Expedited Programs for Regenerative 
Medicine Therapies for Serious 
Conditions 
 
 
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 
http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guida
nces/default.htm. 
 
For questions on the content of this guidance, contact OCOD at the phone numbers or email 
address listed above. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Biologics Evaluation and Research 
February 2019 
 
  Contains Nonbinding Recommendations 
 
 
Table of Contents 
 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  BACKGROUND ............................................................................................................... 2 
III.  EXPEDITED PROGRAMS FOR REGENERATIVE MEDICINE THERAPIES .... 2 
A.  Fast Track Designation......................................................................................... 4 
B.  Breakthrough Therapy Designation ................................................................... 4 
C.  Regenerative Medicine Advanced Therapy Designation .................................. 5 
D.  Priority Review Designation ................................................................................ 9 
E.  Accelerated Approval ........................................................................................... 9 
IV.  CONSIDERATIONS IN CLINICAL TRIAL DESIGN .............................................. 11 
V.  INTERACTIONS BETWEEN SPONSORS AND CBER REVIEW STAFF ........... 13 
VI.  REFERENCES  ............................................................................................................... 14 
i  Contains Nonbinding Recommendations 
 
Expedited Programs for Regenerative  
Medicine Therapies for Serious Conditions 
 
 
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 sponsors engaged in the development of regenerative medicine therapies 
for serious or life-threatening diseases or conditions1 with our recommendations on the expedited 
development and review of these therapies, including as provided under section 506(g) of the 
Federal Food, Drug, and Cosmetic Act (FD&C Act), as added by section 3033 of the 21st 
Century Cures Act (Cures Act).2  Under section 506(g) of the FD&C Act, a regenerative 
medicine therapy can be designated as a regenerative advanced therapy if it meets certain 
criteria.  FDA refers to such designation as regenerative medicine advanced therapy (RMAT) 
designation. (See section III.C of this document).  This guidance describes the expedited 
programs available to sponsors of regenerative medicine therapies for serious conditions, 
including those products designated as RMATs.  To that end, the guidance provides information 
about the provisions in the Cures Act regarding the use of the accelerated approval pathway for 
regenerative medicine therapies that have been granted designation as an RMAT.  Finally, the 
guidance describes considerations in the clinical development of regenerative medicine therapies 
and opportunities for sponsors of such products to interact with CBER review staff. 
 
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 As explained in section III of this guidance, all references to serious conditions include life-threatening conditions, 
and, for purposes of this guidance, the terms condition and disease are used interchangeably. 
2 Public Law 114-255. 
1  Contains Nonbinding Recommendations 
 
II.  BACKGROUND 
 
Regenerative medicine is a rapidly expanding field that has the potential to treat serious 
conditions, particularly in patients with unmet medical needs.  CBER recognizes the importance 
of regenerative medicine therapies and is committed to helping ensure they are licensed and 
available to patients with serious conditions as soon as it can be determined they are safe and 
effective.  The programs described in this guidance are intended to facilitate development and 
review of regenerative medicine therapies intended to address an unmet medical need in patients 
with serious conditions.    
  
In particular, this guidance addresses regenerative medicine therapies which are defined in 
section 506(g)(8) of the FD&C Act as including cell therapies3, therapeutic tissue engineering 
products, human cell and tissue products, and combination products using any such therapies or 
products, except for those regulated solely under section 361 of the Public Health Service Act 
(PHS Act) (42 U.S.C. 264) and Title 21 of the Code of Federal Regulations Part 1271 (21 CFR 
Part 1271).  Based on FDAs interpretation of section 506(g), human gene therapies4, including 
genetically modified cells, that lead to a sustained effect on cells or tissues, may meet the 
definition of a regenerative medicine therapy5 (Ref. 1).  Further, as FDA interprets section 
506(g), xenogeneic cell products may also meet the definition of a regenerative medicine therapy 
(Ref. 1).  Additionally, a combination product (biologic-device, biologic-drug, or biologic-
device-drug) can be eligible for RMAT designation when the biological product constituent part 
is a regenerative medicine therapy and provides the greatest contribution to the overall intended 
therapeutic effects of the combination product (i.e., the primary mode of action of the 
combination product is conveyed by the biological product constituent part).6   
 
 
III.  EXPEDITED PROGRAMS FOR REGENERATIVE MEDICINE THERAPIES  
 
In 1988, FDA issued regulations in 21 CFR Part 312 (Subpart E)7 on expediting the availability 
of promising therapies to patients with serious conditions.  The regulations call for earlier 
attention to drugs that have promise in treating such conditions, including early consultation with 
FDA for sponsors of such products.  In subsequent years, the FD&C Act has been amended 
several times to include several new programs for expedited product development and review, 
including fast track designation, accelerated approval, and breakthrough therapy designation.  
                                                 
3 FDA interprets cell therapies, for purposes of section 506(g)(8) of the FD&C Act, to include both allogeneic and 
autologous cell therapies. 
4  For additional information regarding human gene therapies, please see, e.g., Chemistry, Manufacturing, and 
Control (CMC) Information for Human Gene Therapy Investigational New Drug Applications (INDs); Draft 
Guidance for Industry, available at 
https://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/C
ellularandGeneTherapy/UCM610795.pdf. When finalized, this guidance will represent FDAs current thinking on 
the topic. 
5 Based on FDAs interpretation of section 506(g) of the FD&C Act, microorganisms (e.g., viruses, bacteria, fungi) 
that are not genetically modified do not meet the definition of regenerative medicine therapy. 
6 For additional information, see 21 U.S.C. 353(g)(1)(C) and 21 CFR 3.2.  
7 Food and Drug Administration, Interim Rule, Investigational New Drug, Antibiotic, and Biological Drug Product  
Regulations; Procedures for Drugs Intended to Treat Life-Threatening and Severely Debilitating Illnesses (53 FR  
41516, October 21, 1988). 
2  Contains Nonbinding Recommendations 
 
Most recently, in December 2016, Congress amended section 506 of the FD&C Act (21 U.S.C. 
356) by adding new section 506(g), which specifically addresses the expedited development and 
review of certain regenerative medicine therapies designated as RMATs.  
 
Regenerative medicine therapies to treat, modify, reverse, or cure serious conditions are eligible 
for FDAs expedited programs, including fast track designation, breakthrough therapy 
designation, RMAT designation, accelerated approval, and priority review designation, if they 
meet the criteria for such programs.  Sponsors should consult the Guidance for Industry: 
Expedited Programs for Serious Conditions  Drugs and Biologics dated May 2014 (Expedited 
Programs Guidance) (Ref. 2) for generally applicable information, including the criteria for, and 
benefits of, fast track designation, breakthrough therapy designation, accelerated approval, and 
priority review designation.  This guidance provides additional information about the application 
of those programs to regenerative medicine therapies, as well as information about the new 
RMAT designation program, which CBER intends to administer in a manner that is consistent 
with the other expedited programs, where applicable.  As with other biological products, 
regenerative medicine therapies receiving fast track designation, breakthrough therapy 
designation, and RMAT designation must meet the evidentiary standards for approval, including 
demonstrating effectiveness (regardless of whether the product receives accelerated or traditional 
approval).   
 
Fast track designation, breakthrough therapy designation, and RMAT designation are distinct 
designation programs with different programmatic requirements.  Sponsors may apply for and 
receive more than one designation for a given product, but sponsors should apply for each 
designation separately.  Information that supports more than one designation may be submitted 
in each separate designation request.   
 
For the purposes of this guidance, the terms serious disease or condition, unmet medical need, 
surrogate endpoint, intermediate clinical endpoint, and clinically significant endpoint have the 
same meanings as described in the Expedited Programs Guidance (Ref. 2).  These terms are 
summarized briefly as follows:  
 
A serious disease or condition is a disease or condition associated with morbidity that has 
a substantial impact on day-to-day functioning.  Short-lived and self-limiting morbidity 
will usually not be sufficient, but the morbidity need not be irreversible if it is persistent 
or recurrent.  Whether a disease or condition is serious is a matter of clinical judgment, 
based on its impact on such factors as survival, day-to-day functioning, or the likelihood 
that the disease, if left untreated, will progress from a less severe condition to a more 
serious one.8  Of note, all conditions meeting the definition of life-threatening as set forth 
in 21 CFR 312.81(a) would also be serious conditions.  
 
An unmet medical need is a condition whose treatment or diagnosis is not addressed 
adequately by available therapy.  An unmet medical need includes an immediate need for 
a defined population (i.e., to treat a serious condition with no or limited treatment) or a 
longer-term need for society (e.g., to address the development of resistance to 
antibacterial drugs).   
                                                 
8 21 CFR 312.300(b). 
3  Contains Nonbinding Recommendations 
 
 
A surrogate endpoint is a marker such as a laboratory measurement, radiographic image, 
physical sign, or other measure, that is thought to predict clinical benefit, but is not itself 
a measure of clinical benefit.  
 
An intermediate clinical endpoint is a measurement of a therapeutic effect that can be 
measured earlier than an effect on irreversible morbidity and mortality (IMM) and is 
considered reasonably likely to predict the drugs effect on IMM or other clinical benefit.    
 
Clinically significant endpoint generally refers to an endpoint that measures an effect on 
IMM or on symptoms that represent serious consequences of a disease. It can also refer to 
findings that suggest an effect on IMM or serious symptoms (Ref. 2).  
 
In this guidance, the terms condition and disease are used interchangeably, and any serious 
or life-threatening disease or condition, or serious aspect of a disease or condition, is further 
referred to as a serious condition hereafter. With respect to the expedited programs, for the 
purposes of this guidance, all references to drugs or drug products refer to human drugs, 
including drugs that are biological products, unless otherwise specified.  As a general matter, 
however, this guidance addresses regenerative medicine therapies regulated by CBER as 
biological products under the FD&C Act, section 351 of the PHS Act (42 U.S.C. 262), and 
applicable regulations.   
 
A.  Fast Track Designation 
 
An investigational new drug that is intended to treat a serious condition, and for which 
nonclinical or clinical data demonstrate the potential to address an unmet medical need in 
patients with such condition, can receive fast track designation.  Advantages of fast track 
designation include actions to facilitate development and expedite review of the product, 
such as the possibility for rolling review if FDA determines, after preliminary evaluation 
of clinical data submitted by a sponsor, that the fast track product may be effective.  In 
addition, such a product could be eligible for priority review if supported by clinical data 
at the time of marketing application submission.  
 
CBER bases the decision to grant fast track designation on nonclinical or clinical data 
demonstrating that the product has the potential to address an unmet medical need.  For 
example, at an early stage of development, evidence of the products effect in a relevant 
in vitro or animal model could constitute sufficient evidence of the products potential to 
address an unmet medical need.  If nonclinical or clinical data demonstrate such 
potential, and the product development program is adequately designed to determine 
whether the regenerative medicine therapy will address an unmet medical need in those 
with a serious condition, then CBER would consider granting fast track designation.  
 
B.  Breakthrough Therapy Designation 
 
Under the breakthrough therapy program, an investigational new drug that is intended to 
treat a serious condition, and for which preliminary clinical evidence indicates that the 
4  Contains Nonbinding Recommendations 
 
product may demonstrate substantial improvement over available therapies on one or 
more clinically significant endpoints, may qualify for breakthrough therapy designation.  
Advantages of this designation incorporate all the benefits of fast track designation and 
also include intensive FDA guidance on efficient drug development, as well as an 
organizational commitment to involve senior management in facilitating the products 
development program.   
 
It should be noted that the level of evidence required for breakthrough therapy 
designation is higher than for fast track designation.  Specifically, fast track designation 
requires only that nonclinical or clinical data demonstrate the potential to address an 
unmet medical need, whereas for breakthrough therapy designation, preliminary clinical 
evidence must indicate that the product may demonstrate a substantial improvement over 
existing therapies on one or more clinically significant endpoints.   
 
The following are hypothetical examples of regenerative medicine therapies that CBER 
may consider for breakthrough therapy designation: 
 
  In metastatic breast cancer that is refractory to available therapies, 
administration of allogeneic tumor cell lines expressing tumor-specific 
antigens is associated with complete responses in a substantial portion of 
subjects in an open-label, first-in-human study.  
 
  In advanced forms of age-related macular degeneration, subretinal 
administration of retinal pigment epithelium cells is associated with 
substantial improvement in either visual acuity or visual fields, or a substantial 
reduction in the area of geographic atrophy, at one year post-administration. 
 
  In severe osteoarthritis limiting mobility, intra-articular administration of cells 
derived from hematopoietic stem cells suspended in a balanced buffer 
solution, when compared to the administration of the balanced buffer solution 
alone, is associated with a substantial decrease in pain and improvement in 
function. 
 
In each of the above examples, the preliminary clinical evidence of substantial 
improvement over available therapies on a clinically significant endpoint could generally 
be derived from Phase 1 or Phase 2 trials.   
 
C.  Regenerative Medicine Advanced Therapy Designation  
 
An investigational drug is eligible for RMAT designation if: 
 
  It meets the definition of regenerative medicine therapy (see section II of this 
document); 
5  Contains Nonbinding Recommendations 
 
  It is intended to treat,9 modify, reverse, or cure10 a serious condition; and 
  Preliminary clinical evidence indicates that the regenerative medicine therapy has 
the potential to address unmet medical needs for such condition.   
 
Advantages of the RMAT designation include all the benefits of the fast track and 
breakthrough therapy designation programs, including early interactions with FDA (see 
Comparison of Breakthrough Therapy Designation and Regenerative Medicine Advanced 
Therapy Designation table, which sets forth key similarities and differences between 
breakthrough therapy designation and RMAT designation).  Section 506(g)(5) of the 
FD&C Act specifies that these early interactions may be used to discuss potential 
surrogate or intermediate endpoints to support accelerated approval (see section III.E. in 
this guidance).   
 
Regarding the preliminary clinical evidence to demonstrate the potential of a regenerative 
medicine therapy to address unmet medical needs, we generally expect that such 
evidence would be obtained from clinical investigations specifically conducted to assess 
the effects of the therapy on a serious condition.  Such clinical investigations, particularly 
at the initial stages of product development, may not always be prospective clinical trials 
with a concurrent control. In some cases, clinical evidence obtained from clinical 
investigations with appropriately chosen historical controls may provide sufficient 
preliminary clinical evidence of the potential to address an unmet medical need. In other 
cases, preliminary clinical evidence could come from well-designed retrospective studies 
or clinical case series that provide data systematically collected by treating physicians.  
Such clinical evidence may be from studies conducted outside of the United States (Ref. 
3).  In any case, it is essential that the preliminary clinical evidence be generated using 
the product11 that the sponsor intends to use for clinical development. 
 
When determining whether the preliminary clinical evidence is sufficient to support 
RMAT designation, CBER intends to consider factors, including but not limited to:  the 
rigor of data collection; the consistency and persuasiveness of the outcomes; the number 
of patients or subjects, and the number of sites, contributing to the data; and the severity, 
rarity, or prevalence of the condition.  In addition, CBER intends to consider the potential 
that bias (e.g., bias in the study design, treatment assignment, or outcome assessment) 
may be a factor in the evidence provided in support of RMAT designation.  CBER will 
review the preliminary clinical evidence in each designation request, and will make 
designation decisions on a case-by-case basis.  As opposed to breakthrough therapy 
                                                 
9 As described in section III.A.2 of the Expedited Programs Guidance (Ref. 2), FDA considers a drug to be intended 
to treat a serious condition when the drug is intended to have an effect on a serious condition, or a serious aspect of a 
condition, such as a direct effect on a serious manifestation or symptom of a condition. 
10 This guidance uses the term treat to refer to the terms treat, modify, reverse, and cure, as used in section 506(g) 
of the FD&C Act.  
11 FDA acknowledges that the issue of manufacturing changes is complex; however, manufacturing changes and 
product comparability are beyond the scope of this guidance.  Manufacturing changes made to products during the 
development program would not necessarily preclude initial RMAT designation or cause RMAT designation to be 
rescinded.  Such considerations will be made on a case-by-case basis. 
  
 
6  Contains Nonbinding Recommendations 
 
designation, the RMAT designation does not require evidence to indicate that the drug 
may offer a substantial improvement over available therapies.  As with breakthrough 
therapy designation, an RMAT designation is not the same as an approval and does not 
change the statutory standards for demonstration of safety and effectiveness needed for 
marketing approval.12 
 
The following are hypothetical examples of preliminary clinical evidence that CBER 
would consider sufficient to demonstrate a product has the potential to address unmet 
medical needs in those with a serious condition:  
 
  In a single-arm, open-label study conducted in a center treating patients with 
severe and extensive skin burns, use of allogeneic keratinocyte- and 
fibroblast-based cell therapy is associated with rapid and substantial wound 
re-epithelialization of deep partial thickness burns in the majority of treated 
wounds.  
 
  In a phase 2, dose-finding study, intra-myocardial administration of allogeneic 
human mesenchymal precursor cells to patients with advanced chronic heart 
failure refractory to available medical therapies is associated with dose-dependent 
improvement in several physiological measurements of left ventricular 
performance. 
 
In order to apply for RMAT designation, a sponsor should submit a request to CBER 
either with a new investigational new drug application (IND) or in an IND amendment.  
CBER will not accept requests for RMAT designation for INDs that are inactive or on 
clinical hold.  Additionally, FDA will not further process a pending RMAT designation 
request for an IND that is placed on inactive or hold status while the designation request 
is under review.  If you submit an RMAT designation request as an amendment to your 
IND, the cover letter should specify that the submission contains an RMAT designation 
request.  The request should be in bold, uppercase letters as follows:  REQUEST FOR 
REGENERATIVE MEDICINE ADVANCED THERAPY DESIGNATION.  If the 
request is submitted with an initial IND, the cover letter should specify that the 
submission contains both an initial IND and a request for RMAT designation.  The 
request should be in bold uppercase letters as follows:  INITIAL INVESTIGATIONAL 
NEW DRUG SUBMISSION and REQUEST FOR REGENERATIVE MEDICINE 
ADVANCED THERAPY DESIGNATION.  
 
In general, such a request should contain a concise summary of information that supports 
the RMAT designation, including: 
 
                                                 
12 FDAs SOPP (Standard Operating Policy and Procedure) 8212, entitled Management of Breakthrough Therapy-
Designated Products: Sponsor Interactions and Status Assessment Including Rescinding (Ref. 4), explains that 
breakthrough therapy designation is not the same as an approval and does not change the statutory standards for 
marketing approval. 
7  Contains Nonbinding Recommendations 
 
  A description of the investigational product, including a rationale for the 
investigational new drug meeting the definition of a regenerative medicine 
therapy; 
  A discussion to support that the disease or condition, or the aspect of the disease 
or condition, that the product is intended to treat is serious;  
  A summary of the risks and benefits associated with the therapies, if any, 
currently available for this condition; 
  A description of the unmet medical need that the product has the potential to 
address; and 
  The preliminary clinical evidence that the product has the potential to address the 
specified unmet medical need for this serious condition. 
 
A request for designation as an RMAT should describe the preliminary clinical evidence 
supporting designation.  A description of the preliminary clinical evidence should 
include, for example, the conditions for product administration, outcome assessment, and 
patient monitoring; a description of the patients and their outcomes, including the number 
of patients who have received the drug; and the design, conduct, and analyses of any 
clinical investigations.   
 
No later than 60 calendar days after receipt of the designation request, CBER will notify 
the sponsor as to whether the regenerative medicine therapy has received the RMAT 
designation.  If CBER determines that the regenerative medicine therapy does not meet 
the criteria for RMAT designation, CBER will include a written description of the 
rationale for the determination.  As with other expedited development programs, if 
RMAT designation has been granted but, later in development, the product no longer 
meets the qualifying criteria, then CBER may rescind the RMAT designation.  This is 
because FDA needs to focus its resources on RMAT product development programs that 
continue to meet the programs qualifying criteria. 
 
A comparison of the key features of Breakthrough Therapy Designation and 
Regenerative Medicine Advanced Therapy Designation is provided in the table below: 
   
Comparison of Breakthrough Therapy Designation and Regenerative Medicine Advanced 
Therapy Designation 
 
  Breakthrough Therapy Designation  Regenerative Medicine Advanced 
Therapy Designation 
Statute  Section 506(a) of the FD&C Act, as added  Section 506(g) of the FD&C Act, as added by 
by section 902 of the Food and Drug  section 3033 of the 21st Century Cures Act 
Administration Safety and Innovation Act 
of 2012 (FDASIA) 
Qualifying  A drug that is intended to treat a serious  A drug is a regenerative medicine therapy, AND 
criteria  condition, AND   the drug is intended to treat, modify, reverse, or 
preliminary clinical evidence indicates that  cure a serious condition, AND 
the drug may demonstrate substantial  preliminary clinical evidence indicates that the 
improvement on a clinically significant  drug has the potential to address unmet medical 
endpoint(s) over available therapies  needs for such disease or condition 
8  Contains Nonbinding Recommendations 
 
Features    All fast track designation features,   All breakthrough therapy designation features, 
including:  including early interactions to discuss any 
  Actions to expedite development and  potential surrogate or intermediate endpoints  
review   Statute addresses potential ways to support 
  Rolling review  accelerated approval and satisfy post-approval 
 Intensive guidance on efficient drug  requirements 
development, beginning as early as Phase 
1 
 Organizational commitment involving 
senior managers 
When to  With the IND or after and, ideally, no later than the end-of-phase 2 meeting  
submit 
FDA  Within 60 calendar days after receipt of request 
response   
Designation  Designation may be rescinded later in product development if the product no longer meets the 
Rescission  designation-specific qualifying criteria 
 
D.  Priority Review Designation 
 
A product, including those that received fast track, breakthrough therapy, or RMAT 
designation, may be eligible for priority review, if it meets the criteria for priority review 
at the time the marketing application is submitted.  At the time of a pre-biologics license 
application (pre-BLA) meeting with CBER, sponsors of regenerative medicine therapies, 
including those under expedited development programs, should consider discussing their 
eligibility for priority review. 
 
A regenerative medicine therapy may receive priority review if it treats a serious 
condition, and, if approved, would provide a significant improvement in the safety or 
effectiveness of the treatment of the condition.  A decision about granting priority review 
is made within 60 calendar days of receipt of the marketing application or efficacy 
supplement.  If priority review is granted, CBER has a 6 month goal for reviewing the 
biologics license application (BLA) or efficacy supplement.13   
 
E.  Accelerated Approval 
 
As explained in the Expedited Programs Guidance (Ref. 2), accelerated approval has 
been used primarily in settings in which the disease course is long and an extended period 
of time would be required to measure the intended clinical benefit of a drug.  Section 
506(c) of the FD&C Act provides that FDA may grant accelerated approval to drugs,14 
which include regenerative medicine therapies, for a serious or life-threatening disease 
or condition... upon a determination that the product has an effect on a surrogate 
endpoint that is reasonably likely to predict clinical benefit, or on a clinical endpoint that 
can be measured earlier than irreversible morbidity or mortality, that is reasonably likely 
                                                 
13 For additional information on review goals, see the PDUFA Reauthorization Performance Goals and Procedures 
Fiscal Years 2018 through 2022, available at 
https://www.fda.gov/downloads/forindustry/userfees/prescriptiondruguserfee/ucm511438.pdf 
14 See also 21 CFR Part 314, Subpart H; 21 CFR Part 601, Subpart E. 
 
9  Contains Nonbinding Recommendations 
 
to predict an effect on irreversible morbidity or mortality or other clinical benefit, taking 
into account the severity, rarity, or prevalence of the condition and the availability or lack 
of alternative treatments.  Sponsors of drugs that have been granted accelerated approval 
have been required to conduct post-approval confirmatory studies to verify and describe 
the anticipated effects of their products on irreversible morbidity and mortality or other 
clinical benefit (Ref. 2).15   
 
Section 506(g) of the FD&C Act, as added by the Cures Act, explains that FDA may 
grant accelerated approval to products that have received RMAT designation.  Under this 
provision, as appropriate, RMATs may be eligible for accelerated approval based on: 
 
  previously agreed-upon surrogate or intermediate endpoints that are 
reasonably likely to predict long-term clinical benefit, or 
 
  reliance upon data obtained from a meaningful number of sites, including 
through expansion to additional sites, as appropriate.   
 
The use of surrogate or intermediate endpoints that are reasonably likely to predict long-
term clinical benefit to support accelerated approval is discussed in greater detail in the 
Expedited Programs Guidance (Ref. 2).  Regarding reliance upon data obtained from a 
meaningful number of investigational sites, we expect that the determination of whether 
the number of investigational sites, even if limited, is meaningful will depend on 
whether the evidence of effectiveness is likely to be affected by a site-specific or 
investigator-specific bias, such that any conclusions regarding the products effectiveness 
could not be reliably generalized to other sites.  Thus, we anticipate that this 
determination will be a BLA review issue that will be considered on a case-by-case basis. 
If an RMAT receives accelerated approval based on this provision, it may be appropriate 
for the sponsor to provide post-approval clinical evidence about the product through 
expansion to additional sites.  
 
As further specified in section 506(g)(7) of the FD&C Act, sponsors of products that 
have been granted RMAT designation and which receive accelerated approval may be 
able to fulfill the post-approval requirements from clinical evidence obtained from 
sources other than the traditional confirmatory clinical trials.  Under this provision, as 
appropriate, the post-approval requirements for RMATs receiving accelerated approval 
may be satisfied by the following: 
 
  The submission of clinical evidence, clinical studies, patient registries, or 
other sources of real world evidence such as electronic health records;  
  The collection of larger confirmatory data sets as agreed upon during product 
development; or 
  Post-approval monitoring of all patients treated with such therapy prior to 
approval of the therapy.  
 
                                                 
15 See 21 CFR 601.41. 
10  Contains Nonbinding Recommendations 
 
Upon review of a BLA, CBER will determine what type(s) of post-approval requirements 
(e.g., confirmatory clinical trials, patient registries, electronic health records, or other data 
collections) will be necessary to confirm the clinical benefits of an RMAT that receives 
accelerated approval.  Considerations that CBER anticipates will determine the type of 
post-approval requirements that are necessary include, but are not limited to, the nature of 
the product and its administration, the evidence supporting marketing approval, the 
nature and magnitude of the anticipated benefit, the size of the target population, and the 
feasibility of obtaining confirmatory evidence. Thus, CBER intends to determine post-
approval requirements for verification of clinical benefit on a case-by-case basis.  
 
As with any biological product approved under the accelerated approval pathway, FDA 
may withdraw such marketing approval of a regenerative medicine therapy, including an 
RMAT, if the sponsor fails to comply with the requirements described in section 506(c) 
of the FD&C Act and 21 CFR 601.43(a). 
 
Sponsors of regenerative medicine therapies, including products designated as RMATs, 
may pursue either accelerated approval or traditional approval. The selection of the 
pathway to approval will depend on the design, conduct, and results of the studies that 
provide the primary evidence of effectiveness.  CBER encourages sponsors interested in 
pursuing accelerated approval for their regenerative medicine therapies to consult with 
the Agency early in development.  These interactions can be used to discuss whether 
accelerated approval is appropriate, proposed surrogate or intermediate clinical 
endpoints, plans to collect data obtained from a meaningful number of study sites, other 
clinical trial design issues, and any considerations related to product quality and 
manufacturing. 
 
 
IV.  CONSIDERATIONS IN CLINICAL TRIAL DESIGN 
 
Many regenerative medicine therapies are being developed to address unmet medical 
needs in patients with serious conditions, including rare diseases.  To help facilitate the 
development of data to demonstrate the safety and effectiveness of these products, CBER 
will work with sponsors and encourage flexibility in clinical trial design.  We will 
consider clinical trials in support of a BLA that incorporate adaptive designs (Ref. 5), 
enrichment strategies (Ref. 6), or novel endpoints.   
 
CBER recognizes that, for regenerative medicine therapies for rare diseases, certain 
aspects of drug development that are feasible for common diseases may not be feasible, 
and that development challenges can be greater with increasing rarity of the disease.  For 
example, in some rare diseases, there will likely be a limited number of affected 
individuals eligible to enroll in clinical trials.  Innovative trial designs, such as trials that 
compare several different investigational agents to each other and a common control, 
may be particularly useful in studies of regenerative medicine therapies to treat rare 
diseases.  Historical controls may be considered, if appropriate.  Natural history16 data 
                                                 
16 In this guidance, the natural history of a disease refers to the course a disease takes from its onset, through the 
presymptomatic and clinical stages, to a final outcome in the absence of treatment. 
11  Contains Nonbinding Recommendations 
 
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.   
 
As an alternative to a traditional multi-center clinical trial, innovative trial designs 
whereby multiple clinical sites participate in a trial investigating a regenerative medicine 
therapy with the intent of sharing the combined clinical trial data to support BLAs from 
each of the individual centers/institutions could be considered.17  In such trials, 
manufacturing may be performed at all clinical sites using a common manufacturing 
protocol and product quality testing specifications.  For example, this trial design could 
be considered for the use of stem cells derived from adipose tissue for the treatment of 
debilitating osteoarthritis, whereby the trials are conducted at a specified number of 
orthopedic practices.  In this situation, each practice could submit a BLA that relies on 
both the data from the individual practice and the combined data from all practices that 
participated in the clinical trial.  Each practice would also be required to meet the BLA 
requirements, and product manufacturing would be required to meet current good 
manufacturing practice (CGMP) requirements.  We encourage potential sponsors who are 
considering this trial design to engage in early discussions with FDA.   
 
Furthermore, CBER will work with sponsors to determine the types of endpoints that 
might be appropriate for various phases of clinical development.  We encourage sponsors 
to obtain input from the affected patient communities regarding the endpoints that might 
be clinically meaningful.18  The following are examples of how CBER could consider the 
use of novel endpoints for regenerative medicine therapies: 
 
  Visual acuity is generally accepted as an efficacy endpoint for products used to treat 
visual impairment.  In conditions that lead to advanced visual impairment, such as 
Leber congenital amaurosis, it might not be possible to achieve a statistically 
significant change in visual acuity.  As such, CBER could consider an effect on a 
novel endpoint, such as an improvement in functional vision (i.e., improvement in 
performance of tasks that require visual function) as evidence of effectiveness.  
  
  For regenerative medicine therapies that are cellular or tissue constructs intended to 
replace a tissue or organ, CBER recognizes that assessment of the long-term 
effectiveness of the construct might not be feasible prior to marketing approval.  For 
                                                 
17 This trial design uses a common manufacturing protocol, such that the participating centers manufacture products 
that could be considered the same drug for the purposes of orphan-drug designation and exclusivity. Before 
agreeing to pool their data, participating centers may wish to address any concerns regarding orphan-drug 
exclusivity, which could prevent approval of multiple BLAs.  For additional information, please see section 527 of 
the FD&C Act (21 U.S.C. 360cc) and FDAs Orphan Drug Regulations (21 CFR Part 316). 
18 For additional information, please see Patient-Focused Drug Development: Collecting Comprehensive and 
Representative Input; Draft Guidance for Industry, Food and Drug Administration Staff, and Other Stakeholders, 
June 2018, available at 
https://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm610442.pdf.  When 
finalized, this guidance will represent FDAs current thinking on the topic. 
 
12  Contains Nonbinding Recommendations 
 
these products, CBER could consider short-term performance to be novel, clinically 
meaningful efficacy endpoints.   
  
We encourage sponsors of regenerative medicine therapies to have early discussions with 
CBER about clinical trial design (Ref. 7), including the appropriate study population and 
the number of study subjects that might be necessary to provide sufficient evidence of 
safety and effectiveness.   
 
 
V.  INTERACTIONS BETWEEN SPONSORS AND CBER REVIEW STAFF 
 
CBER recommends that sponsors of regenerative medicine therapies engage in 
discussions with the Office of Tissues and Advanced Therapies (OTAT) review staff 
early during product development (Ref. 8).  The draft guidance entitled Formal 
Meetings Between the FDA and Sponsors or Applicants of PDUFA Products; Draft 
Guidance for Industry (Ref. 9) describes standardized procedures for requesting, 
preparing, scheduling, conducting, and documenting formal meetings between sponsors 
of Prescription Drug User Fee Act products and the FDA.19  In particular, the Type B 
meetings described, including the pre-IND, end-of-phase 2 or pre-phase 3, and pre-BLA 
meetings, represent critical points in the product development life cycle.  In addition, 
early nonbinding, regulatory advice also can be obtained from OTAT through an INitial 
Targeted Engagement for Regulatory Advice on CBER producTs (INTERACT) 
meeting20, which can be used to discuss issues such as a products early preclinical, 
CMC, or clinical development programs.  
 
For some regenerative medicine therapies, it may be necessary for OTAT to engage in 
consultative review with staff from other CBER offices or other FDA Centers.  For 
example, CBER may consult with other Centers on review of regenerative medicine 
therapies that are combination products, in accordance with the Staff Manual Guide 
(SMG) 4101 (Ref. 10).  More generally speaking, for regenerative medicine therapies, as 
for other products, a consultative review may occur when a unique aspect of a products 
indication, formulation, design, or performance raises concerns that require review by 
another Office or Center or when the expertise to review a particular aspect of the 
product resides in another Office or Center.  If OTAT determines that a consultative 
review is necessary, OTAT will initiate contact with the appropriate Office or Center and 
seek advice on specific questions or issues.  The consultative review is used to ensure a 
comprehensive review of the product. 
 
                                                 
19 When finalized, this guidance will represent FDAs current thinking on the topic.  For additional information, see 
SOPP 8101.1 entitled Regulatory Meetings with Sponsors and Applicants for Drugs and Biological Products 
(October 2017) available at 
https://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/ProceduresS
OPPs/UCM324381.pdf, and the final guidance entitled Best Practices for Communication Between IND Sponsors 
and FDA During Drug Development; Guidance for Industry and Review Staff (December 2017), available at 
https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM475586. 
20 For additional information on INTERACT meetings, please see the following website:  
https://www.fda.gov/BiologicsBloodVaccines/ResourcesforYou/Industry/ucm611501.htm. 
13  Contains Nonbinding Recommendations 
 
VI.  REFERENCES  
 
1. Food and Drug Administration, Notice, Application of Current Statutory Authorities to 
Human Somatic Cell Therapy Products and Gene Therapy Products (58 FR 53248, October 14, 
1993), available at 
https://www.fda.gov/downloads/BiologicsBloodVaccines/SafetyAvailability/UCM148113.pdf 
  
2. Guidance for Industry:  Expedited Programs for Serious Conditions  Drugs and Biologics, 
May 2014, available at 
https://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm
358301.pdf. 
 
3. Guidance for Industry and FDA Staff:  FDA Acceptance of Foreign Clinical Studies not 
conducted under an IND Frequently Asked Questions, March 2012, available at   
https://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM294729.pdf.  
 
4.  SOPP 8212:  Management of Breakthrough Therapy-Designated Products: Sponsor 
Interactions and Status Assessment Including Rescinding, June 2016, available at 
https://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInfor
mation/ProceduresSOPPs/UCM506016.pdf.   
 
5.  Draft Guidance for Industry, Adaptive Designs for Clinical Trials of Drugs and Biologics, 
September 2018*, available at 
https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/
UCM201790.pdf.  
 
6.  Draft Guidance for Industry:  Enrichment Strategies for Clinical Trials to Support Approval 
of Human Drugs and Biological Products, December 2012*, available at 
https://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm
332181.pdf. 
 
7. Considerations for the Design of Early-Phase Clinical Trials of Cellular and Gene Therapy 
Products; Guidance for Industry, June 2015, available at 
https://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInfor
mation/Guidances/CellularandGeneTherapy/UCM564952.pdf. 
 
8.  Guidance for Industry: Preclinical Assessment of Investigational Cellular and Gene Therapy 
Products, November 2013, available at 
https://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInfor
mation/Guidances/CellularandGeneTherapy/UCM376521.pdf.  
 
9.  Formal Meetings Between the FDA and Sponsors or Applicants of PDUFA Products; Draft 
Guidance for Industry, December 2017*, available at   
https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/
UCM590547.pdf. 
 
* When finalized, this guidance will represent FDAs current thinking on this topic.  
14  Contains Nonbinding Recommendations 
 
10. SMG 4101:  FDA Staff Manual Guides, Volume IV  Agency Program Directives:  
Combination Products: Inter-Center Consult Request Process, June 2004 and updated June 2018, 
available at 
https://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/StaffManualGuides/UCM28
3569.pdf 
 
 
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