Human Gene Therapy for Rare 
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 
January 2020  Contains Nonbinding Recommendations 
 
Table of Contents 
 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  BACKGROUND ............................................................................................................... 2 
III.  CONSIDERATIONS FOR CHEMISTRY, MANUFACTURING AND CONTROLS  
............................................................................................................................................. 2 
IV.  CONSIDERATIONS FOR PRECLINICAL STUDIES................................................ 3 
V.  CONSIDERATIONS FOR CLINICAL TRIALS .......................................................... 5 
A.  Study Population ................................................................................................... 5 
B.  Study Design .......................................................................................................... 7 
C.  Dose Selection ........................................................................................................ 8 
D.  Safety Considerations ........................................................................................... 9 
E.  Efficacy Endpoints .............................................................................................. 10 
F.  Patient Experience .............................................................................................. 11 
VI.  EXPEDITED PROGRAMS ........................................................................................... 11 
VII.  COMMUNICATION WITH FDA ................................................................................ 12 
VIII.  REFERENCES ................................................................................................................ 13 
i  Contains Nonbinding Recommendations 
 
Human Gene Therapy for Rare 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)1 
products intended to treat a rare disease2 in adult and/or pediatric patients regarding the 
manufacturing, preclinical, and clinical trial design issues for all phases of the clinical 
development program.  Such information is intended to assist sponsors in designing clinical 
development programs for such products, where there may be limited study population size and 
potential feasibility and safety issues, as well as issues relating to the interpretability of 
bioactivity/efficacy outcomes that may be unique to rare diseases or to the nature of the GT 
product itself.  This guidance finalizes the draft guidance of the same title dated July 2018. 
 
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. 
   
                                                 
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 A rare disease is defined by the Orphan Drug Act of 1983 as a disease or condition that affects fewer than 200,000 
persons in the United States.  Public Law 97-414, 96 Stat. 2049 (1983).  Amended by Public Law 98-551 (1984) to 
add a numeric prevalence threshold to the definition of rare diseases. 
1  Contains Nonbinding Recommendations 
 
II.  BACKGROUND 
 
The National Institutes of Health (NIH) reports that nearly 7,000 rare diseases affect more than 
25 million Americans.  Approximately 80% of rare diseases are caused by a single-gene defect, 
and about half of all rare diseases affect children.  Since most rare diseases have no approved 
therapies, there is a significant unmet need for effective treatments, and many rare diseases are 
serious or life-threatening conditions.  As a general matter, developing safe and effective 
products to treat rare diseases can be challenging.  For example, it might be more difficult to find 
and recruit patients with rare diseases into clinical trials.  Additionally, patients may have highly 
diverse clinical manifestations and rates of disease progression that are difficult to predict.  
These challenges are also present for the development of GT products.  However, despite these 
challenges, GT-related research and development in the area of rare diseases continues to grow 
at a rapid rate. 
 
 
III.  CONSIDERATIONS FOR CHEMISTRY, MANUFACTURING AND CONTROLS 
 
The general chemistry, manufacturing and controls (CMC) considerations for product 
manufacturing, testing and release of GT products for rare diseases are the same as those 
described for other GT products (Ref. 1).  However, some aspects of the development programs 
for rare diseases, such as limited population size and fewer lots manufactured, may make it 
challenging to follow traditional product development strategies.  In traditional product 
development, critical quality attributes (CQAs) of the product are evaluated during each phase of 
clinical development, and characterization data from many drug product lots are correlated to 
clinical outcomes.  Smaller study populations may result in the need for fewer manufacturing 
runs, which can make it difficult to establish the critical process parameters (CPP) necessary for 
ensuring CQAs.  In addition, GT products may have CQAs with higher variability than drugs or 
well-characterized biologics, which can add to CQA uncertainty.  However, demonstrating 
process control to ensure a consistent product with defined CQAs for potency, identity and purity 
is required to demonstrate compliance with licensure and regulatory requirements3 (Refs. 2 and 
4). 
 
These factors make it even more critical that a sponsor of a GT product for a rare disease 
establish a well-controlled manufacturing process along with suitable analytical assays to assess 
product CQAs for product concentration, potency, identity and purity as early in development as 
possible, optimally before administration of the GT product to the first subject (Refs. 2 and 3).  
When changes to the manufacturing process are necessary, a comparability assessment may be 
needed.  Importantly, as the Phase 1 study may provide evidence of safety and effectiveness for 
licensure, we recommend that sponsors characterize the products CQAs, and implement 
manufacturing CPPs, before initiating clinical studies.  Innovative strategies for understanding 
CQAs may include applying prior knowledge from other similar products, leveraging product 
characterization data from nonclinical studies, evaluating CPPs during engineering runs, or the 
production of multiple small lots versus a single large product lot.  Sponsors developing GT 
products for rare diseases are strongly encouraged to contact the Office of Tissues and Advanced 
                                                 
3 Section 351(a)(2)(C)(i) of the PHS Act (42 U.S.C. 262(a)(2)(C)(i)); 21 CFR 601.2; 21 CFR 601.20; 21 CFR Part 
610, Subpart B; and 21 CFR 312.23(a)(7). 
2  Contains Nonbinding Recommendations 
 
Therapies (OTAT) in the Center for Biologics Evaluation and Research (CBER) prior to 
investigational new drug application (IND) submission and during product development to 
discuss their product-specific considerations, which may include:  
 
  Product-related variations may have a pronounced effect on the interpretability of clinical 
data in rare disease studies.  Examples of product variations include impurities such as 
empty and wild-type viral particles in viral vectors, and variability in genetically-
modified cell therapies caused by intrinsic differences among subjects cells. 
Establishment of assays for characterization of product-related variants and impurities 
will be important for program success.  
 
  Potency assays are critical to assess product functional activity, consistency and stability, 
and to provide evidence of comparability after changes to the manufacturing process.  To 
better understand product function(s), we strongly encourage the evaluation of multiple 
product characteristics before initiating clinical studies.  These characterization studies 
may in turn be used to establish a potency test, which is critical to successful product 
development.  Therefore, we recommend that a potency test that measures a relevant 
biological activity be qualified for suitability (i.e., accuracy, precision, sensitivity, 
specificity) prior to conducting trials intended to provide substantial evidence of 
effectiveness for a marketing application and validated prior to licensure (Ref. 2). 
 
  It can be challenging to develop and validate a manufacturing process or perform 
comparability studies and develop suitable assays to measure CQAs when there is limited 
availability of starting materials (e.g., autologous cells), a lack of reference materials, or 
limited process understanding (Ref. 3).  Sponsors are 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 for a marketing application.  Importantly, 
if product comparability cannot be demonstrated, additional clinical data may be needed 
(Refs. 4 and 5).  
 
 
IV.  CONSIDERATIONS FOR PRECLINICAL STUDIES 
 
A preclinical program that is tailored to the investigational product and the 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 feasibility 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.  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 V.A. of this document for further discussion).  Preclinical evidence of a prospect of 
3  Contains Nonbinding Recommendations 
 
direct benefit is most important when clinical evidence of effectiveness is not available from 
adult subjects with the same disease.  
 
Further details for general considerations in preclinical studies are available in a separate 
guidance document (Ref. 6).  Although not specific to rare diseases, the following elements are 
recommended in the development of a preclinical program for an investigational GT product:4 
 
  Preclinical in vitro and in vivo proof-of-concept (POC) studies are recommended to 
establish feasibility and support the scientific rationale for administration of the 
investigational GT product in a clinical trial.  Data derived from preclinical POC studies 
may guide the design of both the preclinical toxicology studies, as well as the early-phase 
clinical trials.  The animal species and/or models selected should demonstrate a 
biological response to the investigational GT product that is similar to the expected 
response in humans. 
 
  Biodistribution studies should be conducted to assess the distribution, persistence, and 
clearance of the vector from the site of administration to target and non-target tissues, 
including applicable biofluids (e.g., blood, lymph node fluid, 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. 6-8). 
 
  Toxicology studies for an investigational GT product should incorporate elements of the 
planned clinical trial (e.g., dose range, ROA, dosing schedule, evaluation endpoints, etc.) 
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 resolution, and the effect of 
dose level on these findings.  In some cases, additional assessments may also be 
important to consider, such as safety and feasibility of the proposed GT delivery system 
and procedure, and immune response directed against the vector and the expressed 
transgene product. 
 
  Additional nonclinical studies may be needed to address such factors as:  1) the potential 
for developmental and reproductive toxicity;5 and 2) significant changes in the 
manufacturing process or formulation that may impact comparability between the product 
administered in clinical trials and the product intended for licensure. 
 
                                                 
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 VII of this document).  We will 
consider if such an alternative method could be used in place of an animal test method. 
5 For additional information on developmental and reproductive toxicity, please see section III.B. of the Preclinical 
Assessment of Investigational Cellular and Gene Therapy Products; Guidance for Industry, November 2013, 
https://www.fda.gov/regulatory-information/search-fda-guidance-documents/preclinical-assessment-investigational-
cellular-and-gene-therapy-products. 
4  Contains Nonbinding Recommendations 
 
V.  CONSIDERATIONS FOR CLINICAL TRIALS 
 
Many rare disorders are serious, with no approved treatments, and represent substantial unmet 
medical needs for patients.  Because of phenotypic heterogeneity, disease manifestations are 
likely to vary in onset and severity.  Information obtained from a natural history study can 
potentially provide critical information to guide every stage of drug development from drug 
discovery to determining effectiveness and safety of the drug in treating a disease (Ref. 9).  If 
there is insufficient information on the natural history of the disease to inform the selection of a 
historical comparator or to inform clinical endpoint selection, additional natural history data may 
be needed (Ref. 10). 
 
In a majority of these disorders, clinical manifestations appear early in life, and there are ethical 
and regulatory considerations regarding enrollment of children into clinical trials.  These 
considerations should inform the design of both early- and late-phase clinical trials.  Further 
details of general considerations for GT clinical trials are available in a separate guidance 
document (Ref. 11). 
 
The following important elements are recommended for consideration during clinical 
development of investigational GT products intended for treatment of rare diseases (although 
they are not exclusively applicable to GT products for rare diseases). 
 
A.  Study Population 
 
Selection of the study population should consider existing preclinical or clinical data to 
determine the potential risks and benefits for the study subjects.  In addition, sponsors 
should consider whether the proposed study population is likely to provide informative 
safety and/or efficacy data (Ref. 11).  The following points should be considered with 
respect to trials of GT products for rare diseases:  
 
  If the disease is caused by a genetic defect, the sponsor should perform genetic 
test(s) for the specific defect(s) of interest in all clinical trial subjects.  This 
information is important to ensure correct diagnosis of the disorder of interest.  In 
addition, since many of these disorders can involve either deletions or functional 
mutations at any of several loci within a specific gene, safety and effectiveness 
may be linked to genotype in unpredictable ways.  Given this, early understanding 
of such associations may help in planning future clinical trials.  Therefore, if there 
are no readily available, reliable means of obtaining the needed genetic diagnosis, 
a companion diagnostic may be needed and therefore should be considered early 
in development (Ref. 12).   
 
  Pre-existing antibodies to any component of the GT product may pose a potential 
risk to patient safety and limit its therapeutic potential.  Antibodies to the gene 
therapeutic agent may also limit the potential for re-administration of the product. 
 
   
5  Contains Nonbinding Recommendations 
 
  Sponsors may choose to exclude patients with pre-existing antibodies to the GT 
product.  In such cases, the sponsor should strongly consider contemporaneous 
development of a companion diagnostic to detect antibodies to the GT product.  If 
an in vitro companion diagnostic is needed to appropriately select patients for 
study (and later, once the GT product is approved, for treatment), then submission 
of the marketing application for the companion diagnostic and submission of the 
biologics license application for the GT product should be coordinated to support 
contemporaneous marketing authorizations. 
 
  Severity of disease should be considered in designing clinical GT trials in the 
context of the ability to report and detect adverse events as well as considerations 
related to, the anticipated risk and potential benefits to subjects (Ref. 11).  
Subjects with severe or advanced disease might experience confounding adverse 
events that are related to the underlying disease rather than to the GT product 
itself.  Subjects with earlier stages of disease may derive more benefit from the 
therapy.   
 
  It is important that clinical investigations in pediatric patients address 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, 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.  
 
  The risks of most GT products include the possibility of unintended effects that 
may be permanent, along with adverse effects due to invasive procedures that 
may be necessary for product administration.  Because of these risks, it is 
generally not acceptable to enroll normal, healthy volunteers into GT studies.  A 
well-written informed consent document is also essential.  
 
   
6  Contains Nonbinding Recommendations 
 
B.  Study Design 
 
For rare diseases, there may be a limited number of patients who may qualify for 
enrollment into a clinical study.  As a result, it is often not feasible to enroll unique 
subjects for all studies conducted under different phases of the clinical development 
program.  Limitation in the number of prospective subjects warrants the collection of as 
much pertinent data (e.g., adverse events, efficacy outcomes, biomarkers) as possible 
from every subject, starting from the first-in-human study.  All such data may be valuable 
to inform the design of subsequent studies (e.g., selection of study populations and 
endpoints).  Sponsors developing GT products for rare diseases should consider the 
following: 
 
  The randomized, concurrent-controlled trial is generally considered the ideal 
standard for establishing effectiveness and providing treatment-related safety 
data.  Randomization in early stages of development is encouraged. 
 
  Sponsors should consider designing their first-in-human study to be an adequate 
and well-controlled investigation that has the potential, depending on the study 
results, to provide evidence of effectiveness to support a marketing application. 
 
  Placebo controls, when feasible, are recommended to facilitate the interpretability 
of both safety and efficacy results.  If a study has multiple dose-level cohorts, 
consider randomizing some subjects in each cohort to receive placebo. 
 
  To promote interpretability of data for studies that enroll subjects with different 
disease stages or severities, it is important for sponsors, when applicable, to 
consider stratified randomization based on disease stage/severity. 
 
  For some genetically targeted indications (e.g., a genetic skin disease), the use of 
an intra-subject control design may be useful.  Such intra-subject comparisons 
avoid the problem of variability among subjects that occurs with inter-subject 
controls.  Thus, intra-subject controls can facilitate the assessment of local 
therapeutic effects and are recommended for consideration when appropriate. 
 
  A single-arm trial using historical controls, sometimes including an initial 
observation period, may be considered if there are feasibility issues with 
conducting a randomized, controlled trial. 
 
  If a single-arm trial design with a historical control is necessary, then knowledge 
of the natural history of disease is critical.  Natural history data may provide the 
basis of a historical control, but only if the control and treatment populations are 
adequately matched, in terms of demographics, concurrent treatment, disease 
state, and other relevant factors.  In circumstances where randomized, 
concurrent-controlled trials cannot be conducted and the natural history is well 
characterized, sponsors may consider the clinical performance of available 
7  Contains Nonbinding Recommendations 
 
therapies (if there are any) when setting the performance goal or criteria against 
which the product effect will be tested. 
 
  A small sample size, together with high inter-subject variability in clinical course, 
diminishes a studys power to detect treatment-related effects.  Therefore, 
alternative trial designs and statistical techniques that maximize data from a small 
and potentially heterogeneous group of subjects (including genetic heterogeneity) 
should be considered.  Ideally, an endpoint based on a treatment outcome that is 
not expected to occur spontaneously in the natural course of the disease can 
facilitate the interpretability of a small trial. 
 
  Clinical protocols should include adequate measures to minimize bias.  The 
preferred approach to minimize bias is to use a study design that includes 
blinding. 
 
  Efforts should be made early in the GT product development program to identify 
relevant biomarkers6 and to leverage all scientifically relevant information from 
published investigations for the disease of interest (or related diseases), to the 
extent possible.  Some biomarkers or endpoints are very closely linked to the 
underlying pathophysiology of the disease (e.g., a missing metabolite in a critical 
biosynthetic pathway).  In this case, changes in such biomarkers could be used 
during drug development for dose-selection, or even as an early demonstration of 
drug activity.   
 
  Regarding concomitant medication(s):  In some situations, study subjects may 
continue to take their pre-study medication(s), particularly if medication 
discontinuation would pose substantial risks, and if use of such concomitant 
medication(s) would not interfere with the objectives of the trial.  The dose of 
concomitant medication should be stable over a specific time period (e.g., until 
measurement of the primary endpoint), which should be justified in the clinical 
protocol.   
 
C.  Dose Selection 
 
  Dose selection should be informed by all available sources of clinical information 
(e.g., publications, experience with similar products, experience in related patient 
populations).  
  
  Leveraging non-human data obtained in animal models of disease and in vitro 
data may be, in some cases, the only way to estimate a starting human dose that is 
anticipated to provide benefit.  Additional dosing information can be obtained 
from predictive models based on current understanding of in vitro enzyme 
                                                 
6 Additional information on the biomarkers can be found at:   
https://www.fda.gov/drugs/cder-biomarker-qualification-program/biomarker-guidances-and-reference-materials. 
 
8  Contains Nonbinding Recommendations 
 
kinetics (including characterizing the enzyme kinetics in relevant cell lines), and 
allometric scaling.  
 
  For early-phase studies in subjects with serious or life-threatening diseases and an 
unmet medical need, study treatment should ideally start with a potentially 
therapeutic dose.  However, dose exploration may be needed to identify an 
optimal therapeutic dose.   
 
  If the transgene expression and consequent treatment effect decrease over time, 
consideration may be given to repeat administration of the GT product.  Subjects 
given a GT product may experience an enhanced immune response with repeat 
administration.  Assessment of immunogenicity and its clinical manifestations 
(loss of treatment effect and toxicity) are even more critical in the setting of repeat 
administration. 
 
D.  Safety Considerations 
 
  Clinical trials should include a monitoring plan that is adequate to protect the 
safety of clinical trial subjects.  The elements and procedures of the monitoring 
plan should be based upon the patients disease, what is known about the GT 
product, including dosing frequency (as applicable), preclinical toxicology, as 
well as CMC information, and, if available, previous human experience with the 
proposed product or related products (Ref. 11). 
 
  Innate and adaptive immune responses directed against one or more components 
of GT products (e.g., against the vector and/or transgene) may impact product 
safety and efficacy.  Early development of appropriate assays to measure product-
directed immune responses may be critical to program success.  Development of 
neutralizing and non-neutralizing immune responses that are directed against the 
product should be monitored throughout the clinical trial (Ref. 13).  
 
  When there is limited previous human experience with a specific GT product, 
administration to several subjects concurrently may expose those subjects to 
unacceptable risk.  Most first-in-human trials of GT products should stagger 
administration to consecutively enrolled subjects, for at least an initial group of 
subjects, followed by staggering between dose cohorts.  This approach limits the 
number of subjects who might be exposed to an unanticipated safety risk (Ref. 
11).  The optimal dosing interval between consecutively enrolled subjects and 
dose cohorts should be discussed with OTAT prior to beginning the trial.  
 
  Because of the unique nature of the mechanism of action involving genetic 
manipulation, a potential exists for serious long-term effects that may not be 
apparent during development or even at the time of an initial licensure.  The 
long-term safety of GT products is currently unknown.  The appropriate duration  
   
9  Contains Nonbinding Recommendations 
 
of long-term follow-up depends on the results of preclinical studies with this 
product, knowledge of the disease process, and other scientific information (Ref. 
7).  
 
  Early-phase GT clinical trial protocols should generally include study stopping 
rules, which are criteria for halting the study based on an observed incidence of 
adverse events.  The objective of study stopping rules is to limit subject exposure 
to risk in the event that safety concerns arise.  Well-designed stopping rules may 
allow sponsors to assess and address risks identified as the trial proceeds, and to 
amend the protocol to mitigate such risks and to assure that human subjects are 
not exposed to unreasonable and significant risk of illness or injury. 
 
  The potential for viral shedding should be addressed early in product development 
(Ref. 14). 
 
  Pharmacovigilance systems should actively monitor each recipient of a GT 
product (Refs. 7 and 15).  
 
E.  Efficacy Endpoints 
 
Demonstration of clinical benefit of a GT product follows the same principles as for any 
other product.  However, in some cases there may be unique characteristics of GT 
products (e.g., a protein that is expressed by a GT product may have different bioactivity 
than standard enzyme replacement therapy) that warrant additional considerations both 
pre-approval and post-marketing.  Prior to commencing clinical trials of GT products for 
rare diseases, it is critically important to have a discussion with FDA about the primary 
efficacy endpoint(s).  For many rare diseases, well-established, disease-specific efficacy 
endpoints are not available (Ref. 16).  Endpoint selection for a clinical trial of a GT 
product for a rare disease should consider the following: 
 
  Sponsors should understand the pathophysiology and natural history of a disease 
as fully as possible at the outset of product development.  Full understanding of 
mechanism of product action is not required for marketing approval; however, 
understanding of disease pathophysiology is important in designing clinical trials, 
including selection of endpoints.  
 
  Sponsors may consider seeking accelerated approval of a GT product for a rare 
disease pursuant to section 506(c) of the Federal Food, Drug, and Cosmetic Act 
(FD&C Act) based on a surrogate endpoint.7  Understanding disease 
                                                 
7 According to section 507(e)(9) of the FD&C Act [21 USC 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). 
10  Contains Nonbinding Recommendations 
 
pathophysiology and natural history can help identify potential surrogate 
endpoints that are reasonably likely to predict clinical benefit.  To support 
accelerated approval, the sponsor should provide sufficient data to support a 
conclusion that the proposed endpoint is reasonably likely to predict clinical 
benefit.  In general, such data should, at a minimum, demonstrate a correlation 
between changes in the proposed surrogate endpoint and a beneficial clinical 
effect.   
 
  Sponsors should identify specific aspects of the disease that are meaningful to the 
patient and might also be affected by the GT products activity (Ref. 17). 
 
  Considerable information can be gained by collecting clinical measurements 
repeatedly over time.  Such a longitudinal profile allows the assessments of effect, 
largely based on within patient changes, that otherwise could not be studied. 
 
F.  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.  
 
 
VI.  EXPEDITED PROGRAMS 
 
There are several programs that may be available to sponsors of GTs 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 these therapies.  For example, 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. 18 
and 19).  
 
 
                                                 
8 As defined in section 569(c) of the FD&C Act, [21 USC 360bbb-8c], 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.  
 
11  Contains Nonbinding Recommendations 
 
VII.  COMMUNICATION WITH FDA 
 
FDA recommends communication with OTAT early in product development, before submission 
of an investigational new drug application (IND).  There are different meeting types that can be 
used for such discussions, depending on the stage of product development and the issues to be 
considered.  These include pre-IND meetings prior to submission of the IND (Ref. 20), and 
INitial Targeted Engagement for Regulatory Advice on CBER producTs (INTERACT) 
meetings, which can be used earlier in development to discuss issues such as preclinical 
development or manufacturing, so that the sponsor can obtain non-binding regulatory advice.9    
                                                 
9 Going forward, INTERACT meetings will serve in place of pre-pre-IND meetings.  For additional information 
about INTERACT meetings, please see https://www.fda.gov/vaccines-blood-biologics/industry-biologics/interact-
meetings-initial-targeted-engagement-regulatory-advice-cber-products. 
12  Contains Nonbinding Recommendations 
 
VIII.  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:  Potency Tests for Cellular and Gene Therapy Products, January 
2011.  https://www.fda.gov/media/79856/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.  Comparability of Biotechnology/Biological Products Subject to Changes in their 
Manufacturing Process:  Q5E, ICH Harmonized Tripartite Guideline, Step 4 version, 
November 2004. 
https://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q5E/
Step4/Q5E_Guideline.pdf. 
6.  Preclinical Assessment of Investigational Cellular and Gene Therapy Products; Guidance 
for Industry, November 2013.  https://www.fda.gov/media/87564/download. 
7.  Long Term Follow-Up After Administration of Human Gene Therapy Products; 
Guidance for Industry, January 2020.  https://www.fda.gov/media/113768/download. 
8.  Expectations for Biodistribution (BD) Assessments for Gene Therapy (GT) Products, 
International Pharmaceutical Regulators Programme (IPRP) Reflection Paper, 2018.  
http://development.iprp.backend.dev6.penceo.com/sites/default/files/2018-
09/IPRP_GTWG_ReflectionPaper_BD_Final_2018_0713.pdf. 
9.  Rare Diseases:  Common Issues in Drug Development; Draft Guidance for Industry, 
February 2019.*  https://www.fda.gov/media/120091/download. 
10.  Rare Diseases:  Natural History Studies for Drug Development; Draft Guidance for 
Industry, March 2019.*  https://www.fda.gov/media/122425/download. 
11.  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. 
12.  In Vitro Companion Diagnostic Devices:  Guidance for Industry and Food and Drug 
Administration Staff, August 2014.  https://www.fda.gov/media/81309/download. 
13.  Guidance for Industry:  Immunogenicity Assessment for Therapeutic Protein Products, 
August 2014.  https://www.fda.gov/media/85017/download. 
14.  Design and Analysis of Shedding Studies for Virus or Bacteria-Based Gene Therapy and 
Oncolytic Products; Guidance for Industry, August 2015.  
https://www.fda.gov/media/89036/download. 
13  Contains Nonbinding Recommendations 
 
15.  E2E Pharmacovigilance Planning; Guidance for Industry, April 2005.  
https://www.fda.gov/media/71238/download. 
16.  Guidance for Industry:  Providing Clinical Evidence of Effectiveness for Human Drug 
and Biologic Products, May 1998.  https://www.fda.gov/media/71655/download. 
17.  Clinical Outcome Assessment Qualification Program.  https://www.fda.gov/drugs/drug-
development-tool-qualification-programs/clinical-outcome-assessment-coa-qualification-
program. 
18.  Guidance for Industry:  Expedited Programs for Serious Conditions - Drugs and 
Biologics, May 2014.  https://www.fda.gov/media/86377/download. 
19.  Expedited Programs for Regenerative Medicine Therapies for Serious Conditions; 
Guidance for Industry, February 2019.  https://www.fda.gov/media/120267/download. 
20.  Guidance for Industry:  Formal Meetings Between the FDA and Sponsors or Applicants, 
May 2009.  https://www.fda.gov/media/72253/download. 
 
*When finalized, this guidance will represent FDAs current thinking on this topic. 
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