Evaluation of Devices Used with 
Regenerative Medicine Advanced 
Therapies
 
 
 
Guidance for Industry 
 
 
 
 
 
 
 
 
 
For questions on the content of this guidance, contact Center for Biologics Evaluation and 
Research (CBER), Office of Communication, Outreach, and Development (OCOD) at 800-835-
4709 or 240-402-8010, or email ocod@fda.hhs.gov.  For questions about this document 
concerning products regulated by Center for Devices and Radiological Health (CDRH), contact 
the Office of the Center Director at 301-796-5900.  If you need additional assistance with 
regulation of combination products, contact the Office of Combination Products (OCP) at 301-
796-8930. 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Biologics Evaluation and Research 
Center for Devices and Radiological Health 
Office of Combination Products 
February 2019 
    Contains Nonbinding Recommendations 
Evaluation of Devices Used with 
Regenerative Medicine Advanced 
Therapies
 
 
 
Guidance for Industry 
 
Additional copies are available from: 
Office of Communication, Outreach and Development 
WO71, Room 3103  
Center for Biologics Evaluation and Research 
Food and Drug Administration 
10903 New Hampshire Ave. 
Silver Spring, MD 20993 
Phone: 800-835-4709 or 240-402-8010 
ocod@fda.hhs.gov  
https://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/default.htm   
 
or 
Office of the Center Director 
Guidance and Policy Development 
Center for Devices and Radiological Health 
Food and Drug Administration 
10903 New Hampshire Ave., WO66, Room 5431 
Silver Spring, MD 20993 
Phone: 301-796-5900 
https://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/default.htm 
 
or 
Office of Combination Products 
Office of Special Medical Programs 
Office of the Commissioner  
Food and Drug Administration 
10903 New Hampshire Ave., WO32, Hub 5129 
Silver Spring, MD 20993 
Phone: 301-796-8930 
Fax: 301-847-8619 
combination@fda.gov 
https://www.fda.gov/CombinationProducts/default.htm 
 
 
  Table of Contents 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  SCOPE ............................................................................................................................... 2 
III.  GENERAL APPROACH:  DEVICE CLASSIFICATION AND STREAMLINING 
OF APPLICATION OF REGULATORY REQUIREMENTS .................................... 4 
IV.  COMBINATION PRODUCTS........................................................................................ 9 
V.  FACTORS TO CONSIDER FOR WHEN A DEVICE MAY BE INTENDED FOR 
USE WITH ONLY ONE PARTICULAR TYPE OF CELL-BASED RMAT OR 
WITH MORE THAN ONE TYPE OF CELL-BASED RMAT.................................. 10 
 
 
 
 
 
 
 
i  Contains Nonbinding Recommendations 
Evaluation of Devices Used with Regenerative Medicine Advanced 
Therapies 
 
 
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 manufacturers, applicants, and sponsors engaged in the development of 
regenerative medicine therapies, with FDAs current thinking regarding evaluation of devices 
used in the recovery, isolation, or delivery of regenerative medicine advanced therapies.  
 
Section 3034 of the 21st Century Cures Act1 (Cures Act) mandates that FDA issue guidance 
clarifying how FDA will evaluate devices used in the recovery, isolation, or delivery of 
regenerative advanced therapies, as such term is used in section 506(g) of the Federal Food, 
Drug, and Cosmetic Act (FD&C Act) (21 U.S.C. 356(g)) and which FDA generally refers to as 
regenerative medicine advanced therapies or RMATs.  Accordingly, this guidance discusses 
what FDA will consider when evaluating the devices used with RMATs.  This document 
includes information about the Agencys current thinking regarding a wide range of concepts 
related to the regulation of devices, as they apply to devices used in the recovery, isolation, and 
delivery of RMATs.  Specifically, this guidance addresses how FDA intends to simplify and 
streamline its application of regulatory requirements for combination device and cell or tissue 
products;2 what, if any, intended uses or specific attributes would result in a device used with a 
regenerative therapy product to be classified as a Class III device;3 the factors to consider in 
determining whether a device may be labeled for use with a specific RMAT or class of RMATs; 
when a device may be limited to a specific intended use with only one particular type of cell; and 
application of the least burdensome approach to demonstrate how a device may be used with 
more than one cell type.   
 
                                                 
1 Public Law 114-255. 
2 For purposes of this guidance, the term combination device and cell or tissue products is not necessarily limited 
to combination product as defined under 21 CFR Part 3. 
3 As explained in section III of this guidance, we are unable to provide a definitive list of intended uses or specific 
attributes that would result in a device used with an RMAT being classified as a Class III device, but have instead 
addressed this requirement of section 3034 of the Cures Act by providing information about characteristics of Class 
III devices. 
1  Contains Nonbinding Recommendations 
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. 
 
 
II.  SCOPE 
 
This guidance applies to medical devices used in the recovery, isolation, or delivery of RMATs.  
 
The term device is defined in section 201(h) of the FD&C Act (21 U.S.C. 321) as:  
 
an instrument, apparatus, implement, machine, contrivance, implant, in vitro reagent, or other 
similar or related article, including any component, part, or accessory, which is:  
  recognized in the official National Formulary, or the United States Pharmacopoeia, or 
any supplement to them, 
  intended for use in the diagnosis of disease or other conditions, or in the cure, mitigation, 
treatment, or prevention of disease, in man or other animals, or 
  intended to affect the structure or any function of the body of man or other animals, and  
 
which does not achieve its primary intended purposes through chemical action within or on 
the body of man or other animals and which is not dependent upon being metabolized for the 
achievement of its primary intended purposes. 
Under section 506(g) of the FD&C Act, a drug4 is eligible for RMAT designation if: 
 
  it is a regenerative medicine therapy as defined in section 506(g)(8) of the FD&C Act 
(21. U.S.C. 356(g)(8));5 
  it is intended to treat, modify, reverse, or cure a serious or life-threatening disease or 
condition; and 
  preliminary clinical evidence indicates that the drug has the potential to address unmet 
medical needs for such a disease or condition.  
 
                                                 
4 With respect to the RMAT designation program, all references to drugs or drug products refer to human drugs, 
including drugs that are biological products, unless otherwise specified.  For further discussion of the RMAT 
designation program, please see the guidance document entitled Expedited Programs for Regenerative Medicine 
Therapies for Serious Conditions;  Guidance for Industry, dated February 2019.  As discussed in that guidance, a 
combination product (biologic-device, biologic-drug, or biologic-device-drug) can also 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). 
5 For information regarding FDAs interpretation of regenerative medicine therapy, as defined in section 506(g)(8) 
of the FD&C Act, please see the guidance document entitled Expedited Programs for Regenerative Medicine 
Therapies for Serious Conditions;  Guidance for Industry, dated February 2019. 
 
2  Contains Nonbinding Recommendations 
Although section 3034 of the Cures Act refers to recovery, isolation, or delivery, these terms 
are not defined in the Cures Act. For the purpose of this guidance only,  
 
  recovery means obtaining cells or tissues from a human donor; 
  isolation is processing that results in selection, separation, enrichment, or depletion of 
recovered cells or tissues that will become components of the final product; and 
  delivery refers to any method by which an RMAT is introduced onto or into the body of a 
human recipient, for example, infusion, injection, topical application, or inhalation.  
 
Under Title 21 of the Code of Federal Regulations Part 3.2(e) (21 CFR 3.2(e)), combination 
product includes: 
 
1)  A product comprised of two or more regulated components, i.e., drug/device, 
biologic/device, drug/biologic, or drug/device/biologic, that are physically, chemically, or 
otherwise combined or mixed and produced as a single entity; 
2)  Two or more separate products packaged together in a single package or as a unit and 
comprised of drug and device products, device and biological products, or biological and 
drug products; 
3)  A drug, device, or biological product packaged separately that according to its 
investigational plan or proposed labeling is intended for use only with an approved 
individually specified drug, device, or biological product where both are required to 
achieve the intended use, indication, or effect and where upon approval of the proposed 
product the labeling of the approved product would need to be changed, e.g., to reflect a 
change in intended use, dosage form, strength, route of administration, or significant 
change in dose; or 
4)  Any investigational drug, device, or biological product packaged separately that 
according to its proposed labeling is for use only with another individually specified 
investigational drug, device, or biological product where both are required to achieve the 
intended use, indication, or effect. 
 
FDA recognizes that a wide range of devices may be used in conjunction with an RMAT.  For 
example, the devices can be simple, low risk devices, such as a manual surgical instrument (e.g., 
scalpel) for recovering cells and tissue.  Devices used with RMATs may also be complex, higher 
risk devices, such as an automated cell collection system that selects and processes specific cells 
intended for immediate return back to the patient.  Additionally, devices can be constituent parts 
of an RMAT that is a combination product. 
 
The Agency does not consider device scaffolds combined with a cellular product to be within the 
scope of this guidance.  While such constructs may be eligible for RMAT designation, the 
scaffold constituent part would generally be considered a part of the RMAT and would generally 
not be considered solely a device used in the delivery of an RMAT because such scaffolds 
provide more than a delivery function.  
 
The use of general use equipment (e.g., centrifuges, cell washers, chromatography columns) in 
the manufacture of an RMAT outside of a direct patient care setting is reviewed under the 
Investigational New Drug Applications (IND)/ Biologics License Applications (BLA) for the 
3  Contains Nonbinding Recommendations 
RMAT.  Therefore, this guidance does not address such equipment.  In addition, medical devices 
that are not used in the recovery, isolation, or delivery of RMATs, such as in vitro diagnostics or 
companion diagnostics, are outside the scope of this guidance. 
 
 
III.  GENERAL APPROACH:  DEVICE CLASSIFICATION AND STREAMLINING 
OF APPLICATION OF REGULATORY REQUIREMENTS 
 
The appropriate regulatory evaluation pathway for devices that are not reviewed solely under a 
BLA as a constituent part of a biologic-led combination product and that are used in the 
recovery, isolation, or delivery of RMATs, and Center jurisdiction6 for such devices, may vary 
depending upon the devices technological characteristics and intended uses.  The devices 
characteristics and intended uses are, in turn, generally based on the characteristics and 
conditions of use of the associated RMAT and the role of the device in the final product.   
 
The classification of a device is a primary factor in determining the available premarket pathway 
for the device.  The requirements for device classification are found in section 513 of the FD&C 
Act (21 U.S.C. 360c).  
 
Section 513(a) of the FD&C Act (21 U.S.C. 360c(a)) establishes three classes of devices based 
on the regulatory controls needed to provide reasonable assurance of their safety and 
effectiveness:  Class I (general controls), Class II (special controls in addition to general 
controls), and Class III (premarket approval in addition to general controls).  Although a devices 
intended uses and technological characteristics are considered during classification, FDA has no 
predetermined list of intended uses or specific attributes which would result in a device used 
with an RMAT (or any device) to be classified as a Class III device.  Under section 513(a)(1)(C) 
of the FD&C Act, Class III devices are those that support or sustain human life, are of substantial 
importance in preventing impairment of human health, or which present a potential unreasonable 
risk of illness or injury, and for which there is insufficient information to determine that general 
and/or special controls would provide reasonable assurance of safety and effectiveness.7  Further, 
under section 513(f)(1) of the FD&C Act (21 U.S.C. 360c(f)(1)), postamendments devices 
(devices that were not in commercial distribution before May 28, 1976, the date the Medical 
Device Amendments were enacted) are statutorily classified in Class III unless FDA classifies or 
reclassifies them into Class I or II, or determines that such a device is substantially equivalent  
   
                                                 
6 See, e.g. Guidance for Industry and FDA Staff:  Devices Used to Process Human Cells, Tissues, and Cellular and 
Tissue-Based Products (HCT/Ps), dated July 2007, available at 
https://www.fda.gov/RegulatoryInformation/Guidances/ucm126052.htm, for discussion of Center assignment of 
such devices. 
7 Section 513(a)(1)(C) of the FD&C Act (21 U.S.C. 360c(a)(1)(C)). 
4  Contains Nonbinding Recommendations 
(SE)8 to another device for which premarket approval is not required.9  Thus, a postamendments 
device may be subject to regulation as a Class I or II device in certain circumstances, including 
when:  
 
  the device is within a type of device that has been classified into Class I or II and FDA 
has found the device to be SE to a device within such type; 
  the device is within a type of preamendments device that is unclassified and FDA has 
found the device to be SE to a device within such type; or 
  FDA has classified or reclassified the device type in Class I or II in accordance with 
sections 513(f)(2)10 or 513(f)(3) of the FD&C Act (21 U.S.C. 360c(f)(2), and (3)). 
 
A.  Least Burdensome Principles 
 
FDA applies the level of regulation necessary to provide reasonable assurance that a 
medical device is safe and effective for its intended use.  In accordance with the least 
burdensome provisions of the FD&C Act,11 the least burdensome principles apply to 
FDA requests for information related to (1) demonstrating a reasonable assurance of 
device safety and effectiveness in PMAs12 and (2) determinations of substantial 
equivalence for devices with technological characteristics that differ from those of the 
predicate device.13   
 
In conducting premarket review of a medical device, FDA requests information that is 
necessary to make a determination of whether the statutory standards for marketing 
authorization are met in accordance with the least burdensome principle.  Based on the 
least burdensome principle, the term necessary means that FDA considers the 
minimum required information that would support (1) a determination by [FDA] that 
an application provides reasonable assurance of the safety and effectiveness of the 
device14 or (2) a determination of substantial equivalence between a new device and a 
predicate device.15   
 
                                                 
8 Substantial equivalence is defined at section 513(i) of the FD&C Act (21 U.S.C. 360c(i)).  FDA generally 
evaluates substantial equivalence on the basis of a premarket notification submitted pursuant to section 510(k) of the 
FD&C Act (21 U.S.C. 360(k)).  Certain devices are subject to a statutory exemption from the 510(k) premarket 
notification requirement (see sections 510(l) and (m) of the FD&C Act (21 U.S.C. 360(l) and (m)). 
9 A preamendments device for which premarket approval is not required could be a preamendments device that has 
been classified into Class I or Class II, a preamendments device that has been classified into Class III but for which 
a regulation under section 515(b) of the FD&C Act (21 U.S.C. 360e(b)) requiring the submission of an application 
for premarket approval (PMA) has not yet been issued, or a preamendments device that has not yet been classified. 
10 This process is referred to as De Novo classification, and is described in more detail in section III.B.2. of this 
guidance. 
11The FDA Modernization Act of 1997 (FDAMA) added two provisions, commonly known as the least 
burdensome provisions, to the FD&C Act; related provisions were added to the statute by the FDA Safety and 
Innovation Act of 2012 (FDASIA) (Pub. L. 112-144) and the Cures Act. 
12 Sections 513(a)(3)(D)(ii) and 515(c)(5) of the FD&C Act (21 U.S.C. 360c(a)(3)(D)(ii), 360e(c)(5)). 
13 See section 513(i)(1)(D)(i) of the FD&C Act (21 U.S.C. 360c(i)(1)(D)(i)). 
14 Section 515(c)(5) of the FD&C Act (21 U.S.C. 360e(c)(5)). 
15 Section 513(i)(1)(D)(ii) of the FD&C Act (21 U.S.C. 360c(i)(1)(D)(ii)). 
5  Contains Nonbinding Recommendations 
Additional information related to how FDA intends to apply the least burdensome 
provisions is available in the following FDA guidances (Least Burdensome Guidances) 
that discuss the principles with which the recommendations discussed in this guidance are 
consistent: 
 
  The Least Burdensome Provisions:  Concept and Principles; Guidance for 
Industry and Food and Drug Administration Staff, dated February 5, 2019, 
available at 
https://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidan
ce/GuidanceDocuments/UCM085999.pdf.  
  Developing and Responding to Deficiencies in Accordance with the Least 
Burdensome Provisions; Guidance for Industry and Food and Drug 
Administration Staff, dated September 29, 2017, available at 
https://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidan
ce/GuidanceDocuments/ucm073680.pdf.    
 
B.  Available Premarket Pathways 
 
The appropriate premarket submission pathway for a given medical device is determined 
by the risks associated with the device type as well as the level of regulatory controls 
necessary to provide a reasonable assurance of safety and effectiveness.  The available 
submission pathways (e.g., premarket notification (510(k)), De Novo classification (De 
Novo) request, Premarket Approval (PMA) Application, or Humanitarian Device 
Exemption (HDE)) are briefly discussed in sections III.B.1-4 of this guidance.  
 
When clinical evidence is necessary to support marketing authorization of a medical 
device, an investigational device exemption (IDE) may be necessary.16  An IDE allows 
the investigational device to be used in a clinical study in the United States in order to 
collect safety and effectiveness data.  An approved IDE permits a device to be shipped 
lawfully for the purpose of conducting investigations of the device.  FDA has published 
numerous guidance documents related to IDEs, which can be found at:  
https://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/HowtoMarketYour
Device/InvestigationalDeviceExemptionIDE/ucm162453.htm. 
 
Although a manufacturer or sponsor may submit any form of evidence to FDA in an 
attempt to substantiate the safety and effectiveness of a device, the Agency relies upon 
only valid scientific evidence17 to determine whether there is reasonable assurance that 
the device is safe and effective.  After considering the nature of the device and the rules 
in 21 CFR 860.7, the Commissioner will determine whether the evidence submitted or 
                                                 
16 See Section 520(g) of the FD&C Act (21 U.S.C. 360j(g)) and 21 CFR 812.2.  
17 Valid scientific evidence is defined as evidence from well-controlled investigations, partially controlled studies, 
studies and objective trials without matched controls, well-documented case histories conducted by qualified 
experts, and reports of significant human experience with a marketed device, from which it can fairly and 
responsibly be concluded by qualified experts that there is reasonable assurance of the safety and effectiveness of a 
device under its conditions of use. (21 CFR 860.7(c)(2)). 
 
6  Contains Nonbinding Recommendations 
otherwise available to the Commissioner is valid scientific evidence for the purpose of 
determining the safety or effectiveness of a particular device and whether the available 
evidence, when taken as a whole, is adequate to support a determination that there is 
reasonable assurance that the device is safe and effective for its conditions of use.18 
 
1.  Premarket Notification (510(k)) 
 
If FDA has previously cleared through a 510(k) or granted a De Novo request for 
another device of the same type (i.e., a legally-marketed predicate device),19 as a new 
device, a 510(k) is typically the appropriate pathway for the new device.20  Additional 
information on the 510(k) Program can be found in the guidance document entitled 
The 510(k) Program:  Evaluating Substantial Equivalence in Premarket Notifications 
[510(k)]; Guidance for Industry and Food and Drug Administration Staff, dated July 
28, 2014, available at https://www.fda.gov/ucm/groups/fdagov-public/@fdagov-
meddev-gen/documents/document/ucm284443.pdf. 
 
2.  De Novo Classification Request  
 
Devices of a new type that FDA has not previously classified based on the criteria at 
section 513(a)(1) of the FD&C Act (21 U.S.C. 360c(a)(1)) are automatically or 
statutorily classified into Class III.21  However, if the device appears, based on what 
is known about the device, to meet the statutory standards for classification into Class 
I or II under section 513(a)(1) of the FD&C Act, (i.e., general controls or general and 
special controls would provide reasonable assurance of the safety and effectiveness of 
the device), the device may be eligible for De Novo classification.22  If the requester 
demonstrates that the device meets the statutory standards for classification into Class 
I or II under section 513(a)(1) of the FD&C Act, i.e., that general controls, or a 
combination of general controls and special controls, are sufficient to provide a 
reasonable assurance of safety and effectiveness, FDA will grant the De Novo request 
and issue a written order classifying the specific device and device type in Class I or 
Class II.   
 
Additional information on the De Novo Program can be found in the guidance 
document entitled De Novo Classification Process (Evaluation of Automatic Class 
III Designation); Guidance for Industry and Food and Drug Administration Staff, 
dated October 30, 2017, available at 
https://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/Gui
danceDocuments/ucm080197.pdf. 
                                                 
18 21 CFR 860.7(c)(1). 
19 Under 21 CFR 807.92(a)(3), a legally marketed predicate is a device that: (1) was legally marketed in the United 
States prior to May 28, 1976 (preamendments device) and for which a PMA is not required; or (2) has been 
reclassified from Class III to II or I; or (iii) has been found substantially equivalent (SE) though the 510(k) process.   
20 See section 510(k) of the FD&C Act (21 U.S.C. 360(k)), and 21 CFR Part 807 Subpart E. 
21 Section 513(f)(1) of the FD&C Act (21 U.S.C. 360c(f)(1)). 
22 FDA may decline to undertake a De Novo request if the conditions set forth in section 513(f)(2)(A)(iv) of the 
FD&C Act (21 U.S.C. 360c(f)(2)(A)(iv)) are met. 
 
7  Contains Nonbinding Recommendations 
 
3.  Premarket Approval Application  
 
Premarket approval (PMA) is required before most Class III devices can be 
marketed.23  A PMA application must demonstrate a reasonable assurance of safety 
and effectiveness by weighing any probable benefit to health from the use of the 
device against any probable risk of injury or illness from such use, among other 
relevant factors.24  To aid in this process, PMA applicants submit valid scientific 
evidence, including one or more clinical investigations where appropriate, which 
FDA reviews to determine whether the device will have the effect it purports or is 
represented to have under the conditions of use prescribed, recommended, or 
suggested in the labeling of the device.25 
 
For information regarding PMAs, see FDAs guidance entitled Factors to Consider 
When Making Benefit-Risk Determinations in Medical Device Premarket Approval 
and De Novo Classifications, dated August 24, 2016.  Available at 
https://www.fda.gov/ucm/groups/fdagov-public/@fdagov-meddev-
gen/documents/document/ucm517504.pdf.  Additionally, the guidance document 
entitled Acceptance and Filing Reviews for Premarket Approval Applications 
(PMAs); Guidance for Industry and Food and Drug Administration Staff, dated 
January 30, 2018, may provide useful information to manufacturers when preparing 
PMAs.  Available at http://www.fda.gov/downloads/medicaldevices /deviceregulation 
andguidance/guidancedocuments/ucm313368.pdf.  
 
4.  Humanitarian Device Exemption (HDE) 
 
An HDE provides a regulatory path for devices that are intended to benefit patients 
with rare diseases or conditions.  To be eligible for an HDE, a device must first be 
designated as a Humanitarian Use Device (HUD).26  Additional information about the 
HUD designation process can be found in the draft guidance document entitled 
Humanitarian Device Exemption (HDE) Program; Draft Guidance for Industry and 
Food and Drug Administration Staff, dated June 13, 2018,27 available at 
https://www.fda.gov/ucm/groups/fdagov-public/@fdagov-meddev-
gen/documents/document/ucm389275.pdf.   
 
FDA understands that applicants may have questions prior to submitting a premarket 
application.  We have established a structured process for managing the various types of 
requests for feedback prior to a premarket submission, referred to as Q-Submissions.  
FDA has issued guidance that provides an overview of the mechanisms available to 
                                                 
23 See section 513(a)(1)(C) of the FD&C Act (21 U.S.C. 360c(a)(1)(C)). 
24 See sections 513(a)(2), 515(d)(1)(A), and 515(d)(2)(A)-(B) of the FD&C Act (21 U.S.C. 360c(a)(2), 
360e(d)(1)(A) and (d)(2)(A)-(B)); see also 21 CFR 860.7(b), (d), and (e). 
25 Section 513(a)(3)(A) of the FD&C Act (21 U.S.C. 360c(a)(3)(A)). 
26 21 CFR 814.102(a). 
27 When finalized, this guidance will represent FDAs current thinking on this topic. 
 
8  Contains Nonbinding Recommendations 
applicants through which they can request feedback from FDA regarding potential or 
planned medical device IDE applications or other premarket submissions, such as PMA 
applications, HDE applications, De Novo requests, 510(k)s, and BLAs.28 
 
 
IV.  COMBINATION PRODUCTS 
 
Consistent with section 503(g)(1)(B) of the FD&C Act, added by the Cures Act, and the 
Agencys approach to simplifying and streamlining the regulatory requirements for combination 
products in general, single entity combination products are generally reviewed under a single 
application.29  Devices intended for use with a specific RMAT may, together with the RMAT, be 
considered to comprise a biologic-led combination product and be evaluated for marketing under 
a BLA in the Center for Biologics Evaluation and Research (CBER), with consulting review by 
other center(s) as appropriate.30 
 
Some devices that can be used with approved RMATs may be evaluated independently using 
premarket submissions pathways identified in section III.B of this guidance.  Examples may 
include some devices used in recovery (e.g., surgical tools, syringes, apheresis collection 
devices), or delivery (e.g., syringe, catheter).  When a separate premarket application for a device 
to be used with an RMAT is appropriate, FDA will apply the least burdensome provisions of the 
FD&C Act as noted above to determine the minimum required information necessary for 
marketing authorization of that device.   
 
In some instances, the device constituent part of an RMAT that is a combination product may be 
separately packaged.  Separate marketing applications for each product may be appropriate, 
particularly, for example, if the delivery device may ultimately be labeled for use with multiple 
RMATs that have similar characteristics and administration requirements.  In instances where 
there are separate applications for the RMAT(s) and device(s), fulfillment of regulatory 
requirements may be simplified or streamlined to reduce or avoid redundancy.  For example, 
when appropriate and legally permissible, clinical or performance data generated in association 
with studies of one product may be submitted to support certain aspects of the approval or 
clearance of other, related product applications.  It may also be possible for one regulatory 
submission to cross-reference existing performance data in another regulatory submission when 
available and when such reference is permissible.  FDA intends to apply the least burdensome 
concept and principles in the guidance entitled, The Least Burdensome Provisions: Concept and 
Principles; Guidance for Industry and Food and Drug Administration Staff, dated  
                                                 
28 See Guidance for Industry and Food and Drug Administration Staff:  Requests for Feedback on Medical Device 
Submissions: The Pre-Submission Program and Meetings with Food and Drug Administration Staff, dated 
September 29, 2017, available at: 
https://www.fda.gov/downloads/medicaldevices/deviceregulationandguidance/guidancedocuments/ucm311176.pdf.  
29 Section 503(g)(1)(B) of the FD&C Act (21 U.S.C. 353(g)(1)(B)) provides that FDA shall review combination 
products in a single application, whenever appropriate.  Note that under section 503(g)(6) of the FD&C Act, also 
added by the Cures Act, a sponsor may choose to submit separate applications for the constituent parts of a 
combination product, unless FDA determines that a single application is necessary.  
30 See SMG 4101: Inter-Center Consult Request Process, June 2018, available at 
https://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/StaffManualGuides/UCM283569.pdf.  
 
9  Contains Nonbinding Recommendations 
February 5, 2019,31 in determining the data and information necessary to support marketing 
authorization for the device for its intended use.  FDA intends to apply these least burdensome 
concept and principles in the manner described regardless of how the device is presented for 
review, e.g., under a standalone application for more general use; or a constituent part, reviewed 
under a separate device application, of an RMAT that is a combination product; or under a single 
application for a combination product as a whole.  
 
 
V.  FACTORS TO CONSIDER FOR WHEN A DEVICE MAY BE INTENDED FOR 
USE WITH ONLY ONE PARTICULAR TYPE OF CELL-BASED RMAT OR 
WITH MORE THAN ONE TYPE OF CELL-BASED RMAT  
 
RMAT designation is granted for a specific therapeutic product and specific intended uses. 
RMATs may represent a highly diverse group of products with distinct biological and physical 
characteristics.  These characteristics, along with other factors such as target patient population 
(e.g., adult vs pediatric), intended use and conditions for use must be considered when 
determining which device, or devices, may be suitable for use with a specified RMAT or type of 
RMAT.  These same factors will influence when a device may be limited to a specific intended 
use with only one particular cell-based RMAT or type of cell-based RMAT. 
 
RMATs are likely to differ with regard to characteristics that can impact the way they interact 
with different devices, which may affect the RMATs safety and effectiveness.  In the case of 
cellular products that are RMATs, including cellular products that are constituent parts of 
combination products, the interaction between cells and a device can have an impact on critical 
characteristics, such as cell viability, differentiation potential, activation state and ability to 
respond to stimuli after administration.  Further, differences in physical characteristics such as 
cell size and sensitivity to shearing forces can directly impact the potential utility of a given 
device with a specific RMAT or type of RMAT.  For example, it may not be possible to use a 
small bore catheter or pen/jet injector to deliver an RMAT that contains a large delicate cell type 
because the shearing forces may negatively impact cell viability.  In contrast, an RMAT that 
contains a smaller, more robust cell type may require the use of a small bore catheter to facilitate 
delivery to a specific tissue site, but have special requirements to prevent the cells from 
adsorbing to the interior catheter surface or to each other, resulting in occlusion of the tip.  Such 
factors along with the demonstrated performance will influence whether the device can obtain 
marketing authorization for a broader use or should be limited to use with a specific RMAT(s). 
 
Because cellular products can possess extremely variable sensitivities to physical and chemical 
stimuli, it may be necessary to repeat testing to assess interactions of each new device-RMAT 
combination.  To leverage compatibility data for a different device-RMAT combination, a 
detailed and specific scientific rationale for the applicability of this data would be needed.  
Sufficient compatibility data should be provided to the Agency prior to initiation of clinical 
trials. 
 
                                                 
31 The draft guidance is available at: 
https://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/UCM085999
.pdf 
10  Contains Nonbinding Recommendations 
During development, a given RMAT may be determined to have characteristics and use 
requirements that would allow it to be administered using a general class of devices (e.g., 
conventional syringe or catheter) or a specific subset of delivery device(s) with defined 
characteristics when such devices are used as labeled.  Experience gained over time with a 
specific RMAT or class of RMATs in different use settings may also allow for identification of a 
general class or subset of delivery devices.  If there is sufficient evidence that the safety and 
effectiveness of the RMAT would not be compromised when administered with the identified 
general class or specific subset of delivery devices, the RMAT could be approved with more 
general labeling rather than specifying a particular delivery device.  In such cases, the labeling of 
the RMAT would specify the defined characteristics of the general class of devices (e.g., 
conventional syringe or catheter) or specific subset of delivery device(s) with which it is 
intended to be administered. 
11