issues can limit the ability of the preclinical data to guide various aspects of the 
design of the early-phase clinical trial.  For example, the extrapolation of a potentially 
safe and possibly bioactive starting clinical dose from the animal data can depend on 
5  Contains Nonbinding Recommendations 
 
various factors, such as the animal models used, the clinical route of product 
administration, the biodistribution profile, and any immune response to the administered 
CGT product.  However, traditional PK study designs are generally not feasible for CGT 
products; thus, such data are not available to guide clinical trial design.  Due to various 
issues, such as species specificity and immunogenicity, extrapolation from a CGT 
product dose administered in animals to a clinical dose can be less reliable than the 
customary allometric scaling typically used for small-molecule pharmaceuticals.   
 
To provide additional information about preclinical program objectives, selection of 
suitable animal species and animal models of disease, and overall considerations for the 
design of preclinical studies to support early-phase clinical trials, FDA has published the 
guidance entitled Guidance for Industry:  Preclinical Assessment of Investigational 
Cellular and Gene Therapy Products dated November 2013 (Ref. 3).   
 
 
IV.  CLINICAL TRIAL DESIGN 
 
This section describes specific elements of the design of an early-phase trial for a CGT product.  
For the most part, this guidance does not discuss elements of the trial design, such as efficacy 
endpoints and the analysis plan, that are generally the same for CGT products and other types of 
products.  Instead, the discussion focuses on aspects of early-phase clinical trial design that are 
often different for CGT products than for other types of products.  Due to the wide variety of 
CGT products and their potential applications, a case-by-case assessment is warranted for the 
design of each clinical trial.  Therefore, OCTGT encourages prospective sponsors to meet with 
FDA review staff early in a development program (see Section V). 
 
A.  Early-Phase Trial Objectives 
 
The IND regulations in 21 CFR Part 312 emphasize the importance of the assessment of 
trial risks and the safeguards for trial subjects.  For early-phase clinical trials, especially 
first-in-human trials, the primary objective should be an evaluation of safety  
(21 CFR 312.21).  Safety evaluation includes an assessment of the nature and frequency 
of potential adverse reactions and an estimation of the relationship to dose.  For CGT 
products, these early-phase trials often assess not only safety of specific dose regimens 
and routes of administration, but also other issues, such as feasibility of administration 
and pharmacologic activity. 
 
Sponsors should consider the design of early-phase studies in the context of the 
objectives of the overall development program.  Therefore, sponsors might include 
design elements that could help foster further product development.  For example, some 
Phase 1 studies include selected features of Phase 2 study design in order to gather 
preliminary evidence of effectiveness.  
 
6  Contains Nonbinding Recommendations 
 
1.  Dose Exploration 
 
For some products and conditions, including many uses of CGT products for serious 
or life-threatening diseases, some toxicities may be expected and acceptable.  In these 
situations, a major trial objective might be to identify the maximum tolerated dose 
(MTD), the highest dose that can be given with acceptable toxicity.  To achieve this 
objective, some trials use a well-defined dose-escalation protocol. 
 
For some CGT products, toxicity is not expected to be substantial in the predicted 
therapeutic range.  In this situation, one objective of dose exploration may be to 
determine the range of biologically active or optimal effective doses.  In some cases, 
indicators of potential benefit may appear to plateau above a certain dose, so that 
further dose escalation to reach an MTD may seem unnecessary.  Although 
identifying an MTD may seem unnecessary or impractical, it is important to 
recognize that the effective clinical dose is difficult to estimate early in development.  
Failure to identify an MTD during early development may lead to subsequent clinical 
trials using sub-therapeutic dose levels.  Therefore, dose exploration that includes 
identification of the MTD is generally recommended. 
 
Alternatively, for many CGT products, there are significant practical limits on the 
dose of the product that can be produced or delivered.  In such cases, the trial 
objectives may only be able to focus on achieving a specified target range of exposure 
or characterizing the safety profile of the feasible dose or doses, rather than finding 
the MTD.  
 
For further discussion of considerations relating to dose, see Section IV.D. 
 
2.  Feasibility Assessments 
 
CGT products sometimes require specialized devices or novel procedures for 
administration, customized preparation of products, special handling of products (e.g., 
very short expiration time), or adjunctive therapy.  In these cases, sponsors should 
consider designing early-phase trials to identify and characterize any technical or 
logistic issues with manufacturing and administering the product.  Such issues may 
need to be addressed before proceeding with further product development. 
 
3.  Activity Assessments 
 
A common secondary objective of early-phase trials is to obtain preliminary 
assessments of product activity, using either short-term responses or longer-term 
outcomes that could suggest potential for efficacy.  Such proof-of-concept data can 
support subsequent clinical development.  For CGT products, activity assessments 
might include specialized measures such as gene expression, cell engraftment, or 
morphologic alterations, as well as more common measures such as changes in 
immune function, tumor shrinkage, or physiologic responses of various types. 
 
7  Contains Nonbinding Recommendations 
 
B.  Choosing a Study Population 
 
Choice of the subjects to include in the trial depends on the expected risks and potential 
benefits, recognizing that there will be considerable uncertainty about those expectations 
in an early-phase trial.  Expected risks may be estimated from the nonclinical data, an 
understanding of the biological mechanisms, and any previous relevant human 
experience, but the clinical significance of those risks can depend on the population that 
receives the product.  Similarly, the potential for benefit might depend on the choice of 
study population.  In addition, the choice of study population may affect the ability to 
detect the products activity, either adverse or beneficial.  For example, a biomarker that 
may be indicative of risk or benefit might be more sensitive, meaningful, or interpretable 
in one population versus another.  Some populations may offer advantages (e.g., higher 
cell numbers or viability) as sources for autologous products.  The objective is to select a 
trial population with an acceptable balance between the anticipated risks and potential 
benefits for the study subjects, while also achieving the studys scientific objectives. As 
discussed below in Section IV.E.4 of this guidance, there are special considerations 
regarding selection of the study population for patient-specific products. 
 
1.  Healthy Volunteers2 
 
Study of healthy adult volunteers may be reasonable for an early-phase trial for 
products with short duration of action or in a class with a well understood safety 
profile.  However, the risks of most CGT products include the possibility of extended 
or permanent effects, along with the risks of any invasive procedures necessary for 
product administration.  Therefore, for most CGT trials, the benefit-risk profile is not 
acceptable for healthy volunteers. 
 
2.  Disease Stage or Severity 
 
Selection of the most appropriate study population for an early-phase trial involves 
several considerations, including not only the potential risks, but also the potential 
benefits and the ability of the study population to provide interpretable data.  
 
Subjects with more severe or advanced disease may be more willing to accept the 
risks of an investigational CGT product, or they may be in situations where the risks 
can be more readily justified.  Therefore, sponsors sometimes propose to limit 
enrollment into early-phase trials to subjects with more severe or advanced disease.  
However, in some cases, selection of subjects with less advanced or more moderate 
disease may be appropriate. 
 
Subjects with minimal reserve of physiological function due to severe or advanced 
disease may be less able than subjects with less severe disease to tolerate additional 
loss, which could leave them with no function.  For example, the risk of a decrease in 
visual acuity might be more acceptable in a subject with some visual reserve than in a 
                                                 
2 For the purposes of this guidance, the term healthy volunteers means individuals who do not have the disease or 
condition of interest. 
8  Contains Nonbinding Recommendations 
 
subject for whom that same decrement might result in loss of all functional vision.  
Similarly, a risk of pulmonary or cardiovascular toxicity might be more acceptable in 
a subject with early lung disease than in a subject with more advanced disease and 
less pulmonary reserve.  In addition, subjects with severe or advanced disease may 
not be able to tolerate invasive procedures needed for manufacture (e.g., cell harvest) 
or delivery of the product.  Thus, the decision about the severity of disease to be 
studied in an early-phase trial should be made only after considering the estimated 
nature and magnitude of the risks to the subjects, and the implications of those risks, 
for various stages or severity of the disease.  
 
In addition to considerations regarding risks, assessment of the overall benefit-risk 
profile should take into account any potential for individual subject benefit.  In some 
situations, such as trials in children or trials that involve high-risk procedures, the 
prospect for individual clinical benefit may be an important factor in the overall 
benefit-risk assessment for the selected study population.  The estimated prospect for 
benefit may depend on the severity or stage of disease.  Although subjects with more 
severe or advanced disease may have the greatest need for benefit, there can be 
situations in which a greater potential for benefit might be expected for subjects who 
are less severely affected.  Further, the ability to detect evidence of any benefit could 
depend on the severity or stage of disease in the study population, and the anticipated 
effects of the product might be more clearly discernible in subjects with milder 
disease.  This could be a significant consideration if detecting evidence of treatment 
activity is important to the objectives of the study.   
 
Also, the study population should be chosen with consideration of the potential 
interpretability of study outcomes.  Subjects with severe or advanced disease might 
have confounding adverse events or be receiving concomitant treatment, related to 
underlying disease, that could make the safety or effectiveness data difficult to 
interpret.  If the ultimate target population is patients with milder disease, a trial in 
severe or advanced disease could be essentially uninformative regarding relevant 
safety information and might also have a smaller prospect for benefit to offset risks.   
 
Thus, while severely affected subjects are often included in early-phase CGT trials, 
they should not be an automatic choice.  Several factors should be taken into account 
when selecting the appropriate subjects to include in the study for a specific 
condition.  The study population should be chosen in light of the above 
considerations, and the choice should be discussed and justified in the IND 
submission. 
 
3.  Lack of Other Treatment Options 
 
Early-phase studies of CGT products typically have significant risks and an uncertain 
potential for benefits.  Therefore, early-phase CGT trials sometimes enroll only the 
subset of subjects who have not had an adequate response to available medical 
treatment or who have no acceptable treatment options.  If a trial is designed to enroll 
only subjects for whom no other treatment options are available or acceptable, the 
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trial should include procedures to ensure that each subjects treatment options have 
been adequately evaluated, and it should be designed to capture the pertinent 
information regarding that evaluation. 
 
4.  Other Considerations 
 
There are additional considerations for selecting the subject population for certain 
product types.  For example, for cancer vaccines, it may be important to identify 
subjects whose tumors express a specific target antigen.3  For certain gene therapies, 
pre-existing antibodies to either the vector or the transgene product may influence the 
safety or effectiveness of the product; therefore, the study might exclude subjects 
with such antibodies.4  For products for indications (e.g., severe renal, hepatic, or 
cardiac disease) that might ultimately be amenable to organ transplantation, sponsors 
should consider whether exposure to the investigational agent would cause 
sensitization that could compromise the prospect for future transplant success.  If so, 
early-phase trials might exclude subjects with the most imminent or predictable need 
for transplantation.  The exclusion could be reconsidered for subsequent trials once 
the likelihood of sensitization is better understood. 
 
5.  Pediatric Subjects 
 
Some CGT products are developed specifically for pediatric conditions.  For 
example, GT products might be intended to correct childhood genetic diseases by 
replacing a missing gene or complementing a defective one.  CT products might be 
intended as regenerative medicine to correct congenital deformities or as treatments 
for genetic diseases, such as hematologic or immunologic disorders, which result in 
abnormal cellular function. 
 
Sponsors who are developing CGT products to treat pediatric diseases should 
consider how they will incorporate the additional safeguards for pediatric subjects in 
clinical investigations into the overall development program.  Clinical development 
programs for pediatric indications usually obtain initial safety and tolerability data in 
adults before beginning studies in children (Ref. 9).  Title 21 CFR Part 50 Subpart D 
(Subpart D) provides additional safeguards to children in clinical investigations.  A 
detailed discussion of the individual provisions of Subpart D is beyond the scope of  
                                                 
3 Guidance for Industry:  Clinical Considerations for Therapeutic Cancer Vaccines dated October 2011, 
http://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/Va
ccines/UCM278673.pdf. 
4 In those cases where a special test, such as an antigen or antibody assay, could be critical to the safety or potential 
effectiveness of the product, the test might be regarded as a companion diagnostic product.  If the specific use of the 
test is also investigational, then the Center for Devices and Radiological Health may need to evaluate the risk of that 
use.  For additional information regarding companion diagnostics, please see the guidance document entitled In 
Vitro Companion Diagnostic Devices  Guidance for Industry and Food and Drug Administration Staff dated 
August 2014, 
http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/UCM262327.
pdf.  
10  Contains Nonbinding Recommendations 
 
this guidance, and the FDA has published other documents for that purpose (Refs. 9, 
10).  We highlight the following principles for sponsors and investigators who wish to 
conduct studies of CGT products in pediatric subjects. 
 
Before a clinical trial that meets all other applicable requirements may proceed in 
children, Subpart D requires the Institutional Review Board (IRB) to determine that 
the trial meets additional requirements applicable to studies in pediatric subjects.  The 
IRB must assess the level of risk that the interventions and procedures included in a 
clinical trial would present to pediatric subjects to determine whether they present 
minimal risk (21 CFR 50.51), greater than minimal risk (21 CFR 50.52), or a minor 
increase over minimal risk (21 CFR 50.53).  Because of the special features of CGT 
products described earlier in this guidance, trials of CGT products usually present 
more than a minor increase over minimal risk, and therefore would need to meet the 
requirements of 21 CFR 50.52. 
 
Clinical trials presenting greater than minimal risk may proceed only after the IRB 
finds either that the intervention or procedure presenting that risk holds out the 
prospect of direct benefit for the individual pediatric subjects, or that the monitoring 
procedure presenting that risk is likely to contribute to the subjects well-being.  In 
addition, the IRB must find that: 
 
  the risk is justified by the anticipated benefit to the subjects; 
  the relation of the anticipated benefits to the risk is at least as favorable to the 
subjects as that presented by available alternative approaches; and  
  adequate provisions are made for soliciting the assent of the children and the 
permission of their parents or guardians (21 CFR 50.52 and 50.55).   
When an IRB determines that existing data are inadequate to support the findings 
required under these regulations, it may not permit the study to proceed.5  
 
IND submissions for pediatric trials must provide additional information related to 
plans for assessing pediatric safety and effectiveness (21 CFR 312.23(a)(10(iii)).  The 
IND regulations also require the sponsor to submit to FDA an investigational plan, 
including the rationale for the drug or the research study  
(21 CFR 312.23(a)(3)(iv)(a)).  Accordingly, the sponsor should provide a rationale 
for conducting the CGT study in children.  To obtain the information necessary for a 
benefit-risk assessment under Subpart D, and because of considerations regarding 
informed consent, data to support the rationale are usually obtained in adults before 
                                                 
5 If an IRB cannot conclude that a study meets the requirements of 21 CFR 50.51, 50.52, or 50.53, but finds that the 
clinical investigation presents a reasonable opportunity to further the understanding, prevention, or alleviation of a 
serious problem affecting the health or welfare of children, the IRB may refer the clinical protocol to FDAs Office 
of Pediatric Therapeutics for review under 21 CFR 50.54.  For additional information on this issue, please refer to 
the FDA guidance entitled Guidance for Clinical Investigators, Institutional Review Boards and Sponsors - Process 
for Handling Referrals to FDA Under 21 CFR 50.54 - Additional Safeguards for Children in Clinical Investigations 
dated December 2006, http://www.fda.gov/RegulatoryInformation/Guidances/ucm127541.htm. 
11  Contains Nonbinding Recommendations 
 
initiating pediatric studies.  We recognize that in some situations, it may be 
appropriate to initiate clinical studies of CGT products in children based only on the 
results of preclinical studies.  If the sponsor intends to conduct a pediatric trial when 
there has been no prior safety or efficacy study in adults, the rationale should explain 
why prior adult studies are unethical or infeasible. For example, the common 
childhood form of the disease may have severe manifestations or a rapidly 
deteriorating clinical course, whereas the adult-onset phenotype may be very mild and 
easily managed.  In such a situation, if the intervention is highly invasive, the overall 
benefit-risk assessment for a study in adults might be so unfavorable that an adult trial 
to assess safety or efficacy is unethical.  In other cases, the disease may occur so 
rarely in adults that a study in affected adults would not be feasible, and studies in 
healthy adults might have an unacceptable overall balance of benefits and risks (see 
Section IV.B.1).  
 
FDA has a responsibility to assess the risks presented and determine whether the 
clinical trial presents an unreasonable risk to subjects (21 CFR 312.42(b)(1)(i), 
312.42(b)(1)(iv) and 312.42(b)(2)(i)).  When reviewing studies of CGT products 
proposed to be conducted in pediatric subjects, we intend to assess the reasonableness 
of the risks after full consideration of the information, including information relevant 
to the determinations that the IRB must make to comply with the Subpart D 
safeguards.  The IND submission must provide adequate information to permit FDA 
to make this assessment (21 CFR 312.23(a)(10)(iii) and 312.23(a)(11)).   For 
example, if the sponsor proposes that a study in pediatric subjects meets the criteria in 
21 CFR 50.52 because, among other things, it presents a prospect of direct benefit to 
the subjects, the sponsor should include the available adult human and animal data 
relevant to this determination in the IND submission, and an analysis of the balance 
of anticipated benefit(s) and risks.  In addition to providing the relevant animal or 
adult human data, the IND submission should include a discussion of how those data 
are sufficient to support an assessment that the pediatric study, taking into account the 
proposed starting dose, dosing regimen, and design, offers a prospect of direct 
benefit.  FDA may place on clinical hold an IND that does not provide the 
information FDA needs to assess the risks presented to pediatric subjects  
(21 CFR 312.42(b)(1)(iv) and (b)(2)(i)).   
 
Finally, in accordance with 21 CFR 312.23(a)(11), the sponsor also must provide the 
parent or guardian permission document and a child assent document required under 
21 CFR 50.55. 
 
C.  Control Group and Blinding 
 
The objectives of early-phase trials usually focus on safety, for which rigorous inference 
regarding comparison to a control (e.g., placebo) may not be necessary.  Assessments of 
activity or efficacy, if any are to be made, are usually exploratory.  Therefore, in early-
phase trials, a concurrent control group and blinding are generally not as critical as for a  
12  Contains Nonbinding Recommendations 
 
confirmatory efficacy trial.  However, in early phases of clinical development, a control 
group can be useful to facilitate interpretation of the safety data and provide a comparator 
for any assessments of activity or efficacy. 
 
For example, a concurrent control group may be particularly valuable for trials in 
diseases for which the natural history is not well-characterized or for trials that enroll 
subjects with a wide range of disease severity.  The importance of concurrent controls 
and blinding in any specific trial depends on multiple factors, including not only the 
study objectives, but also the extent to which the study procedures and outcome 
assessments are subject to bias.   
 
For some CGT products, use of an intra-subject control may be a useful and convenient 
way to control a trial.  An example would be injection of the study agent into one limb 
and injection of the control agent into the contralateral limb.  With intra-subject control, 
any systemic effects may confound the interpretation of the results, but comparisons of 
local effects can be facilitated by the elimination of inter-subject variation. 
 
Standard-of-care and no-treatment controls allow evaluation of the risk of the overall 
investigational treatment, including the risks of both the study agent and the 
administration procedure.  With this type of control, blinding of the subject and 
investigator may not be feasible, although it may be possible to maintain the blind for 
subjects for some kinds of standard-of-care controls. 
 
For trials that do include a concurrent control group, blinding of subjects, investigators, 
and assessors can be useful to minimize the risk of bias in the study results.  However, 
rigorous blinding in early-phase trials may not be desirable if it cannot be done simply 
and in a way that minimizes risk to control subjects.  Some CGT products might require 
an invasive procedure for administration (e.g., cardiac catheterization) or for collection of 
tissue to use for starting materials.  Use of the same invasive procedure in a control group 
could help to distinguish product-related from procedure-related adverse reactions.  
However, use of the invasive procedure in the control group solely to administer a 
placebo, or otherwise mimic the active treatment arm for purposes of blinding, could 
represent an unreasonable risk for an early-phase trial, even if it might be appropriate for 
a later confirmatory trial.  For early-phase clinical trials involving children, the use of an 
invasive procedure in the control group should present no more than a minor increase 
over minimal risk, given the absence of a prospect of direct benefit from the control 
intervention. 
 
Thus, the advantages and disadvantages of specific controls and blinding should be 
carefully considered in the context of the objectives and circumstances of the specific 
early-phase clinical trial. 
 
13  Contains Nonbinding Recommendations 
 
D.  Dose and Regimen 
 
1.  Role of Preclinical Data 
 
If animal or in vitro data are available, there might be sufficient information to 
determine if a specific starting dose has an acceptable level of risk.  However, 
conventional allometric scaling methods for CGT products may be less precise than 
for small-molecule drugs, and traditional PK and pharmacodynamic correlations 
might not be possible.  Therefore, it may be difficult to establish an initial starting 
dose based on the considerations used for small-molecule drugs.  If available, 
previous clinical experience with the CGT product or related products, even if by a 
different route of administration or for a different condition, might help to justify the 
clinical starting dose.  
 
2.  Considerations Regarding How Dose is Described 
 
One of the objectives of early-phase trials should be the identification of the product 
attribute (or attributes) that is most relevant to characterizing dose.  To that end, it is 
important to collect data on characteristics of the administered product and clinical 
outcomes that will enable correlative analyses to help in dose definition. 
 
Selecting the study dose(s) of a CT product can be challenging.  Dosing to target a 
therapeutic effect might be based on one cell type, but adverse reactions might 
depend more on a different cell type that is present in the same product.  The active 
cell subset may not be known, so the dose is based on a specific subset that is thought 
to be the best representation of the desired activity.  For example, for a CT product 
derived from cord blood or other hematopoietic tissues, the total number of nucleated 
cells might be used as the measure of dose, but the number of CD3+ cells could be an 
important aspect of the dose for consideration of certain safety outcomes, such as 
graft versus host disease (GVHD).  In situations where there is uncertainty about the 
cell subset(s) responsible for the therapeutic or adverse effects, collecting data on 
various cell subsets in the final CT product, with a comparison of clinical outcomes 
associated with these different subsets, may help to identify the cell subsets most 
relevant to product safety and effectiveness. 
 
For many GT products, dose is based on vector titer.  However, some vector types 
may have specific properties that necessitate dosing using alternative units.  For 
example, viral particles that do not contain the therapeutic gene are unlikely to have 
therapeutic activity.  However, these particles themselves might produce adverse 
reactions, such as an allergic response.  Therefore, if there are such safety 
considerations, the study dose(s) should be based on the total particle number, as is 
the case with adenoviral vectors.  Other considerations for describing dosing may be 
related to the strengths and weaknesses of the methods available to accurately 
quantify specific attributes of the GT products.  For example, adeno-associated viral  
14  Contains Nonbinding Recommendations 
 
(AAV) vectors are typically dosed based on vector genomes, due to the strengths of 
the quantitative polymerase chain reaction (PCR) assay and the difficulties in 
quantitating transducing units. 
 
For gene-modified cells, dosing should consider several factors, including 
transduction efficiency.  For some products, transduction efficiency can vary from lot 
to lot.  This variation might lead to substantial differences in the active dose 
administered to different subjects.  Ideally, manufacturers should work to control 
variability in the transduction process.  If variability in transduction is occurring, and 
if the transduced cell number can be identified prior to product administration, then 
transduced cell number might provide more consistent dosing among subjects.  In 
addition to transduction efficiency, other factors that should be considered in 
determining the dose include the total number of cells administered to subjects, the 
mean number of copies of vector sequences integrated per cell, and cell viability. 
 
3.  Dose Escalation and Regimen 
 
Clinical development of CGT products has often included dose escalation in half-log 
(approximately three-fold) increments.  However, the dosing increments used for 
dose escalation should consider preclinical and any available clinical data regarding 
the risks and activity associated with changes in dose.   
 
Many CGT products can persist in the subject or have an extended duration of 
activity, so that repeated dosing might not be an acceptable risk until there is a 
preliminary understanding of the products toxicity and duration of activity.  
Therefore, most first-in-human CGT trials use a single administration or one-time 
dosing regimen.  However, for some CGT products, such as therapeutic vaccines, 
multiple administrations may be appropriate for early-phase trials. 
 
E.  Treatment Plan 
 
1.  Staggering Administration 
 
When there is no previous human experience with a specific CGT product or related 
product, treating several subjects simultaneously may represent an unreasonable risk.  
To address this issue, most first-in-human trials of CGT products include staggered 
treatment to limit the number of subjects who might be exposed to an unanticipated 
safety risk.   
 
With staggered treatment, there is a specified follow-up interval between 
administration of the product to a subject, or small group of subjects, and 
administration to the next subject or group of subjects.  For example, in a dose-
escalation study, the first several individual subjects within the first cohort might be 
staggered, followed by staggering between cohorts.  Depending on the degree of 
safety concern, staggered treatment of individual subjects within each new cohort  
15  Contains Nonbinding Recommendations 
 
might be appropriate.  When the dose of the CGT product is difficult to quantify 
precisely or is highly variable due to manufacturing issues, it may be necessary to 
stagger additional subjects. 
 
The staggering interval, either within a cohort or between cohorts, is intended to be 
long enough to monitor for acute and subacute adverse events prior to treating 
additional subjects at the same dose, or prior to increasing the dose in subsequent 
subjects.  The choice of staggering interval should consider the time course of acute 
and subacute adverse events that was observed in the animal studies and in any 
previous human experience with related products.  The staggering interval should also 
consider the expected duration of product activity.  However, the staggering interval 
should be practical in the context of overall development timelines.   
 
2.   Cohort Size 
 
For trials that enroll sequential cohorts with dose-escalation between cohorts, the 
choice of cohort size should consider the amount of risk that is acceptable in the study 
population.  Larger cohorts might be necessary to provide reasonable assurance of 
safety before escalating the dose of a product intended to treat a disease that is less 
serious and for which the tolerance for accepting risk might be lower.  Smaller 
cohorts might be adequate for a product that is intended to treat a serious or life-
threatening disease where a greater potential benefit may justify a higher risk.  
Standardized protocol designs, such as the 3+3 design, are often used for dose 
escalation of oncology products.  However, the cohort size in such a design might not 
be appropriate for other therapeutic areas where there is less tolerance of risk, and a 
larger cohort might be needed to provide a greater assurance of safety prior to dose 
escalation.  In addition, other study objectives, such as assessments of tolerability, 
feasibility, and pharmacologic activity may influence choice of cohort size.  
 
For CGT products, manufacturing capacity is often limited, which might place a 
practical limit on cohort size, particularly early in clinical development.  The 
prevalence of the proposed study population may also limit the cohort size.  When 
considering the limitations due to manufacturing capacity and prevalence of the study 
population, sponsors should select a cohort size that is feasible, but still adequate to 
meet the study objectives.  
 
3.  Operator Training and Documentation of Procedures 
 
For product delivery that involves a complex administration procedure or a device 
requiring special training, such as subretinal injection or use of specialized catheters 
for cardiac administration, the skill of the individual administering the product can 
impact the products safety and efficacy.  When individual skill in administering a 
product may affect its safety or effectiveness, the trial should specify minimum 
requirements for the operators training, experience, or level of proficiency.  In some 
cases (particularly, if there are multiple operators), training of operators on the 
specific administration procedures may reduce variability of administration and 
16  Contains Nonbinding Recommendations 
 
thereby improve interpretability of the study results.  Detailed, written standard 
operating procedures (SOPs) can also help ensure safety and consistency in product 
administration.  Careful recording of steps and observations during the administration 
process can help identify the operators compliance with the protocol.  These records 
can also facilitate correlating procedure variations with clinical outcomes and identify 
modifications that may improve the administration process.  
 
4.  Considerations for Patient-Specific Products 
 
As discussed earlier, some CT products or gene-modified cells are manufactured 
using cells or tissue from the intended recipient or from an allogeneic donor selected 
because of immunological matching to the recipient.  In these cases, the product 
needs to be manufactured separately for each subject in a trial. 
 
However, manufacturing of some CGT products may take many weeks or months.  
Although a subject might meet the study enrollment criteria when the tissue or cells 
are first collected, the subject might no longer meet those criteria at the time planned 
for product administration.  For example, the subjects condition may have 
deteriorated so that the subject is no longer expected to tolerate the study procedures 
or survive for the study duration.  To adjust for the possibility of a change in the 
subjects condition, the enrollment criteria may need to include selection for factors 
that would improve the likelihood that the recipient would still be suitable for product 
administration when the manufacturing process is complete.  Alternatively, the trial 
might include separate criteria that need to be met at the time of product 
administration. 
 
If a problem occurs in product manufacturing, there may be no product available to 
administer to an intended recipient.  It is helpful to try to gain an understanding from 
early-phase trials of the likelihood of manufacturing failure and any subject factors 
that may relate to such failures (e.g., subject characteristics that might predict a poor 
cell harvest).  This information can facilitate design of subsequent trials by suggesting 
subject selection criteria to reduce the chance of failure, or by prompting the 
development of a treatment protocol with a formalized manufacturing failure 
contingency plan. 
 
In case of failure to administer the CGT product to a subject, the protocol should be 
designed so that the subject is not committed to any high-risk preparative procedures 
(e.g., myeloablation) until it is known that the product is available.  The protocol 
should also clearly specify whether re-treatment will be attempted with another round 
of manufacturing and whether an untreated subject will be replaced by increasing 
enrollment.  Failure-to-treat may be an important trial endpoint that is part of a 
feasibility evaluation, and there should be plans to analyze the proportion of failure-
to-treat subjects to look for factors that may predict failure to administer the product 
and to evaluate the consequences to the subject if there is a failure to treat. 
 
17  Contains Nonbinding Recommendations 
 
F.  Monitoring and Follow-up 
 
1.  General Monitoring Considerations 
 
Since a major objective of early-phase trials is evaluation of safety, early-phase trials 
should employ general tests and monitoring to look for both expected and unexpected 
safety issues.  General safety monitoring typically includes recording of symptoms 
and common clinical measurements, such as physical examinations, chemistry 
profiles, complete blood counts, and possibly other examinations that are appropriate 
for the condition being investigated.  Examples include continuous 
electrocardiographic monitoring if arrhythmogenicity is a concern, and antinuclear 
antibody (ANA) or other immunology testing if autoimmunity is a concern.  The 
specific monitoring program will depend on multiple factors, such as the nature and 
mechanism of action of the product, the study population, the results of animal 
studies, and any related human experience. 
 
Another objective of many early-phase trials is to provide preliminary evidence of 
efficacy or pharmacologic activity.  Pharmacologic activity may develop slowly or be 
delayed relative to the traditional time course of activity of small molecules.  
Therefore, subjects should continue to be monitored for both safety and 
pharmacologic activity regardless of whether or not they receive the complete 
treatment regimen.  
 
Attribution of individual adverse events to the product, study procedures, or other 
causes can be unreliable.  Therefore, for early-phase trials, sponsors should capture 
all adverse events, even if the investigational product is an add-on to known toxic 
therapies, such as chemotherapy, radiation, or another toxic drug. Many early-phase 
 
CGT trials include a Data Monitoring Committee (DMC) to help ensure subject 
safety.  Although use of a medical monitor may be sufficient, a DMC might be 
considered to enhance subject protection if the trial presents substantial risks to 
subjects.6 
 
In addition to providing evidence of safety, many early-phase clinical trials have the 
secondary objective of obtaining preliminary efficacy or proof-of-concept data to 
support subsequent clinical development.  Therefore, sponsors are encouraged to 
include a wide range of activity or efficacy outcome measures in early-phase clinical 
trials.  
 
2.  Special Monitoring Considerations for CGT Products 
 
In addition to general tests and monitoring to look for unanticipated safety issues, 
evaluations may include assessments targeting specific safety issues that could be 
anticipated with CGT products.  Such product-specific safety issues might include 
                                                 
6 For additional information on DMCs, please see the guidance document entitled Guidance for Clinical Trial 
Sponsors:  Establishment and Operation of Clinical Trial Data Monitoring Committees dated March 2006, 
http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM127073.pdf. 
18  Contains Nonbinding Recommendations 
 
acute or delayed infusion reactions, autoimmunity, graft failure, GVHD, new 
malignancies, transmission of infectious agents from a donor, and viral reactivation.  
Monitoring procedures relevant to specific CGT products or study populations 
include the following: 
 
  If immunogenicity is a concern (e.g., with viral capsids or allogeneic cellular 
products), then each subjects immune response to the product should be 
evaluated.  This evaluation may include monitoring for evidence of both 
cellular and humoral immune responses.  If adequate assays are not yet 
available, baseline and post-treatment blood and/or plasma, as appropriate, 
should be cryopreserved for later evaluation, once assays have been 
developed. 
 
  Attempts should be made to determine the duration of persistence of the 
product and its activity.  Product persistence is assessed by looking for 
evidence of the presence of cells, vector, or virus in biological fluids or 
tissues.  Activity might be assessed by looking for physiologic effects, such as 
gene expression or changes in biomarkers.  In some trials, these assessments 
of persistence or activity could be based on relevant tissue (e.g., from the site 
of administration or the site of intended activity) that becomes available in the 
course of subject management or is easily obtained by biopsy.  In such trials, 
the protocol might include plans for tissue studies.  If some deaths are 
expected to occur during the course of the trial, planning for possible 
postmortem studies to assess product persistence and activity may be useful.  
 
  For CT products, if applicable, the potential for migration from the target site, 
ectopic tissue formation, or other abnormal cell activity should be addressed 
by performing evaluations appropriate to the nature of the concern (e.g., 
imaging studies for potential ectopic tissue, or cardiac rhythm monitoring for 
potential arrhythmogenic foci in cardiac disease). 
 
  For GT products, the potential for viral shedding should be addressed early in 
product development.7, 8 
 
  For GT products that integrate into the genome, monitoring for clonal 
outgrowths should be performed when technically feasible.  Typically, this 
type of monitoring is done when hematopoietic stem cells are transduced with 
an integrating vector.  Vector integration sites in patient peripheral blood 
                                                 
7 Guidance for Industry:  Supplemental Guidance on Testing for Replication Competent Retrovirus in Retroviral 
Vector Based Gene Therapy Products and During Follow-up of Patients in Clinical Trials Using Retroviral Vectors 
dated October 2006, 
http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/CellularandG
eneTherapy/ucm072961.htm. 
8 Draft Guidance for Industry:  Design and Analysis of Shedding Studies for Virus or Bacteria-Based Gene 
Therapy and Oncolytic Products dated July 2014, 
http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceregulatoryInformation/Guidances/CellularandGe
neTherapy/ucm404050.htm.  When finalized, this guidance will represent FDAs current thinking on this topic. 
19  Contains Nonbinding Recommendations 
 
mononuclear cells (PMBCs) can be monitored for outgrowth of a predominant 
clone.  Additional information can be found in the Guidance for Industry:  
Gene Therapy Clinical Trials  Observing Subjects for Delayed Adverse 
Events dated November 2006 (Ref. 11). 
 
  CGT products may affect linear growth and maturation of developing organ 
systems in children.  The systems that are most likely to be affected may vary 
by product, but concerns include potential reproductive, immunologic, 
neurologic, skeletal, or psychological effects.  Therefore, monitoring and 
assessment of effects on these systems may be critical elements in the design 
of pediatric clinical trials.  
 
3.  Duration of Follow-up  
 
In general, the duration of monitoring for adverse events should begin with any 
pretreatment and cover the time during which the product might reasonably be 
thought to present safety concerns.  In addition, the expected time course of 
pharmacologic activity may influence the duration of monitoring.  The appropriate 
duration of follow-up depends on the results of preclinical studies, experience with 
related products, knowledge of the disease process, and other scientific information.  
In case of failure to administer the CGT product to a subject, the protocol should 
stipulate any follow-up time needed to assess the risks of any harvesting procedure or 
other type of preparative treatments (e.g., immune modification) the subject received. 
 
For most CGT products, a year or more of follow-up is appropriate for each subject in 
early-phase trials.  For some CGT products, such as those with an indefinite duration 
of activity, additional long-term follow-up might be appropriate.  For example, long-
term safety monitoring can be useful if the product contains cells for which there is 
concern, either from the animal studies or other scientific information, that the cells 
might transform, migrate, or otherwise have the potential to develop ectopic tissue. 
The monitoring program should account for the duration of risks due to any 
concomitant medications, such as immunosuppressants.  In addition, sponsors should 
consider the duration of follow-up that will provide preliminary evidence of efficacy 
and information on durability of activity. 
 
With respect to extended follow-up, for certain GT products, we recommend 
following the recommendations in the FDA guidance document entitled Guidance 
for Industry:  Gene Therapy Clinical Trials  Observing Subjects for Delayed 
Adverse Events dated November 2006 (Ref. 11).  As stated in that guidance, if the 
product is a GT for which the vector is integrating, or if the vector has latency, such 
as herpes simplex virus, then sponsors should follow subjects for 15 years to identify 
any late safety issues.  Long-term safety monitoring can also be useful if the product 
involves a gene that might predispose subjects to develop secondary malignancies. 
 
20  Contains Nonbinding Recommendations 
 
Sponsors sometimes propose to have one protocol for a CGT study of safety or 
efficacy, and a separate protocol for long-term monitoring.  However, long-term 
follow-up is sometimes necessary for the trial to have an acceptable balance of risks 
and benefits.  In that case, long-term monitoring should be included as an integral part 
of the CGT trial, and not designed as a separate study.  There may be logistical issues 
that influence the feasibility of including long-term monitoring in the initial protocol.  
When there is a separate protocol for long-term monitoring, subjects should be 
consented for all long-term monitoring prior to participation in the initial CGT trial. 
   
Long-term monitoring does not need to be as detailed as the safety monitoring in the 
initial part of a trial.  In general, long-term monitoring for CGT products focuses on 
subject survival and on serious adverse events that are hematologic, immunologic, 
neurologic, or oncologic.  For some purposes, a telephone call to the subject, rather 
than a clinic visit, may be sufficient to obtain the necessary follow-up information.  In 
addition, completion of long-term monitoring usually is not necessary prior to 
initiating subsequent trials or submitting a marketing application.    
 
In the pediatric population, long-term monitoring following the administration of 
CGT products may need to characterize the effects of the intervention on growth and 
development as discussed in Section IV.F.2 of this guidance.  Depending on the 
intervention, children also have the potential to be exposed for a longer time because 
of their younger age.  Thus, clinical follow-up data over an extended period may be 
critical to assess safety and developmental outcomes, particularly when an 
intervention is tested in infants and young children.  Therefore, monitoring the long-
term safety and duration of effects may be more challenging in pediatric studies than 
in adult studies.  Sponsors of all CGT early-phase trials, both adult and pediatric, 
should consider these issues in their proposals for long-term monitoring. 
 
4.  Study Stopping Rules 
 
Because there can be considerable uncertainty about the frequency or severity of 
adverse reactions in trials of CGT products, most early-phase trials of these products 
should include study stopping rules.  The purpose of these rules is to control the 
number of subjects put at risk, in the event that early experience uncovers important 
safety problems. 
 
Study stopping rules typically specify a number or frequency of events, such as 
serious adverse events or deaths, that will result in temporary suspension of 
enrollment and dosing until the situation can be assessed.  Based on the assessment, 
the clinical protocol might be revised to mitigate the risk to subjects.  Such revisions 
could include changes in the enrollment criteria, for example, to exclude individuals 
who might be at relatively high risk for developing particular adverse reactions.  
Revisions might also include dose reduction, some other change in product 
preparation or administration, or changes in the monitoring plan.  Following the 
implementation of such changes in the protocol, it may be safe for the trial to resume.   
21  Contains Nonbinding Recommendations 
 
Therefore, study stopping rules do not necessarily terminate a trial.  Well-designed 
stopping rules allow sponsors to assess and address risks identified as the trial 
proceeds, and to assure that risks to subjects remain reasonable. 
 
 
V.  MEETINGS WITH OCTGT 
 
OCTGT encourages prospective sponsors to meet with FDA review staff.  Meeting with OCTGT 
can be especially beneficial for sponsors who have little experience with the IND process, and 
for sponsors developing a product for the treatment of a rare disease.  In such meetings, OCTGT 
can provide advice that may increase the likelihood that an IND submission will be sufficient to 
support a proposed trial, or that the overall development program will be sufficient to support a 
marketing application. 
 
The FDA guidance document entitled Guidance for Industry:  Formal Meetings Between the 
FDA and Sponsors or Applicants dated May 2009 (Ref. 12), describes the process for 
requesting and preparing for a meeting.  One type of formal meeting is the pre-IND meeting.  A 
pre-IND meeting is intended to help ensure that appropriate work has or will be done to support 
a planned IND.  The sponsors pre-IND briefing package should include a clinical protocol or 
synopsis.  In addition to discussions of preclinical studies and manufacturing issues, appropriate 
clinical topics for such a meeting could include the following: 
 
  the adequacy of the available or planned safety and proof-of-concept information to 
justify the risks of the proposed trial; 
  the choice of study population; 
  the doses to be administered; 
  the dosing schedule; 
  clinical issues related to any invasive administration procedures; 
  the treatment plan for the control group, if one is proposed; 
  staggering plans; 
  the safety monitoring plan, including long-term follow-up; 
  any special safety assessments; 
  stopping rules; 
  selection of trial endpoints; and  
  the overall clinical development program. 
 
 
VI.  GUIDANCE ON SUBMITTING AN IND 
 
The requirements with respect to what needs to be submitted in support of an IND can be found 
in the FDA regulations, 21 CFR 312.23, and recommendations with respect to these submissions 
can be found in the FDA guidance document entitled, Guidance for Industry:  Content and 
Format of Investigational New Drug Applications (INDs) for Phase 1 Studies of Drugs, 
Including Well-Characterized, Therapeutic, Biotechnology-derived Products dated November 
1995 (Ref. 13).  Information on the preparation of the CMC section of an IND for a CGT product 
can be found in the FDA guidances entitled Guidance for FDA Reviewers and Sponsors:  
22  Contains Nonbinding Recommendations 
 
Content and Review of Chemistry, Manufacturing, and Control (CMC) Information for Human 
Somatic Cell Therapy Investigational New Drug Applications (INDs) dated April 2008 (Ref. 1) 
and Guidance for FDA Reviewers and Sponsors:  Content and Review of Chemistry, 
Manufacturing, and Control (CMC) Information for Human Gene Therapy Investigational New 
Drug Applications (INDs) dated April 2008 (Ref. 2).  As noted previously, information on the 
preparation of the preclinical section of an IND for a CGT product can be found in the FDA 
guidance entitled Guidance for Industry:  Preclinical Assessment of Investigational Cellular and 
Gene Therapy Products dated November 2013 (Ref. 3).    
 
The IND submission for an early-phase trial must include a summary of previous human 
experience known to the applicant with the investigational product, along with detailed 
information about such experience that is relevant to the safety of the proposed investigation or 
to the investigators rationale (21 CFR 312.23(a)(9)).  The submission also should include a 
summary of previous human experience with similar or closely related products.  OCTGT 
recommends that the submission include discussion of any of the issues raised in Sections III and 
IV of this guidance that are applicable to the proposed trial. 
 
Sponsors also may find it prudent to develop an overall product development plan early in the 
course of development (prior to clinical trial initiation).  Such a plan should be sufficiently 
flexible to accommodate adaptation based on data acquired through product development.  One 
potential approach to planning development is known as a Target Product Profile (TPP).  FDA 
has published a draft guidance for comment that discusses how this particular planning tool 
might be used (Ref. 14).  When finalized, the TPP guidance will represent our current thinking 
on this topic. 
 
FDA has developed additional resources that sponsors may find useful when preparing an IND 
for CGT products, including guidances relevant to the development of CGT products for selected 
specified conditions.3,9,10,11  Likewise, information on manufacturing, preclinical, and clinical 
topics related to development of CGT products, including discussion of IND submissions and 
meeting requests, is available in the OCTGT Learn webinars on the OCTGT website: 
http://www.fda.gov/biologicsbloodvaccines/newsevents/ucm232821.htm. 
                                                 
9 Guidance for Industry:  Considerations for Allogeneic Pancreatic Islet Cell Products dated September 2009, 
http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/CellularandG
eneTherapy/ucm182440.htm. 
10 Guidance for Industry:  Cellular Therapy for Cardiac Disease dated October 2010, 
http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/CellularandG
eneTherapy/ucm164265.htm. 
11 Guidance for Industry:  Preparation of IDEs and INDs for Products Intended to Repair or Replace Knee 
Cartilage dated December 2011, 
http://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/Ce
llularandGeneTherapy/UCM288011.pdf. 
23  Contains Nonbinding Recommendations 
 
 
VII.  REFERENCES 
 
1.  Guidance for FDA Reviewers and Sponsors:  Content and Review of Chemistry, 
Manufacturing, and Control (CMC) Information for Human Somatic Cell Therapy 
Investigational New Drug Applications (INDs); dated April 2008,  
http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/G
uidances/Xenotransplantation/ucm074131.htm. 
 
2.  Guidance for FDA Reviewers and Sponsors:  Content and Review of Chemistry, 
Manufacturing, and Control (CMC) Information for Human Gene Therapy Investigational 
New Drug Applications (INDs); dated April 2008,  
http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/G
uidances/CellularandGeneTherapy/ucm072587.htm.  
 
3.  Guidance for Industry:  Preclinical Assessment of Investigational Cellular and Gene Therapy 
Products; dated November 2013,  
  http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/G
uidances/CellularandGeneTherapy/ucm376136.htm 
 
4.  Raper S.E., N. Chirmule, F.S. Lee, et al., 2003, Fatal Systemic Inflammatory Response 
Syndrome in a Ornithine Transcarbamylase Deficient Patient Following Adenoviral Gene 
Transfer, Molecular Genetics and Metabolism, 80:148-158. 
 
5.  Hacein-Bey-Abina S., C. Von Kalle, M. Schmidt, et al., 2003, LMO2-Associated Clonal T 
Cell Proliferation in Two Patients after Gene Therapy for SCID-X1, Science, 302:415-419. 
 
6.  Amariglio N., A. Hirshberg, B.W. Scheithauer, et al., 2009, Donor-Derived Brain Tumor 
Following Neural Stem Cell Transplantation in an Ataxia Telangiectasia Patient, PLoS 
Medicine, 6(2):221-230. 
 
7.  Zhang, Y.M., C. Hartzell, M. Narlow, S.C. Dudley, 2002, Stem Cell-Derived 
Cardiomyocytes Demonstrate Arrhythmic Potential, Circulation, 106:1294-1299. 
 
8.  Gu, E., W. Chen, J. Gu, P. Burridge, J. Wu, 2012, Molecular Imaging of Stem Cells: 
Tracking Survival, Biodistribution, Tumorigenicity, and Immunogenicity, Theranostics, 
2(4)335-345. 
 
9.  Guidance for Industry:  E11 Clinical Investigation of Medicinal Products in the Pediatric 
Population; dated December 2000, 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidance
s/UCM073143.pdf 
 
10. Final Rule:  Additional Safeguards for Children in Clinical Investigations of Food and Drug 
Administration-Regulated Products.  78 FR 12937 (February 26, 2013). 
 
24  Contains Nonbinding Recommendations 
 
  
11. Guidance for Industry:  Gene Therapy Clinical Trials  Observing Subjects for Delayed 
Adverse Events; dated November 2006, 
http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/G
uidances/CellularandGeneTherapy/ucm072957.htm. 
 
12. Guidance for Industry:  Formal Meetings Between the FDA and Sponsors or Applicants; 
dated May 2009, 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidance
s/UCM153222.pdf. 
 
13. Guidance for Industry:  Content and Format of Investigational New Drug Applications 
(INDs) for Phase 1 Studies of Drugs, Including Well-Characterized, Therapeutic, 
Biotechnology-derived Products; dated November 1995, 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidance
s/UCM071597.pdf. 
 
14. Draft Guidance for Industry and Review Staff:  Target Product Profile  A Strategic 
Development Process Tool; dated March 2007, 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidance
s/UCM080593.pdf.  
 
25