Principles of Premarket 
Pathways for 
Combination Products 
 
Guidance for Industry and FDA Staff 
 
 
 
Additional copies are available from: 
Office of Combination Products  
Food and Drug Administration  
WO32, Hub/Mail Room #5129  
10903 New Hampshire Avenue 
Silver Spring, MD 20993 
 (Tel) 301-796-8930 
 (Fax) 301-847-8619 
https://www.fda.gov/combination-products 
 
 
 
For questions regarding this document, contact the Office of Combination Products at 
combination@fda.gov. 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Office of Combination Products 
Center for Biologics Evaluation and Research 
Center for Drug Evaluation and Research 
Center for Devices and Radiological Health 
 
January 2022  Contains Nonbinding Recommendations 
 
 
TABLE OF CONTENTS 
 
 
I.  INTRODUCTION ............................................................................................................................... 1 
II.  COMBINATION PRODUCT STATUS AND INTERACTION WITH FDA ............................... 2 
A.  What Are Combination Products and How Are Their Center Assignments Determined? ..... 2 
B.  Basics of Interacting With FDA .................................................................................................... .3 
III.    BASICS OF PREMARKET REGULATION OF COMBINATION PRODUCTS .................... 5 
IV.     PATHWAY AVAILABILITY AND RELATED CONSIDERATIONS ..................................... 8 
A.  Device-Led Combination Products ................................................................................................ 8 
1.  Premarket Approval Applications (PMA) ..................................................................................... 9 
2.  De Novo Classification Requests .................................................................................................. 9 
3.  Premarket Notification (510(k)) Submissions ............................................................................. 11 
B.  Drug-Led Combination Products ................................................................................................ 12 
1.  New Drug Application (NDA) ..................................................................................................... 12 
2.  Abbreviated New Drug Application (ANDA) .............................................................................. 13 
C.  Biologic-Led Combination Products ........................................................................................... 14 
1.  Biologics License Applications (BLAs) Submitted Under Section 351(a) .................................. 15 
2.  BLAs for Biosimilar and Interchangeable Biological Products Submitted Under Section 351(k)
 ..................................................................................................................................................................15 
ANNEX ...................................................................................................................................................... 17 
 
 
   
 
  Contains Nonbinding Recommendations 
 
Principles of Premarket Pathways for Combination Products 
Guidance for Industry and FDA Staff 
 
 
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 office 
responsible for this guidance as listed on the title page. 
 
 
 
I.  INTRODUCTION 
 
This guidance presents the current thinking of FDA on principles for premarket review of 
combination products.1  This guidance offers general, high-level information regarding what 
combination products are, coordination within FDA and interaction between FDA and sponsors 
regarding combination product regulation, and how combination products are reviewed by FDA 
before they are marketed.  The remainder of this guidance focuses on how to determine which 
type of premarket submissions may be appropriate for combination products.  The Agency has 
published guidance on premarket review issues relevant to specific categories of combination 
products2 and will continue to use such guidance as needed to provide more detailed information 
on specific premarket considerations and specific types of combination products. 
  
Section 3038 of the 21st Century Cures Act, enacted in December 2016 (P.L. 114-255) (Cures 
Act), substantially amended section 503(g) of the Federal Food, Drug, and Cosmetic Act (FD&C 
Act) (21 U.S.C. 353(g)), the principal section of the FD&C Act expressly addressing 
combination products.  General themes of these amendments include enhancing clarity, 
predictability, efficiency, and consistency of premarket regulatory expectations for combination 
products, including by ensuring that Agency components and staff coordinate appropriately on 
premarket review of these products, and that Agency thinking is aligned in conducting these 
 
1 Agency policy regarding postmarket regulation of combination products is outside the scope of this guidance.  
Agency regulations at 21 CFR part 4, for example, codify the regulatory requirements for current good 
manufacturing practices and for postmarketing safety reporting for combination products.  
2 We update guidances periodically.  For the most recent version of a guidance, check the FDA guidance web page 
at https://www.fda.gov/regulatory-information/search-fda-guidance-documents, which includes a link to the 
Combination Products Guidance Documents web page. 
 
 
 
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reviews.3  FDA is publishing this guidance as part of its efforts to implement Cures Act section 
3038 and in keeping with the Agencys long-standing commitment to transparency, efficiency, 
and regulatory consistency, to facilitate development of safe and effective combination products. 
 
The contents of this document do not have the force and effect of law and are not meant to bind 
the public in any way, unless specifically incorporated into a contract.  This document is 
intended only to provide clarity to the public regarding existing requirements under the law.  
FDA guidance documents, including this guidance, should be viewed only as recommendations, 
unless specific regulatory or statutory requirements are cited.  The use of the word should in 
Agency guidances means that something is suggested or recommended, but not required. 
 
 
II.  COMBINATION PRODUCT STATUS AND INTERACTION WITH FDA 
 
A.  What Are Combination Products and How Are Their Center Assignments 
Determined? 
 
As set forth in section 503(g) of the FD&C Act and 21 CFR part 3, a combination product is a 
product comprised of two or more different types of medical products (i.e., a combination of a 
drug, device, and/or biological product with one another).  The drugs, devices, and biological 
products included in combination products are referred to as constituent parts of the combination 
product. 
 
Under 21 CFR 3.2(e), combination products include: 
 
  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 (a single entity combination 
product, such as a prefilled syringe or drug-eluting stent);  
 
  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 (a co-packaged combination product, such as a surgical or first-aid kit 
containing bandages and an antiseptic drug); 
 
  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) (a cross-labeled combination product, as might be the case for a light-
 
3 While not the focus of this guidance, section 3038 also amended section 503(g) to clarify premarket data and 
information expectations for combination products that include certain approved constituent parts.  See section 
503(g)(3) of the FD&C Act. 
 
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  Contains Nonbinding Recommendations 
 
emitting device and a light-activated drug indicated for use together for treatment of a 
dermatologic condition); or 
 
  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 (also a cross-labeled combination product). 
 
A combination product is assigned to an Agency center that will have primary jurisdiction (i.e., 
the lead) for that products regulation.  Under section 503(g)(1), assignment of a combination 
product to a lead center is based on a determination of which constituent part provides the 
primary mode of action (PMOA) of the combination product.4  If the PMOA of a device-
biological product combination product is attributable to the biological product, for example, the 
center responsible for premarket review of such a biological product would have primary 
jurisdiction for the regulation of the combination product.  As discussed in section II.B., the 
Agency center with primary jurisdiction works with other Agency centers to ensure appropriate, 
consistent regulation. 
 
If you are uncertain or disagree with a center on product classification or which center is the lead 
for a particular product, you may submit a request for designation (RFD) to obtain a binding 
classification and/or assignment determination from FDA, or a Pre-RFD to obtain informal 
feedback relating to the classification and/or assignment of your product, including regarding 
preparation of an RFD.  While sponsors may propose the classification and/or assignment they 
believe should apply for a pre-RFD, and must do so for an RFD, the Office of Combination 
Products (OCP) makes the final determination with input from the relevant Agency 
components.5  The referenced guidances describe the information FDA needs to conduct these 
assessments and the processes FDA uses for making these determinations.6  
 
B.  Basics of Interacting With FDA 
 
The lead center is a sponsors primary point of contact and typically the Agencys focal point for 
presenting FDAs views to the sponsor.  The premarket processes and procedures of the lead 
center are available to and should be used by sponsors, including pre-submission meetings and  
 
 
4 The PMOA of a combination product is the single mode of action (drug, device, or biological product) expected to 
make the greatest contribution to the overall intended therapeutic effects of the combination product.  See section 
503(g)(1)(C) (added by the Cures Act) and 21 CFR 3.2(m); see also 21 CFR 3.2(k) (which defines mode of action 
and therapeutic). 
5 If OCP does not respond to an RFD within 60 days of filing, the classification or assignment proposed by the 
sponsor will become the final determination.  See section 563(d) of the FD&C Act and 21 CFR 3.8(b). 
6 See the guidance for industry How to Write a Request for Designation (RFD) (April 2011) and How to Prepare a 
Pre-Request for Designation (Pre-RFD) (February 2018). 
 
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  Contains Nonbinding Recommendations 
 
other mechanisms for obtaining Agency feedback.7  While this general approach is available for 
and generally should be used for all combination products, cross-labeled combination products 
for which separate marketing authorizations are being sought for the constituent parts (e.g., a 
new drug application (NDA) for the drug and a premarket notification (510(k)) for the device) 
can raise distinct considerations.  Prior to the filing of separate marketing authorization 
submissions, all interactions with FDA should be through the lead center for these combination 
products, regardless of the feedback being requested.  The sponsor(s) may wish to discuss with 
the centers (and OCP as needed) how best to ensure efficient, coordinated engagement during 
review of marketing authorization submissions (e.g., in light of the differing user fee 
performance goals associated with the submission types for each constituent part).8  
 
As provided in section 503(g)(8)(C)(iv), the centers, in conjunction with OCP when needed, will 
ensure that meetings between the FDA and sponsors are attended by review staff from each 
center as appropriate in light of the topics and purpose of the meeting, and that consulting centers 
complete their premarket reviews in a timely manner.9  As provided in section 503(g)(8)(C)(iii), 
Agency communications regarding the review from the lead center are considered 
communications on behalf of all centers involved with the review, to the extent consistent with 
the provisions of law and requirements of all affected centers.  Accordingly, centers are expected 
to coordinate as appropriate prior to issuance of such communications.10 
 
As provided in section 503(g)(8)(C)(v), sponsors may request in writing the participation of 
representatives of OCP in meetings regarding their products, or to have OCP otherwise engage 
on regulatory matters concerning the product.  Sponsors, for example, may contact OCP for 
 
7 As reflected in section 503(g)(7), the Agency will utilize appropriate Agency resources to ensure adequate review 
of safety, effectiveness, or substantial equivalence.  For additional information regarding ways in which 
combination product sponsors can obtain feedback from FDA on scientific and regulatory questions and best 
practices for FDA and sponsors when interacting on these topics, see the guidance for industry and FDA staff 
Requesting FDA Feedback on Combination Products (December 2020).   
8 As reflected in section II.A, sponsors that are uncertain of whether their products are constituent parts of a cross-
labeled combination product may contact OCP. 
9 While OCP does not routinely engage on product-specific review matters, as a general matter the office is required 
to:  coordinate inter-center premarket reviews for combination products; oversee their timeliness and the alignment 
of feedback to the sponsor; ensure there is a primary point of contact(s) in the lead center; coordinate 
communications between lead and consulting centers if requested; ensure meetings with the sponsor are attended by 
each center as appropriate; ensure that the consulting center(s) advise as appropriate on relevant regulations, 
guidance, and policies; hear disputes concerning timeliness of premarket review; and consult on disputes regarding 
the substance of premarket review that have been presented to the Commissioner in accordance with the 
requirements of section 503(g)(8)(E)(ii).  See section 503(g)(8) of the FD&C Act.   
10 See Staff Manual Guide 4101, Inter-Center Consult Request Process (June 2018) 
(https://www.fda.gov/downloads/aboutfda/reportsmanualsforms/staffmanualguides/ucm283569.pdf), which 
describes expectations and processes for inter-center consults between the Center for Devices and Radiological 
Health (CDRH), the Center for Drug Evaluation and Research (CDER), and the Center for Biologics Evaluation and 
Research (CBER).  See also Staff Manual Guide 4103, Expectations and Procedures for Engagement among 
Medical Product Centers and Office of Combination Products on Regulations and Guidance Pertaining to 
Combination Products (March 2018) 
(https://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/StaffManualGuides/UCM602810.pdf), for a 
description of the expectations and procedures for engagement of the three centers and OCP for the development 
and clearance of regulations and guidance documents that pertain to combination products. 
 
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  Contains Nonbinding Recommendations 
 
assistance, as needed, in identifying appropriate contact points (including those in the lead 
center), resolving substantive issues, or otherwise facilitating interactions with the Agency and 
collaboration among Agency components.  Center dispute resolution mechanisms are available  
with respect to the substance of such reviews.11   
 
Please note that, under section 503(g)(8)(C)(v), sponsors are required to identify their products 
as combination products in seeking Agency action with respect to the product.  It is important 
that combination products be identified on the appropriate form or document:  Form FDA 1571, 
INVESTIGATIONAL NEW DRUG APPLICATION; Form FDA 356h, APPLICATION TO 
MARKET A NEW OR ABBREVIATED NEW DRUG OR BIOLOGIC FOR HUMAN USE; or 
in the cover letter of a pre-investigational new drug application (IND) submission, 
investigational device exemption (IDE) application, Q-submission, 510(k) submission, 
premarket approval application (PMA), and/or request for classification submitted under section 
513(f)(2) of the FD&C Act (De Novo request).12    
 
 
III.   BASICS OF PREMARKET REGULATION OF COMBINATION PRODUCTS 
 
The regulatory requirements for combination products arise from the statutory and regulatory 
requirements applicable to drugs, devices, and biological products, which retain their discrete 
regulatory identities when they are constituent parts of a combination product.13  At the same 
time, combination products comprise a distinct category of medical products that can be subject 
to specialized regulatory requirements, where appropriate.14  Specialized regulatory requirements 
for combination products generally are designed to address the overlaps and distinctions between 
the statutory and regulatory requirements applicable to the drug, device, and biological product 
constituent parts that comprise them.   
 
Section 503(g)(1)(B) and 503(g)(6) of the FD&C Act provide that FDA shall conduct the 
premarket review of any combination product under a single application, whenever appropriate 
and that a sponsor may choose to submit separate applications for the different constituent parts 
of a combination product unless FDA determines that a single application is necessary.  FDAs 
current thinking is that a single application15 would generally be appropriate for a combination 
product, to streamline regulatory interactions with the Agency and to avoid unnecessary 
 
11 See guidance for industry and review staff Formal Dispute Resolution: Sponsor Appeals Above the Division Level 
(November 2017), guidance for industry and Food and Drug Administration staff Center for Devices and 
Radiological Health (CDRH) Appeals Processes (July 2019), and draft guidance for industry Requests for 
Reconsideration at the Division Level Under GDUFA (October 2017) (when final, this guidance will represent 
FDAs current thinking on this topic). 
12 See guidance for industry and Food and Drug Administration staff Refuse to Accept Policy for 510(k)s (September 
2019), Acceptance Review for De Novo Classification Requests (October 2021), and Acceptance and Filing Reviews 
for Premarket Approval Applications (PMAs) (December 2019). 
13 See combination product current good manufacturing practice and postmarketing safety reporting rules, 78 FR 
4307-22 (2013) (21 CFR part 4, subpart A) and 81 FR 92603-26 (2016) (21 CFR part 4, subpart B). 
14 Ibid. 
15 For purposes of this guidance, unless otherwise stated, the term application includes an NDA, abbreviated new 
drug application (ANDA), PMA, 510(k), De Novo request, or biologics license application (BLA), including a BLA 
submitted under section 351(k) of the PHS Act. 
 
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  Contains Nonbinding Recommendations 
 
duplication that may occur with multiple applications.  However, separate applications would 
generally be permissible for the constituent parts of a cross-labeled combination product; when 
using such an approach applicants should coordinate with both centers (and may request OCP 
assistance), to help enable efficient, timely consideration of issues that may be relevant to each 
constituent part, or both, and to their combined use, including with respect to changes during the 
product lifecycle to either constituent part.  In limited situations, FDA may determine that a 
single application is not appropriate and thus that an application for each constituent part is 
warranted.    
 
The marketing application type submitted should generally coincide with the PMOA of the 
combination product (a PMA, De Novo, or 510(k) for a device-led combination product; an 
NDA or ANDA for a drug-led combination product; or a BLA for a biologic-led combination 
product).  To appropriately ensure the safety and effectiveness of a combination product in a 
single application, such application should enable a substantially similar evaluation to that which 
would be applied to each constituent part if they were reviewed under separate applications (e.g., 
an ANDA or NDA for a drug and a PMA, De Novo, or 510(k) for a device), including 
consideration of data and information that would be reviewed under the separate applications.  If 
one type of application coinciding with the PMOA of the combination product (PMOA-based 
application type), e.g., an ANDA, does not enable such an evaluation for each constituent part, 
the combination product should typically be reviewed in a different application type, e.g., an 
NDA, that still coincides with the PMOA of the combination product.16  In limited cases, FDA 
has determined that the product should be reviewed under an application type associated with the 
statutory authorities applicable to the non-lead constituent part.17  If a sponsor believes a 
particular application type is appropriate for other reasons, it should discuss with FDA.     
 
Further, in determining what is needed to demonstrate the safety and effectiveness of the 
combination product, FDA takes into account the questions and considerations, reflected in the 
statutory and regulatory provisions associated with each constituent part in its review of the 
combination product as a whole and its constituent parts.  This includes how the constituent parts 
 
16 For example, if an independent showing of safety and effectiveness would be needed for any constituent part then 
510(k) would likely not be appropriate.  Please refer to the annex of this document and page 7 of the guidance for 
industry and Food and Drug Administration staff The 510(k) Program: Evaluating Substantial Equivalence in 
Premarket Notifications [510(k)] (July 2014). 
17 See, for example, the guidance for industry Questions and Answers on Biosimilar Development and the BPCI Act 
(Biosimilars Q&A Guidance) (September 2021), which discusses regulatory clarity and consistency considerations 
for why a BLA would be the more appropriate application type for antibody-drug conjugates, a type of drug-
biologic combination product that is assigned to CDER regardless of the PMOA of the combination product.  In this 
case, due to factors that included the relative significance of the safety and effectiveness questions raised by the 
constituent parts, particularly the highly specific molecular targeting by the antibody to a cell type, cellular 
component, or other marker at the site of action (as distinguished from mere alteration of systemic PK 
[pharmacokinetics]), the Agency determined that a BLA was a more appropriate pathway to evaluate this type of 
combination product.  In certain scenarios, similar considerations might arise when determining the appropriate 
application type for other combination products such as those containing certain biologics (e.g., blood products and 
products composed of or containing live cells or microorganisms).  In other cases, incorporation of a biological 
product component that is already licensed under section 351 of the PHS Act into the combination product is likely 
to be the most effective way to facilitate a substantially similar evaluation of a non-lead biological product 
constituent part.   
 
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  Contains Nonbinding Recommendations 
 
may interact and interrelate.  For example, for a device-led combination product reviewed in an 
appropriate device application that includes a drug constituent part (that would otherwise be 
reviewed in an NDA), nonclinical pharmacology and toxicology and clinical pharmacology 
(including pharmacokinetic) data and chemistry, manufacturing, and controls (CMC) 
information are among the types of information that would typically be necessary.  Similarly, for 
a combination product that is not biologic-led and includes a biological product constituent part, 
certain information, including regarding the identity of the biological product constituent part, 
and indicating compliance with donor eligibility or lot release requirements, where applicable, 
would typically be necessary.18  Likewise, for a combination product that is not device-led and 
includes a device constituent part, engineering, biocompatibility, performance data, and other 
design validation data would typically be necessary.  Regardless of which center may have the 
lead and which application type may be appropriate, consistent with section 503(g) of the FD&C 
Act, FDA is committed to applying a consistent, risk-based approach to address similar 
regulatory questions, including scientific questions, similarly, utilizing relevant expertise from 
the lead and consulted centers.19   
 
It bears noting that the data and information needed to address safety and effectiveness questions 
related to the non-lead constituent part of a combination product may differ from the data and 
information needed to obtain marketing authorization for that article as a stand-alone product 
that is not part of a combination product.  For example, a drug may be coated on a device to 
mitigate undesired local physiological responses associated with the implantation procedures or 
the use of the product.  Examples of this may include an anti-inflammatory drug on a cardiac 
lead to reduce inflammation at the implantation site or an anti-coagulant bound to the inner-
lumen of a catheter to prevent clot formation within the catheter thereby maintaining catheter 
patency.  Given their role in supporting the function of the device, these drug coatings often 
involve a lower dose and/or primarily local, rather than systemic, exposure to a drug as 
compared to what it is otherwise approved for a stand-alone drug product.  As such, there may be 
differing conditions of use for the drug due to the intended use in the context of the combination 
product that may raise different safety and effectiveness concerns.   
 
 
18 As additional examples in the case of a drug or device-led combination product that includes a biological product 
constituent part, commercial scale process validation data, information sufficient to enable FDA to conduct pre-
approval inspections of the proposed commercial product during manufacturing operations, and information 
demonstrating that the applicant has knowledge of and direct control over the manufacturing process for the 
biological product constituent part (rather than by reference to a drug or device master file) if the biological product 
constituent part is not licensed for that use, typically would be necessary to include in a marketing application to 
support a determination that the combination product is safe and effective.  Please note that the examples provided 
in this guidance are not an exhaustive list.  Failure to provide this information may result in FDA refusing to file the 
marketing application.   
19 The Food and Drug Administration Modernization Act of 1997 and subsequent statutory amendments by the Food 
and Drug Administration Safety and Innovation Act and the Cures Act directed FDA to take a least burdensome 
approach to medical device premarket evaluation.  The least burdensome concept and Agency guidance interpreting 
this concept, accordingly, also apply to device constituent parts of combination products.  See the guidance for 
industry and Food and Drug Administration staff The Least Burdensome Provisions:  Concept and Principles 
(February 2019).  While the statutory least burdensome expectation does not apply to drugs or biological products, 
FDA is committed to the principle of avoiding unnecessary regulatory burden for all medical products including 
combination products.   
 
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  Contains Nonbinding Recommendations 
 
The premarket review of a combination product can be significantly streamlined in instances 
where its sponsor is legally authorized to rely on FDAs finding of safety and/or effectiveness or 
substantial equivalence with respect to a previously approved or cleared combination product or 
constituent part, or where the sponsor has a right of reference for another sponsors data.20  For a 
device-led, device-drug combination product containing an approved drug (as defined in section 
503(g)(5)(B) of the FD&C Act21), reliance on FDAs finding of safety and/or effectiveness for 
the approved drug is permissible in a device application, when scientifically appropriate, subject 
to the provisions of section 503(g)(5), as added by the Cures Act.22  A similar approach applies 
for drug-led combination products where the sponsor has a right of reference to the data upon 
which a device or device-led combination product was cleared or approved.  In such 
circumstances, FDA generally should only require additional data and information as may be 
needed to address additional questions of safety or effectiveness raised by the proposed use or 
function of the device in the combination product, if any.23     
 
 
IV.      PATHWAY AVAILABILITY AND RELATED CONSIDERATIONS 
 
This section discusses pathways available for combination products based on their PMOA, and 
considerations for making such pathway determinations. 
 
A.  Device-Led Combination Products 
 
As discussed above, Cures Act section 3038 addressed various aspects of the regulation of 
combination products.  Among other matters, the legislation reflects and clarifies the availability  
 
 
20 Master files may be useful tools when several applications are submitted for different products which use a 
common material, process, etc., such as a platform delivery device, to help preserve the trade secrets of a third party 
such as a supplier or facility.  Please note that the adequacy of relevant information contained in master files to 
support safety and effectiveness is considered only in the context of a specific marketing application referencing 
such files.  For more information on biologics, device, and drug master files, see CBERs Master Files for CBER-
Regulated Products web page (available at https://www.fda.gov/vaccines-blood-biologics/development-approval-
process-cber/master-files-cber-regulated-products, CDRHs Master Files web page (available at 
https://www.fda.gov/medical-devices/premarket-approval-pma/master-files), and CDERs Drug Master Files (DMF) 
web page (available at https://www.fda.gov/drugs/forms-submission-requirements/drug-master-files-dmfs), 
respectively, and FDAs proposed rule on Biologics License Applications and Master Files (84 FR 30968, June 28, 
2019).   
21 In relevant part, the definition states that approved drug means an active ingredient that was in an application 
previously approved under section 505(c)...relied upon by the applicant [for the combination product]. 
22 See also section 520(h)(4) of the FD&C Act regarding permissibility of using information from an approved 
PMA. 
23 For additional information regarding data requirements when adding or changing a constituent part of a 
combination product and the bridging mechanisms that may be available to leverage relevant existing data, see the 
draft guidance for industry Bridging for Drug-Device and Biologic-Device Combination Products (December 2019).  
When final, this guidance will represent FDAs current thinking on this topic. 
 
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of the PMA, De Novo classification, and 510(k) pathways for device-led combination 
products.24  This discussion and the annex are intended to clarify Agency thinking on the 
availability of PMA, De Novo, and 510(k) pathways for device-led combination products, in 
light of Cures Act section 3038. 
 
1.  Premarket Approval Applications (PMA) 
 
PMA approval is required by FDA before devices that are class III25 can be legally marketed.26  
PMA approval is based on a determination by FDA that the PMA contains sufficient valid 
scientific evidence to reasonably assure that the device or device-led combination product is safe 
and effective for its intended use(s).27  Sponsors should ensure that PMA applications for device-
led combination products contain sufficient data to demonstrate the safety and effectiveness of 
the combination product as a whole, including data regarding all constituent part(s).  The PMA 
includes sections containing, among other things, technical data, non-clinical laboratory studies, 
and clinical investigations.28  Before approving or denying a PMA, the appropriate FDA 
advisory committee29 may review the PMA at a public meeting and provide FDA with the 
committees recommendation on whether FDA should approve the submission.30   
 
2.  De Novo Classification Requests  
 
Devices of a new type that FDA has not previously classified or reclassified based on the criteria 
in section 513(a)(1) of the FD&C Act are automatically classified into class III by operation of 
section 513(f)(1) of the FD&C Act, and may be classified into class I or class II under the De 
Novo classification process.   
 
24 While beyond the scope of this guidance, section 3038 also included amendments to section 503(g) of the FD&C 
Act to subject device-led combination products to certain exclusivity and patent-related provisions applicable to new 
drug applications pursuant to section 505(b)(2) of the FD&C Act.  See section 503(g)(5).  For more information 
regarding these requirements see the guidance for industry and Food and Drug Administration staff Refuse to Accept 
Policy for 510(k)s and Acceptance and Filing Reviews for Premarket Approval Applications (PMAs). 
25 Class III devices are devices (1) for which there is insufficient information to determine that general controls and 
special controls are sufficient to provide reasonable assurance of safety and effectiveness, and (2) which are 
purported or represented to be for a use in supporting or sustaining human life or for a use which is of substantial 
importance in preventing impairment of human health, or which present a potential unreasonable risk of illness or 
injury (see section 513(a)(1)(C) of the FD&C Act). 
26 See section 515 of the FD&C Act.   
27 For FDA to approve a PMA, there must be a reasonable assurance of safety and effectiveness.  See section 
515(d)(2)(A) and (B) of the FD&C Act.  Effectiveness is determined on the basis of well-controlled investigations, 
including one or more clinical investigations, where appropriate, unless FDA determines there exists other valid 
scientific evidence sufficient to determine effectiveness, from which it can fairly and responsibly be concluded by 
qualified experts that the product will have the effect it purports or is represented to have under the conditions of use 
prescribed, recommended, or suggested in the labeling.  Section 513(a)(3) of the FD&C Act.   
28 See 21 CFR 814.20.  
29 For more information see the guidance for industry and Food and Drug Administration staff Procedures for 
Meetings of the Medical Devices Advisory Committee (September 2017). 
30 See 21 CFR 814.44. 
 
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If a sponsor believes its product is appropriate for classification into class I31 or class II,32 it may 
submit a request for De Novo classification.33  If the sponsor demonstrates that the criteria in 
section 513(a)(1)(A) or (B) of the FD&C Act are met, FDA grants the request for De Novo 
classification and issues a written order classifying the specific product and product type in class 
I or class II.  If the product is classified as class II, it is granted marketing authorization subject 
to general controls, as well as identified special controls which provide a reasonable assurance of 
safety and effectiveness.34  Such a product may serve as a legally marketed (predicate)35 product 
for future 510(k) submissions.  If the product cannot be classified as class I or II, the De Novo 
request is declined and the product remains in class III and subject to PMA approval.  
  
Special controls set forth criteria for class II products that are necessary to provide the assurance 
of safety and effectiveness to justify classification in class II.  To be class II by being within the 
same type as the product that was the subject of the De Novo, future products must be found 
substantially equivalent and comply with general controls and applicable special controls for the 
product type; a failure to comply with special controls will cause the product to be class III and 
subject to PMA approval.36  
 
A sponsor may request De Novo classification without submitting a 510(k) first; FDA may 
decline to undertake such request if FDA identifies a predicate product that could provide a 
reasonable basis for review of substantial equivalence, or if FDA determines either that the 
product submitted is not of low to moderate risk or that general controls would be inadequate to 
control the risks and special controls to mitigate the risks cannot be developed.37  Among other 
considerations, understanding of the biological product or drug constituent parts, including 
limitations of such understanding, need to be considered when determining the suitability of the 
De Novo pathway for such device-led combination products.  Because certain products present 
unique concerns (such as, for certain biological products,38 considerations associated with 
infectious disease transmission and challenges associated with ensuring reproducibility of such 
 
31 Class I products are subject to a set of regulatory authorities called general controls (see section 513(a)(1)(A) of 
the FD&C Act).  General controls include, but are not limited to, provisions that relate to establishment registration 
and listing, premarket notification, prohibitions against adulteration and misbranding, records and reports, and good 
manufacturing practices.   
32 Class II products are products for which general controls, by themselves, are insufficient to provide reasonable 
assurance of the safety and effectiveness of the product, and for which there is sufficient information to establish 
special controls necessary to provide such assurance (see section 513(a)(1)(B) of the FD&C Act).  Special controls 
are product type-specific and may include promulgation of performance standards, requirements for postmarket 
surveillance, patient registries, labeling, and performance testing and clinical/non-clinical data.   
33 See section 513(f)(2) of the FD&C Act and 21 CFR part 860, subpart D (86 FR 54826, October 5, 2021).  See also 
the guidance for industry and Food and Drug Administration staff De Novo Classification Process (Evaluation of 
Automatic Class III Designation) (October 2021).   
34 Such special controls will generally be established through consultation and alignment with the non-lead center. 
35 A legally marketed (predicate) device to which a new device may be compared for a determination regarding 
substantial equivalence is a device that was legally marketed prior to May 28, 1976, or a device which has been 
reclassified from class III to class II or I, or a device which has been found to be substantially equivalent through the 
510(k) premarket notification process (see 21 CFR 807.92(a)(3)). 
36 See sections 513(a)(1)(B), 513(f)(1), 513(i), and 515(a)(2) of the FD&C Act; S. REP. NO. 105-43 at 35 (1997). 
37 See section 513(f)(2)(A)(ii) and (iv) of the FD&C Act. 
38 For example, blood, gene therapies, or human cellular or tissue products. 
 
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biological products), management of such concerns should be considered in determining the 
suitability of the De Novo pathway.  
 
See annex for illustrative examples on how these principles can be applied. 
 
3.  Premarket Notification (510(k)) Submissions 
 
The 510(k) review standard (substantial equivalence of a new product to a predicate product) 
differs from the PMA and De Novo review standards.  The 510(k) review standard is 
comparative, whereas the PMA and De Novo review standards rely on an independent 
demonstration of safety and effectiveness.  Nonetheless, the principles of safety and 
effectiveness underlie the substantial equivalence determination in every 510(k) review.     
 
The standard for a determination of substantial equivalence in a 510(k) review is set out in 
section 513(i) of the FD&C Act.  A product is substantially equivalent to a predicate product if 
it:  
 
  has the same intended use as the predicate product; and 
 
  has the same technological characteristics as the predicate product; 
 
or 
 
  has the same intended use as the predicate product;  
 
  has different technological characteristics39; and 
  
  the information submitted to FDA, including appropriate clinical or scientific data if 
deemed necessary, demonstrates that the product: 
 
-  does not raise different questions of safety and effectiveness than the predicate 
product; and 
 
-  demonstrates that the product is as safe and effective as the predicate product.40   
 
FDA considers the products relative safety and effectiveness in the substantial equivalence 
determination, and safety and effectiveness considerations are also critical to the Agencys 
evaluation of compliance with any applicable special controls, all of which FDA has determined 
to be necessary to provide a reasonable assurance of safety and effectiveness for the product 
type.   
 
39 Different technological characteristics are defined as significant change in the materials, design, energy source, 
or other features from the predicate.  Section 513(i)(1)(B) of the FD&C Act and 21 CFR 807.100(b)(2)(ii)(A). 
40 See section 513(i)(1)(A) of the FD&C Act; 21 CFR 807.100(b).  See also the guidance for industry and Food and 
Drug Administration staff The 510(k) Program: Evaluating Substantial Equivalence in Premarket Notifications 
[510(k)].     
 
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The following products cannot be cleared in a 510(k) submission: 
 
  Product with a new intended use as compared to the predicate product 
 
  Product with different technological characteristics than the predicate product if such 
differences raise different questions of safety and effectiveness than the predicate 
product.41   
 
Generally, a device that is not combined with a drug or biological product constituent part could 
not be successfully used as a predicate for a 510(k) for a device-led combination product.  This is 
because the addition of the drug or biological product constituent part would likely result in a 
new intended use and/or constitute a different technological characteristic that raises different 
questions of safety and effectiveness as compared to the predicate.  In addition, a product with a 
different active ingredient from a predicate would differ significantly in features such as design 
and materials, which would likely raise different questions of safety and effectiveness as well. 42 
 
See annex for illustrative examples on how these principles can be applied. 
 
B.  Drug-Led Combination Products 
 
An NDA or ANDA is generally the appropriate marketing authorization pathway for a drug-led 
combination product.  This discussion outlines current Agency thinking on the availability of the 
NDA and ANDA pathways to obtain marketing authorization for drug-led combination products. 
 
1.  New Drug Application (NDA) 
 
An NDA is generally the appropriate pathway for drug-led combination products other than 
generic versions of already-approved drug-led combination products.  An NDA for a drug-led 
combination product must contain, among other things, a demonstration of the safety and 
effectiveness of the product for the conditions prescribed, recommended, or suggested in the 
proposed labeling. 
   
There are two types of NDAs described in section 505 of the FD&C Act.  A 505(b)(1) 
application, also known as a stand-alone NDA, contains full reports of investigations of safety 
and effectiveness that were conducted by or for the applicant or for which the applicant has a 
right of reference or use.  A 505(b)(2) application also contains full reports of investigations of 
safety and effectiveness, but at least some of the safety or effectiveness information required for 
approval comes from studies not conducted by or for the applicant and for which the applicant 
has not obtained a right of reference or use.43  Section 505(b)(2) permits reliance on FDAs 
 
41 Ibid. 
42 In certain instances, it may be possible for special controls to specify multiple specific active ingredients or an 
active ingredient class, provided general and special controls are sufficient to provide a reasonable assurance of 
safety and effectiveness for the product.   
43 See the draft guidance for industry Applications Covered by Section 505(b)(2) (October 1999).  When final, this 
guidance will represent FDAs current thinking on this topic.  
 
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finding of safety and/or effectiveness for an approved drug product (or an approved drug-led 
combination product), as well as on published literature.  The 505(b)(2) pathway should not be 
used to obtain approval of duplicates of existing drug-led combination products that are eligible 
for approval under section 505(j) of the FD&C Act (see next section) (see 21 CFR 
314.101(d)(9)).  Both 505(b)(1) and 505(b)(2) applications are submitted under section 505(b)(1) 
and approved under section 505(c) of the FD&C Act. 
 
By way of example, a 505(b)(1) application may be appropriate for a drug-led combination 
product that contains a new molecular entity, such as a novel corticosteroid for treatment of 
asthma delivered via inhalation.  The drug-device combination product may, for example, be an 
inhalation aerosol (also known as a metered dose inhaler (MDI) or inhalation powder (also 
known as a dry powder inhaler (DPI)).  These products consist of a drug formulation and a 
container closure system that includes, or is, a device constituent part.  A 505(b)(2) application 
may be appropriate, however, if, for example, the corticosteroid has already been approved as an 
oral tablet and the sponsor seeks to rely upon FDAs finding of safety and/or effectiveness for 
the tablet dosage form in seeking approval of a drug-device combination product (MDI or DPI 
consisting of the drug formulation containing the corticosteroid and the container closure system 
that includes, or is, the device constituent part), provided that the 505(b)(2) applicant establishes 
a scientific bridge to demonstrate that the extent of reliance on the oral tablet product is 
scientifically appropriate, any differences between the proposed and relied upon products are 
otherwise supported, and the applicant complies with additional requirements, including but not 
limited to requirements related to patent certification described in section 505(b)(2)&(3) of the 
FD&C Act.44  A 505(b)(2) applicant could also rely, in part, upon FDAs NDA approval of a 
drug-device combination product containing the corticosteroid indicated for treatment of asthma 
as one source of support for approval of a drug-device combination product containing the same 
corticosteroid for treatment of chronic obstructive pulmonary disease.  Again, the 505(b)(2) 
applicant would need to establish a scientific bridge to demonstrate that reliance is appropriate, 
would need to submit data to support differences between the products, and would need to 
comply with requirements for a 505(b)(2) application (including but not limited to requirements 
related to patent certification).45 
 
2.  Abbreviated New Drug Application (ANDA) 
 
An ANDA is generally the appropriate pathway for a drug-led combination product that has the 
same active ingredient(s), dosage form, strength, route of administration, conditions of use, and 
(with certain permissible differences) labeling as a product (i.e., a reference listed drug46 (RLD)) 
previously approved under section 505(c) of the FD&C Act.47  In addition to the above, an  
 
44 In addition, approval of the 505(b)(2) application might be delayed because of exclusivity or patent protections for 
a listed drug.   
45 Ibid. 
46 21 CFR 314.3(b).  RLDs are identified in FDAs Approved Drug Products With Therapeutic Equivalence 
Evaluations, generally known as the Orange Book, available at https://www.accessdata.fda.gov/scripts/cder/ob/.   
47 See generally sections 505(j)(2)(A) and 505(j)(4) of the FD&C Act and 21 CFR 314.94 and 314.127.   
 
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ANDA must also include sufficient information to demonstrate that the proposed product is 
bioequivalent48 to the RLD, and to ensure the products identity, strength, quality, and purity.  To 
obtain approval, an ANDA applicant is not required to provide independent evidence to establish 
the safety and effectiveness of the proposed product; instead, an ANDA relies on FDAs finding 
that the RLD is safe and effective.  
   
ANDAs for drug-led combination products should include sufficient information to demonstrate 
that the non-lead constituent part is compatible for use with the final formulation of the drug 
constituent part.  Potential applicants should refer to relevant FDA guidance documents and 
other sources that provide information on what data and information should be included to 
support a device constituent part(s) of a proposed generic combination product (e.g., information 
analyzing the proposed user interface for a generic drug-device combination product when 
compared to the user interface for the RLD).49  
 
As a general matter, in assessing the therapeutic equivalence of a proposed generic drug-device 
combination product, FDA intends to consider whether the proposed generic product can be 
expected to have the same clinical effect and safety profile as the RLD when administered to 
patients under the conditions specified in the labeling.50  While FDA does not expect the 
proposed generic combination product and its RLD to be identical in all respects, any differences 
identified between a proposed generic combination product and its RLD should be adequately 
analyzed, scientifically justified, and otherwise not preclude approval under an ANDA.  The 
extent to which differences between the proposed generic combination product and the RLD 
affect the approvability of the ANDA product will be evaluated on a case-by-case basis. 
 
C.  Biologic-Led Combination Products 
 
Biologic-led combination products are licensed through one of the two BLA pathways under 
section 351 of the Public Health Service Act (PHS Act), either under a section 351(a) BLA (i.e.,  
 
 
 
 
 
 
 
 
48 Bioequivalence means the absence of a significant difference in the rate and extent to which the active ingredient 
or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug 
action when administered at the same molar dose under similar conditions in an appropriately designed study.  See 
21 CFR 314.3(b). 
49 See the draft guidance for industry Comparative Analyses and Related Comparative Use Human Factors Studies 
for a Drug-Device Combination Product Submitted in an ANDA (January 2017).  When final, this guidance will 
represent FDAs current thinking on this topic.  
50 See 21 CFR 314.3.  See also the Orange Book, preface to the 41st edition, at page vii. 
 
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a stand-alone BLA) or under a section 351(k) BLA for a biosimilar or interchangeable 
biological product.51     
 
1.  Biologics License Applications (BLAs) Submitted Under Section 351(a) 
 
To be licensed, a biological product must be shown to be safe, pure, and potent, and the facility 
in which the biological product is manufactured, processed, packed, or held must meet standards 
designed to ensure that the biological product continues to be safe, pure, and potent.52  A BLA 
submitted under section 351(a) of the PHS Act is a stand-alone application in that all of the 
information and data necessary to demonstrate that these requirements are met are included in 
the application.  This pathway is generally appropriate for biologic-led combination products 
other than products that are proposed to be biosimilar to, or interchangeable with, a previously 
licensed biological product.53 
 
For example, this pathway would be appropriate for the following products when the sponsor is 
not seeking to rely on FDAs licensure of another biological product in order to demonstrate 
biosimilarity to, or interchangeability with, such product: 
 
  a gene therapy combined with a specialized delivery catheter 
 
  a vaccine in a pre-filled syringe  
 
  a protein product in an autoinjector 
 
2.  BLAs for Biosimilar and Interchangeable Biological Products Submitted Under 
Section 351(k) 
 
 
51 Some protein products historically have been approved under section 505 of the FD&C Act.  On March 23, 2010, 
the Biologics Price Competition and Innovation Act of 2009 (BPCI Act) was enacted as part of the Patient 
Protection and Affordable Care Act (Public Law 111-148).  The BPCI Act amended the statutory definition of 
biological product in section 351(i) of the PHS Act to include a protein (except any chemically synthesized 
polypeptide) and described procedures for submission of a marketing application for certain biological products.  
On December 20, 2019, the Further Consolidated Appropriations Act, 2020 (Public Law 116-94), further amended 
the statutory definition of biological product in section 351(i) of the PHS Act to remove the parenthetical (except 
any chemically synthesized polypeptide) from the statutory category of protein.  On March 23, 2020, the Agency 
codified its interpretation of the statutory term protein in 21 CFR 600.3(h)(6) (85 FR 10057).  The BPCI Act also 
required that a marketing application for a biological product (that previously could have been submitted under 
section 505 of the FD&C Act) must be submitted under section 351 of the PHS Act starting March 23, 2010, subject 
to certain exceptions during a 10-year transition period ending on March 23, 2020.  As of March 23, 2020, all 
approved applications for biological products under section 505 of the FD&C Act were deemed to be licenses for 
the biological products (i.e., approved BLAs) under section 351 of the PHS Act.  As of March 23, 2020, all sponsors 
seeking approval of a biological product that previously could have been submitted under section 505 of the FD&C 
Act must submit a marketing application under section 351 of the PHS Act.  For additional information, see the 
guidance for industry Interpretation of the Deemed to be a License Provision of the Biologics Price Competition 
and Innovation Act of 2009 (December 2018). 
52 Section 351(a)(2)(C) of the PHS Act. 
53 See footnote 17. 
 
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Section 351(k) of the PHS Act sets forth the requirements for the licensure of biological products 
shown to be biosimilar to, or interchangeable with, an FDA-licensed biological reference 
product.54  Section 351(i)(2) of the PHS Act defines biosimilarity to mean that the product is 
highly similar to the reference product notwithstanding minor differences in clinically inactive 
components and that there are no clinically meaningful differences between the two products 
with respect to safety, purity, and potency.  To meet the interchangeability standard, an applicant 
must show that its product is biosimilar to the reference product, and must further show that 
the product can be expected to produce the same clinical result as the reference product in any 
given patient and that, for a product that is administered more than once to an individual, the 
risk in terms of safety or diminished efficacy of alternating or switching between use of the [two 
products] is not greater than the risk of using the reference product without such alternation or 
switch.55  Interchangeable products may be substituted for the reference product without the 
intervention of the prescribing healthcare provider (see section 351(i)(3) of the PHS Act). 
 
FDA has published guidance indicating the availability of this abbreviated pathway for 
combination products, as well as considerations related to demonstrating biosimilarity or 
interchangeability of such products.  With respect to demonstrating biosimilarity, Q.I.4 of the 
guidance for industry Questions and Answers on Biosimilar Development and the BPCI Act 
(Biosimilars Q&A Guidance) states that some design differences in the delivery device used with 
the proposed biosimilar product may be permissible, and explains that it may be possible to 
obtain licensure of a proposed biosimilar product in a pre-filled syringe or auto-injector, for 
example, even though the reference product is a biological product licensed in a vial 
presentation, provided that the proposed biosimilar product meets the statutory standard for 
biosimilarity.   
 
The Biosimilars Q&A Guidance also explains that licensure under section 351(k) would not be 
possible if design difference in a delivery device results in any of the following: 
 
  A clinically meaningful difference between the proposed product and the reference 
product in terms of safety, purity, and potency;  
 
  A different route of administration;   
 
  A condition of use (e.g., indication, dosing regimen) for which the reference product has 
not been previously approved; or  
 
  A proposed biosimilar product that otherwise does not meet the standard for 
biosimilarity. 
 
See Biosimilars Q&A Guidance for considerations for seeking licensure of a combination 
product as biosimilar to, or interchangeable with, a reference product.  
 
54 Section 351(i)(4) of the PHS Act. 
55 Section 351(k)(4) of the PHS Act. 
 
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ANNEX 
Analysis of Pathway Availability for Device-Led Combination Products   
Illustrative Examples 
 
To date, questions regarding pathway availability for combination products have focused most 
often on device-led combination products.  Accordingly, we have included this annex to address 
common questions utilizing the analyses discussed in section IV.A.  The outcomes are also 
consistent with the expectations discussed in section III, that the application enable evaluation 
substantially similar to that which would occur if the constituent parts were reviewed under 
separate applications for the use.   
 
These hypothetical examples are not intended to reflect a complete analysis of the premarket 
review considerations that need to be addressed for the types of products discussed in the 
examples or other types of combination products.  In addition, specific products may raise 
distinct issues that are not taken into account in the examples below.  If manufacturers have  
specific questions relating to their particular products, the Agency recommends that they contact 
the lead center for the product or OCP, as needed, for assistance.   
 
For the purposes of the illustrative examples below, it is assumed that the sponsor submitted a 
510(k) to CDRH for the combination product.  
   
 
Example 1:  Antimicrobial coating added for the first time to a previously classified device type  
 
Predicate Product:  A previously classified hypothetical class II device (product has no drug or 
biological product constituent part), which is subject to 510(k) requirements (e.g., an externally-
communicating device intended to be implanted in the abdominal cavity for drainage of 
excessive fluids). 
 
Drug Constituent Part:  A hypothetical antimicrobial coating (Antimicrobial A) that contains 
the same active ingredient that is in an NDA drug product approved for intravenous 
administration that has a well-established and understood risk profile as an antimicrobial 
indicated for the treatment of acute bacterial skin and skin structure infections.  The sponsor has 
provided FDA documentation of a right of reference to the NDA.56 
 
New Product:  The sponsor proposes to add an antimicrobial coating (Antimicrobial A) to the 
predicate product described above, making a single-entity combination product (hereinafter 
referred to as Product A).  The purpose of adding the antimicrobial to this device is to prevent 
infections associated with the surgical procedure and continued use of the product.  The sponsor 
requests the product be considered substantially equivalent to the previously cleared uncoated 
version of the device.  An antimicrobial drug product has never been combined with this device 
 
56 Alternatively, the sponsor could rely on FDAs finding of safety and/or effectiveness for the NDA approved 
antimicrobial product, provided all of the requirements of 503(g)(5)(A) and (C) are satisfied and it is scientifically 
justified.  FDA may then consider such findings in its review of a device premarket submission. 
 
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type.  To make a substantial equivalence determination, the following questions are generally 
asked: 
 
1.  Is the predicate product legally marketed?  Yes. 
 
2.  Does the predicate product have the same intended use?  While both the predicate and 
the new combination product are intended to drain excessive fluid from the abdominal 
cavity, the addition of the proposed drug constituent part and the indication of preventing 
infection are not applicable to the predicate product.  These changes raise different 
questions of safety and effectiveness, precluding a meaningful comparison with the 
predicate product.57  Therefore, these changes in indications for use of the product and of 
adding the constituent part would result in a new intended use, and the product would be 
found not substantially equivalent (NSE).  Also, the addition of Antimicrobial A is a 
different technological characteristic that would raise different questions of safety and 
effectiveness. 
 
Further, in this case the 510(k) pathway would not allow for an evaluation substantially similar 
to that which would be applied to the drug constituent part under a separate application (see 
section III).  Specifically, comparison of the new product to the predicate would not allow for a 
sufficient demonstration of the safety and effectiveness of the drug constituent part for its 
proposed new conditions of use  the combination of the new drug indication, route of 
administration, and the combined use of the drug with the device.   
 
Depending on its ability to meet the criteria in section 513(a)(1)(A) or (B) and 513(f)(2) of the 
FD&C Act, the product may be a suitable candidate for the De Novo process.  In determining 
whether to grant a request for De Novo classification, because the sponsor in this example has a 
right of reference to the data in the drug sponsors NDA, FDA would consider this data in its 
review of the De Novo request.58  See discussion in section III.  If the product does not meet the 
requirements for De Novo classification, a PMA would be required.   
 
For purposes of this illustrative example, it is assumed that the sponsor demonstrates that the 
criteria in section 513(a)(1)(B) (class II) of the FD&C Act are met.  Accordingly, FDA has 
determined that the safety and effectiveness of Product A can be reasonably assured by a 
combination of general and special controls, and Product A is granted marketing authorization.   
 
Further, in this case, the De Novo pathway, including the NDA data incorporated in the 
submission via the right of reference, permits an evaluation substantially similar to that which 
would be applied to the drug constituent part under a separate application (see section III).59  
Specifically, a demonstration that general and special controls provide a reasonable assurance of 
 
57 See 21 CFR 807.92(a)(5) and the guidance for industry and Food and Drug Administration staff The 510(k) 
Program: Evaluating Substantial Equivalence in Premarket Notifications [510(k)]. 
58 If the applicant were able to rely upon findings of safety and effectiveness supporting the NDA approval, to the 
extent scientifically justified and subject to the requirements of section 503(g)(5), FDA could consider them in 
determining whether to grant the De Novo. 
59 Ibid. 
 
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safety and effectiveness is sufficient to demonstrate the safety and effectiveness of the change to 
the drug.    
 
The classification regulation regarding Product A identifies the drug constituent part as being 
limited to Antimicrobial A.  Table 1 below shows an illustrative example of identified risks and 
potential mitigation measures and special controls for each risk for Product A and follow-on 
combination products seeking to use Product A as a predicate for the same intended use. 
 
Table 1  Identified Risks and Potential Mitigations for Product A   
Identified Risks  Potential Mitigation Measures  Potential Special Controls 
Toxicity     Biocompatibility evaluation    Clinical data must demonstrate lack of unreasonable risk of 
  Animal performance testing/study  illness or injury associated with the use of the product 
information   under anticipated conditions of use. 
  Clinical data    In vivo (animal) evaluation60 must demonstrate lack of 
  Labeling   unreasonable risk of illness or injury associated with the 
  Post-market surveillance (e.g.,  use of the product under anticipated conditions of use. 
evaluate potential drug-related    Labeling must include:  
toxicity in a broader population)  -  Information on the patient population for which the 
combination product has been demonstrated to be 
effective. 
-  A detailed summary of the non-clinical and/or clinical 
testing pertinent to use of the combination product. 
-  A detailed summary of the product- and procedure-
related adverse events pertinent to use of the 
combination product.   
  Post-market surveillance (PMS) must be conducted and 
completed in accordance with FDA-agreed-upon PMS 
protocol.  
Inability to prevent    Clinical data on effectiveness    Clinical data must demonstrate ability to prevent infection 
infection     Animal study information  for its anticipated conditions of use.   
  Non-clinical bench performance    In vivo (animal) evaluation must demonstrate ability to 
testing (e.g., assays)  prevent infection for its anticipated conditions of use.  
  Labeling    Assays must demonstrate antibacterial activity of the 
product. 
  Same labeling special controls as outlined above. 
Product    Technical    The technical specifications of the combination product 
failure/malfunction  specifications/technological  must include [specific parameters for a particular product], 
characteristics   to ensure the combination product retains appropriate 
  Chemistry  performance characteristics. 
  Stability    Drug constituent part and drug-device finished combination 
    product characterization must be included. 
  Validated protocols must be provided and demonstrate 
ability to establish technical specifications. 
  Performance data must support the stability of the product 
by demonstrating continued functionality over the 
identified shelf life.  
 
 
60 We encourage sponsors to consult with us if they wish to use a non-animal testing method they believe is suitable, 
adequate, validated, and feasible.  We will consider whether such an alternative method could be assessed for 
equivalency to an animal test method. 
 
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Example 2:  New drug indication added  
 
Predicate Product:  Product A described above, which was granted a De Novo classification.  
 
Drug Constituent Part:  The same drug constituent part as in Product A.  The sponsor has 
provided FDA documentation of a right of reference to the NDA.  
 
New Product:  The sponsor subsequently proposes to add a new anti-inflammatory indication to 
the labeling of Product A, due to the pharmacological properties of the drug constituent part.  
The intent is not only to maintain the previously supported use regarding the products 
antimicrobial properties, but to also demonstrate an increase in its overall performance by 
reducing inflammation in the host environment following implantation.  
 
1.  Is the predicate product legally marketed?  Yes. 
 
2.  Does the predicate product have the same intended use?  No.  While both products are 
intended to drain excessive interstitial fluid from the abdominal cavity, the new anti-
inflammatory indication and the associated labeling regarding reducing inflammation 
were not applicable to the predicate product.  These changes raise different questions of 
safety and effectiveness, precluding a meaningful comparison with the predicate product.  
Therefore, these changes in indications for use of the product and of the constituent part 
would result in a new intended use, and the product would be found NSE. 
 
Further, in this case, the 510(k) pathway would not allow for an evaluation substantially similar 
to that which would be applied to the drug constituent part under a separate application (see 
section III).  Specifically, comparison of the new product to the predicate (Product A) would not 
allow for a sufficient demonstration of the safety and effectiveness of the drug constituent part 
for the proposed new drug indication.   
 
The proposed product would require an approved PMA before it could be legally marketed. 
Alternatively, the product may be suitable for a new De Novo classification. 
 
 
Example 3:  Different method of drug coating  
 
Predicate Product:  Product A described above, which was granted a De Novo classification.  
 
Drug Constituent Part:  The same drug constituent part as Product A.  The sponsor has 
provided FDA documentation of a right of reference to the NDA.  
 
New Product:  The sponsor proposes to modify Product A by altering the method of drug 
coating by using a polyurethane-drug coating solution.  A polyurethane coating was not used in 
Product A.  The intent of the change is to mitigate drug release from the device constituent part, 
thereby preventing potential adverse reactions and toxicities, while maintaining effectiveness of 
the drug.  
 
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1.  Is the predicate product legally marketed?  Yes. 
 
2.  Does the predicate product have the same intended use?  Yes.  There is no change to the 
intended use or labeling.   
 
3.  Do the products have the same technological characteristics?  No.  The products do not 
have the same technological characteristics as there are significant changes in the 
materials and other features of this product from those of the predicate product.  The 
proposed product has a different coating and therefore a different formulation of the drug 
as compared to Product A. 
 
4.  Do the different technological characteristics of the product raise different questions of 
safety and effectiveness that were not otherwise considered with the predicate product? 
No.  The different technological characteristics of the products do not raise different 
questions of safety and effectiveness since the safety and effectiveness questions 
surrounding the different coating (e.g., with respect to this drugs release, safety and 
effectiveness profile, infection rate, biocompatibility) were applicable to the predicate 
product.  
 
5.  Are methods available to evaluate the different technological characteristics effects on 
safety and effectiveness?  Yes.  FDA reviews performance data (e.g., bench, animal, 
and/or clinical) to determine whether such differences pose a significant safety or 
effectiveness concern for the new product.  This information is necessary to demonstrate 
the new product is substantially equivalent to Product A and/or is compliant with the 
applicable special controls.  
 
6.  Do the data demonstrate substantial equivalence?  FDA would assess the submission, 
including performance data to determine substantial equivalence, and would also assess 
compliance with applicable special controls.  If the performance data fail to demonstrate 
substantial equivalence, or there is not compliance with applicable special controls, the 
product would be NSE. 
 
We note that in this case, the 510(k) pathway permits an evaluation substantially similar to that 
which would be applied to the drug constituent part under a separate application (see section III).  
Specifically, a demonstration of substantial equivalence and compliance with the special controls 
could be sufficient to demonstrate the safety and effectiveness of the change to the drug 
constituent part for the previously granted intended use.  In this hypothetical, provided 
substantial equivalence and compliance with applicable special controls are demonstrated, the 
proposed device-led combination product would be granted marketing authorization.     
  
 
 
 
 
 
 
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Example 4:  Same drug constituent part with a lower concentration  
 
Predicate Product:  Product A described above, which was granted a De Novo classification. 
 
Drug Constituent Part:  The same drug as in Product A.  However, the drug constituent part 
that is impregnated into the surface has a lower concentration (e.g., changed from 500 g/cm to 
400 g/cm).  The sponsor has provided FDA documentation of a right of reference to the NDA.  
 
New Product:  The only change the sponsor proposes to Product A is to include a lower 
concentration of the drug constituent part that is impregnated into the surface by lowering it from 
500 g/cm to 400 g/cm as compared to Product A.  The intent is to maintain the products 
effectiveness but reduce the amount of the drug that might be released from the product, thereby 
mitigating the potential for adverse reactions to the drug. 
 
1.  Is the predicate product legally marketed?  Yes. 
 
2.  Does the predicate product have the same intended use?  Yes.  There is no change to the 
intended use or labeling.   
 
3.  Do the products have the same technological characteristics?  No.  The products do not 
have the same technological characteristics as there are significant changes in the 
materials and other features of this product from those of the predicate product.  The 
proposed product has a lower concentration of the drug.  
 
4.  Do the different technological characteristics of the product raise different questions of 
safety and effectiveness that were not otherwise considered with the predicate product? 
No.  The different technological characteristics of the products do not raise different 
questions of safety and effectiveness since the safety and effectiveness questions 
surrounding the concentration of this drug were applicable to the predicate product.  For 
example, these questions include ones related to release and safety and effectiveness 
profile at the proposed drug concentration, as well as infection rate.  
 
5.  Are methods available to evaluate the different technological characteristics effects on 
safety and effectiveness?  Yes, FDA reviews performance data (including clinical data 
when necessary) to determine whether such differences pose a significant safety or 
effectiveness concern for the new product.  This information is necessary to demonstrate 
the new product is substantially equivalent to Product A and/or is compliant with the 
applicable special controls.   
 
6.  Do the data demonstrate substantial equivalence?  FDA would assess the submission, 
including performance data to determine substantial equivalence, and would also assess 
compliance with applicable special controls.  Here, the special controls require clinical 
data to demonstrate the ability to prevent infection for its anticipated conditions of use, in 
this case the lower concentration of the drug.  If the performance data fail to demonstrate 
 
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substantial equivalence, or there is not compliance with applicable special controls, the 
product would be NSE. 
 
We note that in this case, the 510(k) pathway permits an evaluation substantially similar to that 
which would be applied to the drug constituent part under a separate application (see section III).  
Specifically, a demonstration of substantial equivalence and compliance with the special controls 
could be sufficient to demonstrate the safety and effectiveness of the reduced concentration of 
the drug constituent part.  In this hypothetical, provided substantial equivalence and compliance 
with applicable special controls are demonstrated, the proposed device-led combination product 
would be granted marketing authorization.     
 
 
Example 5:  Replacing a drug constituent part with a different antimicrobial 
 
Predicate Product:  Product A described above, which was granted a De Novo classification.  
 
Drug Constituent Part:  A different hypothetical antimicrobial that contains an active 
ingredient that is in another NDA approved drug product indicated for the treatment of acute 
bacterial skin and skin structure infections (Antimicrobial B).  The sponsor has provided FDA 
documentation of a right of reference to the NDA for this different antimicrobial.  
  
New Product:  The sponsor replaces Antimicrobial A in Product A with Antimicrobial B.  The 
sponsor does not change the indications or directions for use of the new product as compared to 
Product A. 
 
In this example, the special controls in the classification regulation regarding Product A resulting 
from FDA granting the De Novo request specifically require the active ingredient in the drug 
constituent part to be the active ingredient in Antimicrobial A.  As the new product contains a 
different active ingredient from Product A, it would not be within the same type, and would thus 
be NSE.  Even if the special controls did not specify a particular active ingredient, a product with 
a different active ingredient from a predicate would differ significantly in features such as design 
and materials, which would likely raise different questions of safety and effectiveness and cause 
the product to be NSE.61 
 
Further, in this case the 510(k) pathway would not allow for an evaluation substantially similar 
to that which would be applied to the drug constituent part under a separate application (see 
section III).  Specifically, comparison of the new product to the predicate would not allow for a 
sufficient demonstration of the safety and effectiveness of the different drug constituent part for 
its proposed conditions of use  i.e., for both this drug indication and for the combined use of 
this drug with the device.   
 
The proposed product would require an approved PMA before it could be legally marketed. 
Alternatively the product may be suitable for a new De Novo classification. 
 
61 See footnote 42.   
 
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