Human Gene Therapy for Rare Diseases: Guidance for Industry

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

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

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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

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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.
FDA’s guidance documents, including this guidance, do not establish legally enforceable
responsibilities. Instead, guidances describe the FDA’s 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 FDA’s 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.

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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 product’s 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).

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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 subject’s 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 product’s 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

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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.

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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.

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• 	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. FDA’s 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.

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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

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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 study’s 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.

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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 patient’s 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

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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).

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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 product’s 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.

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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.

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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.

Contains Nonbinding Recommendations
14
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 FDA’s current thinking on this topic.