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 [email protected], 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.
B.
C.
D.
E.

Fast Track Designation......................................................................................... 4
Breakthrough Therapy Designation ................................................................... 4
Regenerative Medicine Advanced Therapy Designation .................................. 5
Priority Review Designation ................................................................................ 9
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 conditions 1 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.
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

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 therapies 3, 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 FDA’s interpretation of section 506(g), human gene therapies 4, including
genetically modified cells, that lead to a sustained effect on cells or tissues, may meet the
definition of a regenerative medicine therapy 5 (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 biologicdevice-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 FDA’s current thinking on
the topic.
5
Based on FDA’s 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 FDA’s 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 drug’s 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 product’s effect in a relevant
in vitro or animal model could constitute sufficient evidence of the product’s 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 product’s
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 cure 10 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 product 11 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

FDA’s SOPP (Standard Operating Policy and Procedure) 8212, entitled “Management of Breakthrough TherapyDesignated 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 program’s 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
Statute

Qualifying
criteria

Section 506(a) of the FD&C Act, as added
by section 902 of the Food and Drug
Administration Safety and Innovation Act
of 2012 (FDASIA)
A drug that is intended to treat a serious
condition, AND
preliminary clinical evidence indicates that
the drug may demonstrate substantial
improvement on a clinically significant
endpoint(s) over available therapies

8

Regenerative Medicine Advanced
Therapy Designation
Section 506(g) of the FD&C Act, as added by
section 3033 of the 21st Century Cures Act

A drug is a regenerative medicine therapy, AND
the drug is intended to treat, modify, reverse, or
cure a serious condition, AND
preliminary clinical evidence indicates that the
drug has the potential to address unmet medical
needs for such disease or condition

Contains Nonbinding Recommendations
Features

When to
submit
FDA
response
Designation
Rescission

D.

• 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
With the IND or after and, ideally, no later than the end-of-phase 2 meeting
Within 60 calendar days after receipt of request
Designation may be rescinded later in product development if the product no longer meets the
designation-specific qualifying criteria

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 longterm 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 product’s 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:
•
•
•

15

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.

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 postapproval 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 history 16 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 FDA’s 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 FDA’s 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)
meeting 20, which can be used to discuss issues such as a product’s 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 product’s
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 FDA’s 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 FDA’s 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

15