Human Gene Therapy for 
Neurodegenerative Diseases
 
 
 
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 
October 2022  Contains Nonbinding Recommendations 
Table of Contents 
 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  CONSIDERATIONS FOR CHEMISTRY, MANUFACTURING AND CONTROLS 
(CMC) ................................................................................................................................ 2 
III.  CONSIDERATIONS FOR PRECLINICAL STUDIES ............................................... 5 
IV.  CONSIDERATIONS FOR CLINICAL TRIALS .......................................................... 7 
A.  Study Design .......................................................................................................... 8 
B.  Study Population ................................................................................................... 9 
C.  Dose Selection ...................................................................................................... 11 
D.  Safety Considerations ......................................................................................... 11 
E.  Study Endpoints .................................................................................................. 12 
F.  Follow-Up Duration ............................................................................................ 12 
G.  Patient Experience .............................................................................................. 13 
V.  EXPEDITED PROGRAMS ........................................................................................... 13 
VI.  COMMUNICATION WITH FDA ................................................................................ 14 
VII.  REFERENCES ................................................................................................................ 15 
i  Contains Nonbinding Recommendations 
Human Gene Therapy for Neurodegenerative Diseases 
 
 
Guidance for Industry 
 
 
This guidance represents the current thinking of the Food and Drug Administration (FDA or 
Agency) on this topic.  It does not establish any rights for any person and is not binding on FDA 
or the public.  You can use an alternative approach if it satisfies the requirements of the 
applicable statutes and regulations.  To discuss an alternative approach, contact the FDA staff 
responsible for this guidance as listed on the title page.  
 
 
I.  INTRODUCTION 
 
This guidance provides recommendations to sponsors developing human gene therapy (GT) 
products1 for neurodegenerative diseases affecting adult and pediatric patients.  
Neurodegenerative diseases are a heterogeneous group of disorders characterized by progressive 
degeneration of the structure and function of the central nervous system or peripheral nervous 
system.  These diseases vary in etiology, prevalence, diagnosis, and management, and include 
genetic as well as age-related diseases.2  This guidance focuses on considerations for product 
development, preclinical testing, and clinical trial design.  This guidance finalizes the draft 
guidance of the same title dated January 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 
the word should in Agency guidances means that something is suggested or recommended, but 
not required. 
 
 
 
   
 
1 Human gene therapy seeks to modify or manipulate the expression of a gene or to alter the biological properties of 
living cells for therapeutic use.  FDA generally considers human gene therapy products to include all products that 
mediate their effects by transcription or translation of transferred genetic material, or by specifically altering host 
(human) genetic sequences.  Some examples of gene therapy products include nucleic acids (e.g., plasmids, in vitro 
transcribed ribonucleic acid (RNA)), genetically modified microorganisms (e.g., viruses, bacteria, fungi), engineered 
site-specific nucleases used for human genome editing, and ex vivo genetically modified human cells.  Gene therapy 
products meet the definition of biological product in section 351(i) of the Public Health Service (PHS) Act (42 
U.S.C. 262(i)) when such products are applicable to the prevention, treatment, or cure of a disease or condition of 
human beings (see Federal Register Notice:  Application of Current Statutory Authorities to Human Somatic Cell 
Therapy Products and Gene Therapy Products (58 FR 53248, October 14, 1993), 
https://www.fda.gov/media/76647/download). 
2 The principles in this guidance may also apply to GT products for other types of neurological diseases, including 
neurodevelopmental disorders. 
1  Contains Nonbinding Recommendations 
II.  CONSIDERATIONS FOR CHEMISTRY, MANUFACTURING AND CONTROLS 
(CMC)  
 
Treatment of neurodegenerative diseases may include the use of GT products, such as viral 
vectors, that have tropism to neuronal tissue to contribute to treatment effect.  The general CMC 
considerations for product manufacturing, testing and release of GT products for 
neurodegenerative diseases are the same as those described for other GT products (Ref. 1).  
However, some aspects of GT products for neurodegenerative diseases, such as challenges 
associated with the route of administration, volume of product that can be administered, the 
delivery device, and the study population size, may involve additional CMC considerations.3   
 
Typically, critical quality attributes (CQAs) of an investigational drug product are evaluated 
during each phase of clinical development, and characterization data from multiple drug product 
lots are correlated to clinical outcomes.  Early-phase clinical studies of neurodegenerative 
diseases involving small study populations, in addition to focusing on safety assessments, may 
also provide early evidence on effectiveness.  In cases where early-phase clinical studies are used 
to provide evidence of effectiveness to support a marketing application, the products CQAs and 
manufacturing critical process parameters (CPPs) should be thoroughly evaluated and 
appropriate controls implemented during the early clinical development phase.  In addition, 
innovative manufacturing strategies such as the production of multiple small lots versus a single 
large product lot may be considered to increase manufacturing process experience and product 
knowledge (Ref. 2).  GT products may have quality attributes with higher variability than small 
molecule drugs or well-characterized biological products, and sponsors should consider 
additional product characterization studies to establish acceptance limits for the CQAs.  For 
licensure, it is important to demonstrate process control to ensure a consistent product with 
predefined CQAs for product strength (e.g., vector genomes/mL), potency, identity, and purity 
(Refs. 1 and 3).  Products used to treat neurodegenerative diseases may have to be administered 
in small volumes to sites of the disease or condition, such as the brain or spinal cord.  These sites 
also have reduced clearance of the administered product, and final product volume and 
formulation are important considerations.  Product CQAs may also influence the final 
formulation parameters, and decisions regarding these product aspects may need to be made 
early in the manufacturing process development.  Therefore, we recommend that assays for 
evaluating product quality attributes be implemented early in product development and qualified 
as suitable (i.e., accurate, precise, sensitive, and specific). 
 
Sponsors developing GT products for neurodegenerative diseases are strongly encouraged to 
contact the Office of Tissues and Advanced Therapies (OTAT) in the Center for Biologics 
Evaluation and Research (CBER) (refer to section VI of this document) prior to submitting an 
investigational new drug application (IND) (21 CFR Part 312) and during product development 
to discuss their product-specific considerations, which may include:  
 
 
3 This guidance is not designed to be a stand-alone guidance on CMC considerations for GT products for 
neurodegenerative disorders.  Sponsors also should refer to the general CMC guidance documents on cell and gene 
therapies available from the FDAs web site:  https://www.fda.gov/vaccines-blood-biologics/biologics-
guidances/cellular-gene-therapy-guidances. 
2  Contains Nonbinding Recommendations 
  Design of GT products should be based on current scientific knowledge and an 
evaluation of potential risks posed by the product to study subjects.  GT products may 
induce unintended immune responses against host cells, become latent in neuronal 
tissues, or cause unwanted gene expression.  Some latent GT products also can be 
reactivated in response to external signals, leading to viral replication, damage to the host 
cells, and environmental shedding.  We recommend that all GT products for 
neurodegenerative diseases be designed to reduce unintended immune responses, reduce 
the possibility of becoming latent, and not contain foreign genes that do not directly 
contribute to the biological function of the investigational product (e.g., reporter genes). 
 
  Drug product purity should be carefully evaluated early in product development.  Purity 
assessment generally includes the evaluation of residual product-related impurities (e.g., 
incomplete viral particles, cellular subtypes) and process-related impurities (e.g., residual 
host cell proteins, host cell DNA, endotoxin).   
 
  Product-related impurities in GT viral vector-based products used to treat 
o
neurodegenerative conditions include empty and wild-type viral particles, and 
replication-competent viruses.  We recommend that qualified assays for 
evaluation of empty particles (where applicable), product-related variants 
(mutations in the viral genome, transgene, etc.), and non-recombinant viral 
particles (e.g., replication-competent viruses, wild-type viruses) be established 
early in the product development cycle. 
 
  Process-related impurities, such as host cell proteins, may contribute to unwanted 
o
immunogenic reactions in the study subject.  For this reason, we recommend that 
the residual host cell protein levels be as low as can be reasonably achieved based 
on manufacturing experience.  Depending on the location of product 
administration and the expected low turnover in the neuronal tissue, administered 
host-cell DNA impurity may be expected to persist for a prolonged period of time, 
and may contribute to the development of adverse events.  As such, we 
recommend that sponsors carefully consider characteristics of the cell lines used 
in the manufacture of viral vectors that may impact the safety of the final product 
(such as presence of tumorigenic sequences) and limit residual host cell-DNA 
levels and DNA size.  For additional information, refer to the CMC guidance 
(Ref. 1).  The endotoxin levels should be kept to less than 0.2EU/kg body 
weight/hour when the drug product is administered by the intrathecal route.  
Lastly, plasmids can also be a source of process-related contaminants in viral 
vector (e.g., adeno-associated virus (AAV))-based GT products.  Plasmids used to 
generate recombinant viral vectors should meet acceptable limits for purity, and 
manufacturing controls should be in place to avoid cross-contamination of 
plasmids.  If the plasmids are manufactured in a multi-product manufacturing 
facility, they should be tested for the presence of other contaminating plasmids 
that may have been co-purified.  Alternatively, a risk assessment may be 
conducted to provide assurance of freedom from other contaminating plasmids 
that may have been co-purified. 
 
3  Contains Nonbinding Recommendations 
  Drug product identity should be established prior to the initiation of any nonclinical 
studies designed to evaluate the products suitability for use in a clinical investigation 
under an IND.  For additional information, refer to the CMC guidance (Ref. 1).  
 
  Drug product potency assays are critical to assess the products functional activity, 
consistency, and stability, and to provide evidence of comparability after changes to the 
manufacturing process (Refs. 4 and 5).  For products designed to treat neurodegenerative 
diseases, where the product may exhibit more than one mode of action, we encourage the 
evaluation of multiple product characteristics that could be used to establish a matrix or 
other similar approach to potency evaluation during initial clinical studies.  We 
recommend that a potency test (Ref. 6) that measures relevant biological activities be 
qualified for suitability (i.e., accuracy, precision, sensitivity, specificity) prior to 
conducting clinical trials intended to provide substantial evidence of effectiveness to 
support a marketing application.  The potency test should be validated prior to submitting 
a biologics license application (BLA) under section 351 of the PHS Act and 21 CFR 
601.2.  
 
  Drug product strength is a CQA that should be carefully measured and evaluated.  This is 
especially crucial for GT vectors that may be expected to have sustained biological 
activity over the lifetime of the subject, including pediatric subjects.  GT product strength 
should be evaluated with an assay qualified as suitable (i.e., accurate, precise, sensitive, 
and specific) prior to initiating clinical studies (Ref. 1).  
 
  Sponsors should evaluate the effect of manufacturing process changes on the products 
CQAs.  Sponsors should be prepared to conduct a risk analysis and, if necessary, a 
comparability study.  The risk analysis should be based on a prospective analysis of the 
potential effects of process changes using a side-by-side analysis of the product pre- and 
post-change.  Sponsors should discuss comparability protocols and changes to the 
manufacturing plans with FDA prior to implementing changes.  The extent of 
comparability studies should depend on the manufacturing change, the ability of 
analytical methods to detect changes in the product, and the stage of clinical 
development.  After discussing the proposed comparability protocol and manufacturing 
changes with FDA, sponsors should be prepared to perform the comparability study.  It is 
critical that sufficient samples are retained (such as in-process materials, drug substance 
(DS), DS intermediates, and drug product (DP)).  After the comparability study is 
conducted, sponsors should submit the data from the comparability studies as an 
amendment to the IND (21 CFR 312.31(a)(1)) for FDA review prior to implementing the 
change for investigational use in clinical studies.  For general recommendations on the 
design of comparability studies, sponsors may refer to the FDA comparability guidance 
(Ref. 4) and the International Council for Harmonisation (ICH) Q5E document (Ref. 5).  
Sponsors are also encouraged to consider, where possible, implementing manufacturing 
changes needed for commercial-scale production and demonstrating product 
comparability prior to the initiation of clinical trials intended to provide substantial 
evidence of effectiveness to support a marketing application.  Importantly, if product 
comparability cannot be demonstrated, additional clinical studies may be needed to 
support BLA approval. 
4  Contains Nonbinding Recommendations 
 
  When a device is used to deliver the investigational product, compatibility of the product 
with the delivery device (e.g., no loss of strength or potency, no increase in impurities, 
etc. of the investigational product after passing through the delivery device) should be 
demonstrated prior to initiating Phase 1 safety studies (21 CFR 312.23(a)(10)(iv) and 21 
CFR 312.23(a)(11)).  Such studies should be carried out with the final formulated 
investigational product that is intended to be used in the clinical study, under conditions 
that would mimic those planned in the clinical study.  Specifically, the delivery device, 
product concentration (tested over the planned dose-range), drug product formulation, 
final infusion volume, duration and rate of infusion, and temperature for the device 
compatibility studies should be representative of what will be used in the clinical study.  
 
  If a sponsor plans to use a delivery device within the cleared or approved indications for 
use, compatibility of the investigational product with the delivery device should be 
demonstrated prior to initiating Phase 1 safety studies, as discussed above.  If use of a 
delivery device falls outside the cleared or approved indications for use or if the delivery 
device has not been cleared or approved by the FDA for any indication, we recommend 
early discussion with FDA (see section VI of this document) to determine the additional 
information that may be needed to inform FDAs safety evaluation of the delivery device 
when used with the investigational product for the proposed clinical study.   
 
  FDA encourages sponsors to discuss pharmaceutical quality development plans early, 
such as at the pre-investigational new drug application (pre-IND) meeting, and 
throughout the drug development process.  This continuous engagement with the Agency 
can decrease the potential for developmental or approval delays related to manufacturing 
changes introduced at various stages in the products life cycle.  
 
 
III.  CONSIDERATIONS FOR PRECLINICAL STUDIES 
 
A preclinical program that is tailored to the investigational product and planned early-phase 
clinical trial contributes to characterization of the products benefit/risk profile for the intended 
patient population.  The overall objectives of a preclinical program for a GT product include:  1) 
identification of a biologically active dose range; 2) recommendations for an initial clinical dose 
level, dose-escalation schedule, and dosing regimen; 3) establishment of the rationale for, and 
reasonable safety of, the proposed clinical route of administration (ROA); 4) support of patient 
eligibility criteria; and 5) identification of potential toxicities and physiologic parameters that 
help guide clinical monitoring for a particular investigational product.  It is also important to 
provide scientific support for the method of dose level extrapolation between animals and 
humans.  In addition, to justify conducting a pediatric first-in-human clinical trial that is 
associated with more than a minor increase over minimal risk, the preclinical program should 
include studies designed to demonstrate a prospect of direct benefit (21 CFR 50.52) of the 
investigational GT product (refer to section IV.B. of this document for further discussion).  
Preclinical evidence to support a prospect of direct benefit is most important when clinical 
evidence of effectiveness is not available from adult subjects with the same disease.  
 
5  Contains Nonbinding Recommendations 
Further details for general considerations in preclinical studies of these investigational GT 
products are available in a separate guidance document (Ref. 7).  The following elements are 
recommended in the development of a preclinical program for an investigational GT product 
intended for treatment of a neurodegenerative disease:  
 
  Preclinical in vitro and in vivo proof-of-concept (POC) studies to establish feasibility and 
to support the scientific rationale for administration of the investigational GT product in a 
clinical trial should be considered.  Data derived from preclinical POC studies may guide 
the design of the preclinical toxicology studies, as well as the early-phase clinical trials. 
Animal models of neurodegenerative disorders are often used to generate POC data.  
Such models may provide the opportunity for identification of disease-relevant risks and 
biomarkers of activity that may be applicable for monitoring in clinical trials.  The animal 
species and/or models selected should demonstrate a biological response to the 
investigational GT product that is expected to be similar to the response in humans.4  
 
  Biodistribution studies should be conducted to assess the distribution, persistence, and 
clearance of the vector and possibly the expressed transgene product, from the site of 
administration to target and non-target tissues, including applicable biofluids (e.g., blood 
and cerebrospinal fluid (CSF)), as feasible.  These data can determine extent of tissue 
transduction and transgene expression, evaluate whether expression is transient or 
persistent, and guide the design of the preclinical toxicology studies as well as the 
early-phase clinical trials (Refs. 7, 8, and 9).  
 
  Toxicology studies for an investigational GT product can be conducted in animal models 
of neurodegenerative disease, as well as in healthy animals, as appropriate.  Study 
designs should incorporate elements of the planned clinical trial (e.g., dose range, ROA, 
dosing schedule, and evaluation endpoints), to the extent feasible.  Study designs should 
be sufficiently comprehensive to permit identification, characterization, and 
quantification of potential local and systemic toxicities, their onset (i.e., acute or delayed) 
and potential mitigation and/or resolution, and the effect of dose level on these findings.  
In some cases, additional assessments may also be important to consider, such as clinical 
neurological evaluations, neuropathology, and the immune response directed against the 
vector and the expressed transgene product.  In addition, for any significant abnormal 
findings or lesions, sponsors should determine the frequency, severity, potential cause, 
and possible clinical significance.  
 
  Due to differences in anatomy in rodents as compared to the central and peripheral 
nervous systems in humans, animals with larger brains or spinal columns, such as pigs or 
nonhuman primates, may provide additional safety information and facilitate dose 
 
4 The preclinical program for any investigational product should be individualized with respect to scope, complexity, 
and overall design.  We support the principles of the 3Rs, to reduce, refine, and replace animal use in testing when 
feasible.  Proposals, with justification for any potential alternative approaches (e.g., in vitro or in silico testing), 
should be submitted during early communication meetings with FDA (see section VI of this document).  We would 
consider whether such an alternative method could be used in place of an animal test method. 
 
 
6  Contains Nonbinding Recommendations 
extrapolation.  Inclusion of larger animals may also allow for the evaluation of the 
surgical dosing procedures and delivery device systems intended for clinical use (refer to 
section II of this document for additional discussion of delivery devices).  Scientific 
justification should be provided to support selection of animal models.  These animal 
models, and their justification, will be evaluated by the FDA in the context of each 
investigational GT product and proposed clinical indication.   
  
  Functional endpoints for POC studies in models of neurodegenerative disease often 
require neurobehavioral testing to demonstrate activity following administration of the 
investigational GT product.  Adequate training of personnel, inclusion of appropriate 
controls, masked assessment of study endpoints, and use of well-defined scoring systems 
are recommended to avoid potential bias in these studies. 
 
  Evaluation of the potential for developmental and reproductive toxicity may be 
warranted, depending on such factors as the vector construct, the expressed transgene 
product, biodistribution data, and the target clinical population.  If significant changes in 
the manufacturing process or product formulation occur during product development 
which may impact comparability between the product administered in clinical trials and 
the product intended for licensure, the conduct of additional pharmacology/toxicology 
studies should be considered. 
 
 
IV.  CONSIDERATIONS FOR CLINICAL TRIALS 
 
The fundamental considerations for clinical development programs of GT products for 
neurodegenerative diseases are similar to those considerations for other biological products, as 
detailed in relevant FDA guidance documents (Refs. 10 and 11).  The following are general 
recommendations regarding development of clinical programs of investigational GT products for 
neurodegenerative diseases. 
 
FDA recognizes that neurodegenerative diseases constitute a heterogeneous group of disorders.  
Some neurodegenerative diseases are monogenic disorders with relatively well-characterized 
pathogenesis and pathophysiology (e.g., infantile spinal muscular atrophy due to mutations in the 
survival motor neuron 1 gene).  When the natural history of such monogenic disorders is also 
well-characterized and relatively consistent (i.e., not highly variable), and when the expected 
clinically meaningful treatment effect is large, self-evident, and closely associated temporally 
with the intervention, innovative clinical trial designs, rather than randomized, 
placebo-controlled trials, may be feasible to expedite clinical development.  In contrast, many 
other neurodegenerative disorders have a poorly understood etiology and/or pathophysiology, 
with a poorly characterized or highly variable natural history (e.g., sporadic amyotrophic lateral 
sclerosis or sporadic Alzheimers disease).  For these disorders, randomized, concurrent-
controlled (e.g., placebo, sham-procedure) clinical trials with appropriate blinding may be the 
most efficient means of obtaining persuasive evidence of effectiveness.  For any 
neurodegenerative disorder, regardless of etiology, pathophysiology, and natural history, 
sponsors are encouraged to consider whether innovative trial designs (e.g., adaptive designs, 
enrichment designs, dose-controlled studies, or historical controls) both may be justified and may 
7  Contains Nonbinding Recommendations 
facilitate product development.  In all cases, however, to promote product development, we 
encourage sponsors to discuss clinical development plans with FDA early in product 
development. 
 
A.  Study Design 
 
  All subjects in trials of GT products for neurodegenerative diseases should 
receive the best standard of care, and no patient should be denied effective 
therapies in order to be randomized to a placebo-only arm.  While comparison to 
a placebo may be optimal to determine the effectiveness of some products, 
various strategies may be applied to minimize unnecessary exposure of subjects to 
placebo.  For studies involving placebo, FDA recommends add-on designs, in 
which a treatment previously shown to be effective for the neurodegenerative 
condition is given to all subjects participating in the trial, with subjects then 
randomized to receive the added GT product or added placebo.   
 
  With the provisions above in mind, whenever possible FDA generally 
recommends that sponsors conduct randomized, concurrent-controlled (e.g., 
placebo, sham-procedure), double-blind clinical trials, even for first-in-human 
studies.  Such randomized designs best facilitate interpretation of clinical data and 
can be the most efficient way to demonstrate safety and effectiveness of GT 
products.  For conditions where the disease course is well-characterized, highly 
predictable, and can be objectively measured and verified (e.g., temporally 
predictable mortality), randomized studies potentially may not be needed, 
especially if the clinically meaningful treatment effect is large and such 
improvement would not be expected without treatment.  
 
  Sponsors developing a GT product for a rare neurodegenerative disease should 
consider designing their first-in-human study to be an adequate and 
well-controlled investigation so that the results of such a study may provide 
evidence of effectiveness to support a marketing application.  Even though first-
in-human studies may have limited power to detect differences in effectiveness, 
the design elements, such as randomization, concurrent-control, blinding, and use 
of clinically meaningful efficacy endpoints, enhance interpretability of 
preliminary safety and efficacy data to guide further clinical development.  
 
  When appropriate, crossover designs may also be considered in 
concurrent-controlled trials to allow patients in the control group to receive the 
GT product after completion of the randomized, controlled portion of the trial.  To 
allow for additional prespecified effectiveness assessments, we recommend that 
during the open label extension period, patients, investigators, site personnel, and 
site monitors remain blinded to treatment group assignment from the randomized 
treatment period. 
 
8  Contains Nonbinding Recommendations 
  For trials using a sham procedure as the concurrent control, FDA recommends the 
sham procedure be as minimally invasive as possible while still maintaining 
blinding of appropriate parties (e.g., evaluators, study patients, and families).5 
 
  Trials using external controls (e.g., a natural history control) rather than a 
concurrent comparator group to which a suitable fraction of enrolled subjects are 
randomized for comparison may be appropriate under certain circumstances, such 
as with a GT product intended to treat a rare and serious neurodegenerative 
disease for which (1) there is an unmet medical need; (2) inclusion of a concurrent 
control is not practical or ethical; (3) the disease course is well-documented, 
highly predictable, and can be objectively measured and verified, such as high and 
temporally predictable mortality; (4) the study population and the external 
controls are suitably comparable; and (5) the expected treatment effect is large, 
self-evident, and closely associated temporally with the intervention.  Even under 
these circumstances, however, external controls may be inadequate (e.g., if 
important prognostic covariates either are unknown or were not recorded in the 
historical record) (Refs. 12 and 13).  As a result, FDA generally does not 
encourage use of external controls in place of a concurrent comparator group. 
 
B.  Study Population 
 
  For clinical trials of GT products for treatment of a neurodegenerative disorder 
due to mutation(s) in a gene, genetic diagnosis is essential for identifying 
potential clinical trial participants; presence of the genetic mutation should be 
confirmed prior to enrollment.  If a reliable genetic diagnostic test is not readily 
available, a companion diagnostic may need to be developed to appropriately 
select subjects for the study.   
 
  Sponsors may choose to exclude potential trial participants who have pre-existing 
antibodies to elements of the GT product (e.g., capsid, transgene) above certain 
level(s) justified by scientific data.  In those cases, the sponsor should strongly 
consider development of a companion diagnostic to reliably detect such 
antibodies.   
 
  Early in product development, sponsors should communicate with the Agency 
about the possible need for companion diagnostics and the proper development 
pathway (e.g., the study risk determination and the need for an Investigational 
Device Exemption application).  If an in vitro companion diagnostic is needed to 
appropriately select subjects for a study (and later for treatment, once the GT 
product is approved), the sponsor should coordinate submission of the marketing 
application for the companion diagnostic with submission of the BLA for the GT 
product, to support contemporaneous marketing authorizations (Refs. 14 and 15). 
 
 
5 See also Guidance for Industry:  ICH E10 Choice of Control Group and Related Issues in Clinical Trials, May 
2001; https://www.fda.gov/media/71349/download; and https://www.wma.net/policies-post/wma-declaration-of-
helsinki-ethical-principles-for-medical-research-involving-human-subjects/.  
9  Contains Nonbinding Recommendations 
  In general, eligibility for first-in-human GT trials should consider disease severity 
or stage as part of the benefit-risk profile.  Further details on this topic are 
available in a separate guidance document (Ref. 10).  If preliminary safety data 
support further clinical development, sponsors are encouraged to then include a 
broader patient population in future trials. 
 
  Certain neurodegenerative diseases affect adults as well as children.  Sponsors 
who are developing GT products for these diseases should consider the following: 
 
  Whenever feasible, the first-in-human trial should be initiated in adult 
o
subjects who are able to understand the risks, and to provide informed 
consent.  Sponsors should obtain preliminary safety and tolerability data 
(and in some situations, data to support preliminary effectiveness or 
substantial evidence of effectiveness) in adult subjects prior to beginning 
studies in pediatric subjects.  
 
  When no prior human safety or efficacy data are available, sponsors 
o
planning to conduct first-in-human trials in pediatric subjects should 
provide a rationale as to why adult studies are either not feasible or not 
ethical. 
 
  It is important that clinical investigations in pediatric subjects address 
o
ethical considerations for conducting investigations in vulnerable 
populations.  FDA regulations at 21 CFR Part 50, Subpart D contain 
additional safeguards for children in clinical investigations.  Clinical 
investigations involving no greater than minimal risk may involve children 
in accordance with 21 CFR 50.51.  Clinical investigations involving 
greater than minimal risk but presenting the prospect of direct benefit to 
individual subjects may involve children as set forth in 21 CFR 50.52.  An 
investigation involving greater than minimal risk and no prospect of direct 
benefit to individual subjects, but which is likely to yield generalizable 
knowledge about the disorder or condition, may involve children as set 
forth in 21 CFR 50.53, which includes, for example, a finding by the IRB 
that the risk represents a minor increase over minimal risk.  FDAs 
regulation at 21 CFR 50.54 also addresses clinical investigations not 
otherwise approvable and describes a process to follow to determine 
whether the investigation may involve children.  In addition to the 
determinations required under applicable provisions of Subpart D 
described above, adequate provisions must be made to obtain the 
permission of the parents and the assent of the child as described in 21 
CFR 50.55.  
 
   
10  Contains Nonbinding Recommendations 
C.  Dose Selection 
 
  For early-phase trials of GT products, dose-ranging study designs are 
recommended.  FDA encourages substantial dose exploration throughout clinical 
development, to identify potentially safe and therapeutic dose(s) for a wide group 
of subjects.  Doing so may be of heightened importance for some gene therapy 
products, since subjects may have only one chance to receive the product:  
stimulation of antibodies and T-cell immune responses to the product may 
preclude repeat administration.  For these products, the clinical study should start 
with a likely therapeutic dose. 
 
  The choice of an initial dose and dose regimen should be supported by preclinical 
studies and/or available clinical information.  Such data should indicate that the 
initial dose not only is reasonably safe, but also has therapeutic potential, 
particularly when the procedure for administering the product carries substantial 
risks, or when the product will be administered to children. 
 
  Invasive surgical procedures may be necessary to administer a GT product (e.g., 
intracranial delivery to a targeted region of the brain or spinal cord).  In such 
cases, FDA recommends that the sponsor use a staged approach:  initiating the 
early-phase study with unilateral administration in a reasonable number of 
subjects, and if no significant safety concerns related to product administration 
arise, then proceeding to bilateral administration of the GT product in the 
early-phase study.  
 
  To ensure consistency across study sites, sponsors should include in the study 
protocol a detailed description of both the product delivery procedure and the 
devices used for delivery.   
 
D.  Safety Considerations 
 
  Immune responses to GT products may pose important safety risks, such as by 
damaging the tissues transduced by viral vectors carrying a therapeutic transgene.  
To monitor for systemic immune reactions, sponsors should perform 
immunoassays measuring cellular and humoral immune responses to both the 
vector and the transgene-encoded protein.  
 
  To minimize immune responses, immunosuppressant treatments (e.g., 
corticosteroids) may be used before and after product administration.  Sponsors 
should provide justification for the immunosuppressant regimen, based on 
available clinical data for the investigational product or related products.  Because 
immunosuppressant drugs may cause adverse events, subjects should be closely 
monitored and treated, as necessary, to minimize the risk of complications.  
 
   
11  Contains Nonbinding Recommendations 
E.  Study Endpoints 
 
  FDA encourages sponsors to explore a wide range of endpoints to assess 
preliminary safety, activity and efficacy of a GT product in early-phase trials.  
Clinical endpoints should enable assessment of potential clinical benefit; 
biomarkers and potential surrogate endpoints6 may indicate activity of the GT 
product.  Such endpoint assessments may help guide further clinical development.   
 
  In trials intended to provide evidence of effectiveness to support a marketing 
application, primary efficacy endpoints should be either clinically meaningful 
endpoints that directly measure a clinical benefit, or surrogate endpoints that are 
reasonably likely to predict a clinical benefit.  
 
Because many neurodegenerative diseases are rare and complex, with limited 
understanding of their pathogenesis, identification and characterization of a 
surrogate or intermediate endpoint is often challenging.  Therefore, an effect on a 
clinically meaningful endpoint generally would be used to support a marketing 
application under the traditional approval pathway. 
 
  When a suitable surrogate endpoint is identified, it may be used to support a 
marketing application under the accelerated approval pathway.7  Use of a 
surrogate endpoint may be appropriate under certain circumstances, such as when 
a GT product directly targets an underlying, well-understood and well-
documented monogenic change that causes a serious neurodegenerative disorder.  
In these cases, the GT product could alter the underlying genetic defect and 
thereby treat or cure the disease. 
 
Sponsors proposing to develop surrogate endpoint(s) to support accelerated 
approval should communicate with the Agency early in product development, 
preferably well before initiating clinical trials.  Further information on the 
accelerated approval pathway is available in separate guidance documents (Refs. 
16 and 17). 
 
F.  Follow-Up Duration 
 
The length of follow-up necessary to provide sufficient information regarding the 
safety and efficacy of the GT product depends on many aspects of a GT product, 
including vector persistence, genome integration, and transgene activity, and the 
 
6 According to section 507(e)(9) of the Federal Food, Drug, and Cosmetic Act (FD&C) Act [21 U.S.C. 357(e)(9)] 
[t]he term surrogate endpoint means a marker, such as a laboratory measurement, radiographic image, physical 
sign, or other measure, that is not itself a direct measurement of clinical benefit, and 
(A) is known to predict clinical benefit and could be used to support traditional approval of a drug or biological 
product; or 
(B) is reasonably likely to predict clinical benefit and could be used to support the accelerated approval of a drug 
or biological product in accordance with Section 506(c). 
7 Further information on the accelerated approval pathway is available in separate guidance documents (Refs. 16 and 
17). 
12  Contains Nonbinding Recommendations 
goal of the follow-up (e.g., safety vs. durability of clinical effect).  In addition to 
monitoring for safety, long-term follow-up is recommended to evaluate durability 
of the clinical effect.  More detailed discussion of long-term follow-up is provided 
in a separate FDA guidance document (Ref. 8). 
 
G.  Patient Experience 
 
Patient experience data8 may provide important additional information about the clinical 
benefit of a GT product.  FDA encourages sponsors to collect patient experience data 
during product development, and to submit such data in the marketing application.  
 
 
V.  EXPEDITED PROGRAMS 
 
There are several programs available to sponsors of GT products intended to address unmet 
medical needs in the treatment of serious or life-threatening conditions.  These programs, 
including regenerative medicine advanced therapy designation, breakthrough therapy 
designation, fast track designation, accelerated approval, and priority review, are intended to 
facilitate and expedite development and review of such therapies.  In particular, regenerative 
medicine advanced therapy designation and breakthrough therapy designation call for increased 
FDA attention to these potentially promising therapies, offering sponsors more-frequent 
interactions with FDA on efficient trial design and overall drug development.  Further 
information on these expedited programs is available in separate guidance documents (Refs. 16 
and 17).  
 
 
   
 
8 As defined in section 569C(c) of the FD&C Act, the term patient experience data includes data that are: 
  Collected by any persons (including patients, family members and caregivers of patients, patient advocacy 
organizations, disease research foundations, researchers, and drug manufacturers); and  
  Intended to provide information about patients experiences with a disease or condition, including the 
impact (including physical and psychosocial impacts) of such disease or condition, or a related therapy or 
clinical investigation, on patients lives; and patient preferences with respect to treatment of such disease or 
condition. 
Additional information on Patient-Focused Drug Development can be found on this website:  
https://www.fda.gov/drugs/development-approval-process-drugs/cder-patient-focused-drug-development and on: 
https://www.fda.gov/vaccines-blood-biologics/development-approval-process-cber/center-biologics-evaluation-and-
research-patient-engagement-program.   
13  Contains Nonbinding Recommendations 
VI.  COMMUNICATION WITH FDA 
 
FDA encourages communication with OTAT early in product development, before submission 
of an IND.  Different meeting types are available, depending on the stage of product 
development and the issues to be considered.  These include pre-IND meetings and, earlier in 
development, INitial Targeted Engagement for Regulatory Advice on CBER producTs 
(INTERACT) meetings.9  Early, nonbinding regulatory advice can be obtained from OTAT 
through an INTERACT meeting, which can be used to discuss issues such as a products early 
preclinical program, and/or through a pre-IND meeting prior to submission of the IND (Ref. 18). 
   
 
9 For additional information about INTERACT meetings, please see  https://www.fda.gov/vaccines-blood-
biologics/industry-biologics/interact-meetings 
 
14  Contains Nonbinding Recommendations 
VII.  REFERENCES 
 
1.  Chemistry, Manufacturing, and Control (CMC) Information for Human Gene Therapy 
Investigational New Drug Applications (INDs); Guidance for Industry, January 2020; 
https://www.fda.gov/media/113760/download. 
2.  Guidance for Industry:  Q11 Development and Manufacture of Drug Substances, 
November 2012; https://www.fda.gov/media/80909/download .  
3.  Guidance for Industry:  Process Validation: General Principles and Practices, January 
2011; https://www.fda.gov/media/71021/download. 
4.  Comparability Protocols for Human Drugs and Biologics:  Chemistry, Manufacturing, 
and Controls Information; Draft Guidance for Industry, April 2016*; 
https://www.fda.gov/media/97148/download. 
5.  Guidance for Industry:  Q5E Comparability of Biotechnological/Biological Products 
Subject to Changes in Their Manufacturing Process, June 2005; 
https://www.fda.gov/media/71489/download 
6.  Guidance for Industry:  Potency Tests for Cellular and Gene Therapy Products, January 
2011; https://www.fda.gov/media/79856/download. 
7.  Guidance for Industry:  Preclinical Assessment of Investigational Cellular and Gene 
Therapy Products, November 2013; https://www.fda.gov/media/87564/download. 
8.  Long Term Follow-Up After Administration of Human Gene Therapy Products; 
Guidance for Industry, January 2020;  
https://www.fda.gov/media/113768/download. 
9.  Expectations for Biodistribution (BD) Assessments for Gene Therapy (GT) Products, 
International Pharmaceutical Regulators Programme (IPRP) Reflection Paper, 2018;  
https://admin.iprp.global/sites/default/files/2018-
09/IPRP_GTWG_ReflectionPaper_BD_Final_2018_0713.pdf . 
10.  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. 
11.  Guidance for Industry:  Providing Clinical Evidence of Effectiveness for Human Drug 
and Biologic Products, May 1998; https://www.fda.gov/media/71655/download. 
12.  Rare Diseases:  Natural History Studies for Drug Development; Draft Guidance for 
Industry, March 2019*; https://www.fda.gov/media/122425/download. 
13.  Rare Diseases:  Common Issues in Drug Development; Draft Guidance for Industry, 
February 2019*; https://www.fda.gov/media/120091/download. 
14.  In Vitro Companion Diagnostic Devices:  Guidance for Industry and Food and Drug 
Administration Staff, August 2014; https://www.fda.gov/media/81309/download. 
15.  Principles for Codevelopment of an In Vitro Companion Diagnostic Device with a 
Therapeutic Product:  Draft Guidance for Industry and Food and Drug Administration 
Staff, July 2016*; https://www.fda.gov/media/99030/download.  
16.  Guidance for Industry:  Expedited Programs for Serious Conditions  Drugs and 
Biologics, May 2014; https://www.fda.gov/media/86377/download. 
17.  Expedited Programs for Regenerative Medicine Therapies for Serious Conditions; 
Guidance for Industry, February 2019; https://www.fda.gov/media/120267/download. 
18.  Guidance for Industry:  Formal Meetings Between the FDA and Sponsors or Applicants, 
May 2009; https://www.fda.gov/media/72253/download. 
15  Contains Nonbinding Recommendations 
*When finalized, this guidance will represent FDAs current thinking on this topic. 
16