Human Gene Therapy for Retinal 
Disorders 
 
 
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.  CONSIDERATIONS FOR CHEMISTRY, MANUFACTURING AND CONTROLS 
............................................................................................................................................. 2 
III.  CONSIDERATIONS FOR PRECLINICAL STUDIES................................................ 2 
IV.  CONSIDERATIONS FOR CLINICAL TRIALS .......................................................... 4 
A.  Natural History Studies ........................................................................................ 4 
B.  Study Design .......................................................................................................... 5 
C.  Study Population ................................................................................................... 6 
D.  Study Use ............................................................................................................... 7 
E.  Safety Considerations ........................................................................................... 8 
F.  Study Endpoints .................................................................................................... 8 
G.  Follow-Up Duration ............................................................................................ 10 
H.  Patient Experience .............................................................................................. 10 
V.  EXPEDITED PROGRAMS ........................................................................................... 10 
VI.  COMMUNICATION WITH FDA ................................................................................ 11 
VII.  REFERENCES ................................................................................................................ 12 
 
 
i  Contains Nonbinding Recommendations 
 
Human Gene Therapy for Retinal Disorders 
 
 
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 for retinal disorders affecting adult and pediatric patients.  These disorders vary in 
etiology, prevalence, diagnosis, and management, and include genetic as well as age-related 
diseases.  These disorders manifest with central or peripheral visual impairment and often with 
progressive visual loss.  This guidance focuses on issues specific to GT products for retinal 
disorders and provides recommendations related to product development, preclinical testing, and 
clinical trial design for such GT products. 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 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). 
1  Contains Nonbinding Recommendations 
 
II.  CONSIDERATIONS FOR CHEMISTRY, MANUFACTURING AND CONTROLS 
 
There are multiple GT products being studied in clinical trials in the United States for retinal 
disorders.  GT products are commonly delivered by intravitreal or subretinal injections through a 
medical delivery system.  In some cases, the GT products are encapsulated in a device to be 
implanted intravitreally. 
 
The general chemistry, manufacturing and controls (CMC) considerations for product 
manufacturing, testing and release of GT products for retinal disorders are the same as those 
described for other GT products (Ref. 1).  For early-phase clinical trials, a sponsor should be able 
to evaluate the identity, purity, quality, dose, and safety of a GT product.  A potency assay to 
assess the biological activity of the final product, with relevant lot release specifications, should 
be established prior to the initiation of clinical trials intended to provide substantial evidence of 
effectiveness for a marketing application (Ref. 2).  To support licensure of a GT product, 
manufacturing processes and all testing methods for product release must be validated (21 CFR 
211.165(e)).  Sponsors developing GT products for retinal disorders are strongly encouraged to 
contact the Office of Tissues and Advanced Therapies (OTAT) in the Center for Biologics 
Evaluation and Research (CBER) early in product development to discuss product-specific 
issues.  
 
Sponsors of GT products for retinal disorders should take into account general CMC 
considerations for all GT products (Ref. 1), as well as CMC considerations specific to the 
products intended for treatment of retinal disorders, including: 
 
  Consideration of the final product formulation and concentration for the expected dose 
and volume;   
 
  The endotoxin limit for intraocular delivery should follow the specifications in USP 
<771> (not more than (NMT) 2.0 Endotoxin Unit (EU)/dose/eye or NMT 0.5 EU/mL); 
 
  GT vector-based final products should be tested for particulate matter, and the test 
method and release criteria should follow USP <789>;  
 
  Product testing and release should include testing of the final product configuration;   
 
  Compatibility of the GT product and the delivery system(s) should be evaluated (Ref. 1). 
 
 
III.  CONSIDERATIONS FOR PRECLINICAL STUDIES 
 
A preclinical program that is tailored to the investigational product and the planned early-phase 
clinical trials 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 level 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 
2  Contains Nonbinding Recommendations 
 
eligibility criteria; and 5) identification of potential toxicities and physiologic parameters that 
help guide clinical monitoring for a particular investigational product.  
 
Further details for general considerations in preclinical studies are available in a separate 
guidance document (Ref. 3).  The following elements are recommended in the development of a 
preclinical program for an investigational GT product intended for treatment of retinal 
disorders:2  
 
  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 and possibly the expressed transgene product in vivo, from the 
site of administration to target ocular and non-ocular tissues, intraocular fluids, and 
blood.  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. 3-5). 
 
  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.  For any abnormal ophthalmic findings or lesions, sponsors 
should determine the frequency, severity, potential cause, and clinical significance. 
Inflammatory or immune responses should be further characterized to assess potential 
attribution to the vector or transgene.  
 
  Animal models of retinal disorders are frequently developed in rat or mouse strains (e.g., 
transgenic or knockout models) and these models are often utilized to generate POC data.  
However, due to differences in ocular size and anatomy in rodents as compared to the 
human eye, animals with more human-like eyes, such as rabbits, pigs, or nonhuman 
primates, may also provide applicable safety information.  Inclusion of the larger animals 
also facilitates relevant experience with the surgical procedures and delivery systems 
intended for clinical use.  
 
                                                 
2 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 will 
consider if such an alternative method could be used in place of an animal test method. 
3  Contains Nonbinding Recommendations 
 
  Differences between the immune responses of animals and humans are important 
considerations when interpreting preclinical data.  Retinal disorders typically are bilateral 
and chronic.  However, a second administration of a GT product to either the 
contralateral eye or to the same eye may not be feasible due to an immunologic reaction 
against the vector and/or the transgene product.  Therefore, clinical data, rather than 
preclinical data, may provide the most relevant safety information for repeat product 
administration.   
 
  As the clinical development program for an investigational GT product advances to late-
phase clinical trials and possible marketing approval, additional preclinical studies may 
be indicated.  Further testing may be necessary to address factors such as any significant 
changes in the manufacturing process or formulation, which may affect comparability of 
the late-phase product to product administered in early-phase clinical trials (Refs. 6 and 
7).  
 
  The preclinical program for any investigational product should be individualized with 
respect to scope, complexity, and overall design.  Sponsors are encouraged to explore 
opportunities to reduce, refine, and replace animal use in the preclinical program. 
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). 
 
 
IV.  CONSIDERATIONS FOR CLINICAL TRIALS  
 
The fundamental considerations for clinical development programs of GT products for retinal 
disorders are similar to those for other biological products.  Early-phase trials of GT products 
should not only evaluate safety and feasibility, but also gauge bioactivity and preliminary 
efficacy.  Later-phase trials should be designed as adequate and well-controlled studies that can 
provide substantial evidence of effectiveness to support an application for marketing.  For further 
details of general considerations for gene therapy clinical trials, please refer to relevant FDA 
guidance documents (Refs. 8 and 9).  
 
The following important elements are recommended for consideration during development of 
clinical programs of investigational GT products intended for treatment of retinal disorders.  
 
A.  Natural History Studies 
 
A thorough understanding of the natural history of a disease is an important element in all 
clinical development programs.  Many degenerative retinal disorders are rare, and their 
natural history is often poorly characterized.  Early in product development, sponsors 
should evaluate the depth and quality of existing natural history data.  When such  
information is insufficient to guide clinical development, FDA recommends that a 
sponsor consider performing a careful natural history study to facilitate the product  
   
4  Contains Nonbinding Recommendations 
 
development program, although FDA does not require these studies.  Early interactions 
between FDA and sponsors are welcome regarding the design of natural history studies 
(Ref. 10).   
 
B.  Study Design  
 
To facilitate interpretation of clinical data, inclusion of a randomized, concurrent parallel 
control group is recommended for clinical trials whenever possible.  Administration of 
the vehicle alone may serve as a control.  In general, while intravitreal injection of the 
vehicle alone is often feasible as a placebo control, it may not be considered ethically 
acceptable unless the physical properties of an injection in a closed space have a potential 
therapeutic benefit (e.g., creation of vitreous detachment).  When ethically acceptable, 
such a control is especially helpful early in clinical development, to evaluate bioactivity 
of the investigational GT product and possibly to provide initial evidence of its clinical 
efficacy.  However, FDA acknowledges the risks associated with intravitreal and 
subretinal injection procedures and vehicles; without any prospect of direct benefit, these 
risks may not be acceptable under certain circumstances, such as for pediatric patients (21 
CFR Part 50, Subpart D).  Other possibilities to vehicle controls include alternative 
dosing regimens, alternative dose levels, and existing products approved for the 
indication being sought.  
 
Measurement of certain efficacy and safety endpoints such as visual acuity is subjective, 
and results can be influenced by effort on the part of the patient, leading to a potential 
source of bias in the clinical trial.  For trials intended to form the primary basis of an 
efficacy claim to support a marketing application, concurrent parallel group(s) should be 
used as a control (placebo or active) to decrease potential bias.  
To further reduce potential bias, sponsors should include adequately-designed masking3 
procedures.  Masking can decrease the likelihood of biased observations, and decrease 
bias in assessments of outcome measure, particularly when the assessment includes 
subjectivity.  Differences between the procedure used for product delivery and a sham 
procedure may enable patients to distinguish the eye which received the product from 
that which received the sham treatment (e.g., a sham intravitreal injection mimics a real 
intravitreal injection but does not penetrate the eye).  FDA recommends multiple 
measures to reduce bias including at least two treatment arms, utilizing different doses 
but the same product administration procedures, and separation of clinical evaluators and 
personnel involved in product administration/sham procedure to minimize patients 
ability to identify their treatment arm, in addition to a sham control group.  In addition to 
facilitating masking, the second treatment arm has value as a dose-ranging control. 
 
Although use of the contralateral eye to which the GT product is not administered as a 
control may potentially be considered, it is generally not recommended due to the 
following:  
 
                                                 
3 In this guidance, the term masking refers to the process of keeping the study treatment group assignment hidden 
to patients, investigators, clinical evaluators, etc. after allocation. 
5  Contains Nonbinding Recommendations 
 
  For most indications in which GT products are likely to be used, the treated eye 
and contralateral eye are often at different stages of disease at the time of trial 
entry.  In addition, disease progression in the two eyes is not necessarily similar 
over the relatively short duration of the trial.   
 
  When a patient is exposed to different procedures in the two eyes (e.g., one eye 
receives a GT product and the other eye receives sham procedure), it frequently 
leads to unmasking, which can confound the interpretation of the study results, 
particularly for endpoints where patient effort can make a difference, such as 
visual function measures.  
 
C.  Study Population 
 
For clinical trials of GT products providing gene replacement, the correct genetic 
diagnosis is essential for identifying potential participants.  Thus, confirmation of the 
genetic mutation prior to enrollment is recommended as an important element of the 
clinical trial.  If there are no readily available, reliable means of obtaining the needed 
genetic diagnostic testing, a companion diagnostic may be needed and therefore should 
be strongly considered early in development.  FDA encourages sponsors to discuss 
companion diagnostics early in product development.  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.   
 
Patients with severe visual impairment, or a disease that is likely to progress to severe 
visual impairment, may be more willing to accept the potential or unknown risks of a 
novel GT product, and those risks may be more readily justified in this population.  
However, in some cases  for example, a GT product designed to restore function to 
remaining viable retinal cells  severely affected patients who have a minimal number of 
viable retinal cells may not benefit from administration of the GT product nor would use 
in these patients provide information about the effectiveness of the product.  In general, 
first-in-human GT trials should enroll patients with severities of visual impairment that 
offer a favorable benefit-risk profile.  If preliminary safety data supports further clinical 
development, sponsors may consider a broader patient population in future trials. 
 
Many retinal disorders affect both children and adults, and therefore pediatric studies are 
a critical part of drug development.  For diseases that affect both adults and children, 
trials in adult patients should be conducted prior to trials in pediatric patients, whenever 
feasible.  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 
6  Contains Nonbinding Recommendations 
 
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.  
 
D.  Study Use  
 
For early-phase trials, dose-ranging study designs are recommended.  Comparing a range 
of doses can identify potential therapeutic doses for a wider group of patients.  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 is not 
only reasonably safe, but also has therapeutic potential, particularly when the 
administration procedure carries substantial risks. 
 
Most retinal indications for which GT products are studied involve bilateral disease; 
consideration, therefore, should be given during product development to the planned 
administration of the GT product in both eyes.  Because of safety concerns related to the 
product, administration procedure, and any ancillary medications, administration to each 
eye for an individual patient should be performed sequentially, rather than 
simultaneously.  While the eye with more advanced disease often receives the GT 
product initially, a rationale should be developed for deciding which eye will receive the 
GT product first.  This rationale should consider input from study investigators and 
patients.  The time interval between administration in each eye should be carefully 
planned for each patient based on available human experience of the investigational 
product or similar products.  For products intended for both eyes, the overall 
development plan prior to approval should include clinical trials in which both eyes 
receive the GT product. 
 
To ensure consistency across study sites, sponsors should include in the study protocol a 
detailed description of the product delivery procedure and devices used for delivery.   
 
A single administration of a GT product in each eye may not always be sufficient for a 
variety of reasons (e.g., a GT product has limited duration of effectiveness after single 
administration; or exposure to a GT product may be limited to a part of the target area in 
the eye with the initial administration and a repeat administration to the same eye may 
extend the treatment to additional parts of the target area for additional effect).  In such 
cases, careful studies, especially trials in humans, are recommended to explore the 
feasibility of repeat administration in the same eye.   
 
   
7  Contains Nonbinding Recommendations 
 
E.  Safety Considerations 
 
Intraocular administration (e.g., intravitreal or subretinal injection) may be the most 
efficient method to deliver GT products intended for treatment of retinal disorders.  Risks 
of such procedures include intraocular infection, elevated intraocular pressure, media 
opacities, and retinal damage.  Therefore, the procedure should be performed by 
individuals experienced in the method of planned delivery.  
 
Safety measures and post intervention follow up schedules should be incorporated into 
the study design based on the anticipated potential for adverse reactions for the specific 
disease, target patient population and test article attributes. 
 
Local or systemic immune responses to GT products may pose important safety risks.  
For certain GT products, such as those using various viral vectors to introduce therapeutic 
transgene(s) in vivo, immune reactions also may decrease transduction efficiency and 
thereby diminish the treatment effect.  Biomicroscopy and optical coherence tomography 
are recommended to detect inflammatory reactions within the globe.  To monitor 
systemic immune reactions, immunoassays should be performed to measure cellular and 
humoral immune responses to the vector and the transgene-encoded protein.   
 
To minimize immune responses, immunosuppressants such as corticosteroids may be 
considered before and after product administration.  Justification of immunosuppressant 
regimens should be based on available clinical data of the product or related product(s).  
Immunosuppressant drugs may cause increased intraocular pressure, cataracts, and other 
adverse events.  Patients should be closely monitored and treated as necessary to 
minimize the risk of developing glaucoma, vision loss, and other complications.  
 
F.  Study Endpoints 
 
Early-phase clinical trials typically focus on safety.  However, for trials of GT products, 
early assessment of potential clinical benefit is also important, particularly for rare 
diseases with a limited number of patients available to participate in clinical 
development.  To guide further clinical development, FDA encourages sponsors to 
explore a wide spectrum of potential clinical endpoints and other clinical effects in early-
phase trials.  For example, sponsors may include endpoints based on retinal imaging 
(optical coherence tomography, retinal photography, fluorescein angiography), visual 
acuity (low and high luminance), visual fields, color vision, contrast sensitivity, other 
measures of visual function (i.e., how well the eye and visual system function), and 
functional vision (i.e., how well the patient performs vision-related activities of daily 
living).  For later-phase trials intended to provide substantial evidence of effectiveness to 
support a marketing application, primary efficacy endpoints should reflect clinical 
benefit, such as improvement in function or symptoms.  
 
Examples of established efficacy endpoints that can be used to evaluate clinical benefit of 
GT products intended for treatment of retinal disorders include:  
 
8  Contains Nonbinding Recommendations 
 
  Best corrected distance visual acuity, measured with the Early Treatment of 
Diabetic Retinopathy Study (ETDRS) chart or other visual acuity charts with an 
equal number of letters per line and equivalent spacing between lines.  A halving 
(or doubling) of the visual angle represented by a gain (or loss), respectively, of at 
least 15 letters on the ETDRS chart from baseline is considered clinically 
meaningful.   
 
  Rate of photoreceptor loss, determined by measures such as optical coherence 
tomography or autofluorescence photography.  The comparison should be made 
between the baseline and at least two subsequent area images, with intervals of 6 
months or more between images.  The best curve fit analyses demonstrating 
reduction in the rate of photoreceptor loss exceeding measurement uncertainty are 
considered clinically meaningful. 
 
FDA encourages sponsors to develop and propose novel endpoints to measure clinically 
meaningful effects, or surrogate endpoints4 that are reasonably likely to predict clinical 
benefit, in patients with retinal disorders.  This can be especially pertinent to some rare 
retinal disorders for which the established efficacy endpoints may not be appropriate to 
assess clinically meaningful effect of an investigational product.  Sponsors are welcome 
to engage FDA early in this process, and FDA is committed to working with sponsors to 
develop acceptable endpoints. 
 
  For example, a novel primary efficacy endpoint measuring mobility under 
different levels of illumination was utilized to support marketing approval for 
voretigene neparvovec-rzyl (a recombinant adeno-associated vector (AAV) 
carrying the gene for human retinal pigment epithelium-specific 65 kDa protein). 
During the clinical trials, the sponsor worked with FDA to develop this clinically 
meaningful primary efficacy endpoint.  
   
                                                 
4 According to section 507(e)(9) of the Federal Food, Drug, and Cosmetic Act (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). 
 
9  Contains Nonbinding Recommendations 
 
G.  Follow-Up Duration  
 
The length of follow-up to provide additional 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 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. 4). 
 
H.  Patient Experience 
 
Patient experience data5 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 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 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. 11 and 12).  
 
 
   
                                                 
5 As defined in the 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.   
10  Contains Nonbinding Recommendations 
 
VI.  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. 13), 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.6 
   
                                                 
6 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. 
 
11  Contains Nonbinding Recommendations 
 
VII.  REFERENCES  
 
1.  Chemistry, Manufacturing, and Control (CMC) Information for Human Gene Therapy 
Investigational New Drug Applications (IND); 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.  Preclinical Assessment of Investigational Cellular and Gene Therapy Products; Guidance 
for Industry, November 2013.  https://www.fda.gov/media/87564/download.  
4.  Long Term Follow-Up After Administration of Human Gene Therapy Products; 
Guidance for Industry, January 2020.  https://www.fda.gov/media/113768/download. 
5.  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.   
6.  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.  
7.  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. 
8.  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.    
9.  Guidance for Industry:  Providing Clinical Evidence of Effectiveness for Human Drug 
and Biological Products, May 1998.  https://www.fda.gov/media/71655/download.  
10.  Rare Diseases:  Common Issues in Drug Development; Draft Guidance for Industry, 
February 2019.*  https://www.fda.gov/media/120091/download.  
11.  Guidance for Industry:  Expedited Programs for Serious Conditions  Drugs and 
Biologics, May 2014.  https://www.fda.gov/media/86377/download. 
12.  Expedited Programs for Regenerative Medicine Therapies for Serious Conditions; 
Guidance for Industry, February 2019.  https://www.fda.gov/media/120267/download.  
13.  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. 
 
12