1

Welcome to today’s

FDA/CDRH Webinar

Thank you for your patience while we register all of today’s 

participants.

If you have not connected to the audio portion of the 

webinar, please do so now:

Dial: 800-369-2040

International: 1-773-756-4813

Passcode: 1397061

Conference Number: PWXW6784811
Combination Product Updates for 

“Acceptance and Filing Reviews for 

Premarket Approval Applications” and 

“Refuse to Accept Policy for 510(k)s” 

March 20, 2018

James Bertram, Ph.D.

Policy Analyst 

Center for Devices and Radiological Health

Office of Device Evaluation

March 22, 2018
3

PURPOSE

The purpose of this webinar is to help clarify the Agency’s recommendations 

related to the content of these guidance documents

• The 21st Century Cures Act (“Cures”) amended section 503(g) of the 

Federal Food, Drug, and Cosmetic Act (FD&C Act) and requires sponsors 

of device led combination products to

• Accurately self-identify the product as a combination product

• If the drug constituent has been previously approved by CDER: 

• Provide patent certification/statement if they contain a “listed drug”

• Consider whether any new drug application (NDA) is protected by 

exclusivity that could affect approval/clearance

• FDA has updated refuse to accept (RTA) checklists to take into account 

necessary elements and contents of a complete application

• These provisions do not apply to non-combination products
4

OUTLINE

• Introduction to New Statutory Provisions 

• Identification of Combination Products

• Patent Provisions

• Exclusivity Provisions

• Review and Conclusions

• Case Studies

• Questions
5

INTRODUCTION TO NEW 

STATUTORY PROVISIONS
6

INTRODUCTION

Drug Price Competition and Patent Term Restoration 

Act of 1984

• Also known as the Hatch/Waxman Amendments

• Speeds entry of generic drugs into the market and 

provides additional protection to innovators

• Provided for “Exclusivity”

• Gives certain holders of an approved NDA limited protection from 

new competition in the marketplace

• Could preclude submission or approval of a 505(b)(2) application or 

an abbreviated NDA (ANDA) for a prescribed time period

• Patent Protections

• Innovators provide relevant patents to FDA

• FDA lists in Orange Book

• Applicants of 505(b)(2) applications and ANDA must certify to 

patents listed for relied-upon listed drug
7

INTRODUCTION

The 21st Century Cures Act applies these provisions to 

device-drug combination products

We have updated the PMA and 510(k) RTA Checklists 

to address these provisions

RTA Updates apply to submissions received after April 

2, 2018 (provisions in effect since December 13, 2016)
8

Introduction

Section 503(g) of the Food, Drug and Cosmetic 

Act (FD&C Act) was amended and now requires 

sponsors of combination products to:

• Accurately self-identify the product as a 

combination product (FD&C Act sec. 

503(g)(8)(C)(v))

• Provide patent certification/statement if they 

contain an ‘approved drug’ (FD&C Act sec. 

503(g)(5)(A))

• Consider whether the drug constituent is 

covered by exclusivity (FD&C Act sec. 

503(g)(5)(C)))
9

INTRODUCTION

FD&C Act sec. 503(g)(5)(B) - ‘Approved drug’ means an 

active ingredient –

• that was in an application previously approved under 

section 505(c);

• where such application is relied upon by the applicant;

• for which full reports of investigations that have been 

made to show whether such drug is safe and effective 

for use were not conducted by or for the applicant; 

and

• for which the applicant submitting the application or 

request has not obtained a right of reference.
10

INTRODUCTION

These provisions apply to the following device led 

combination product submission types:

• 510(k)s (traditional, special and abbreviated) 

• De Novo Requests

• Original PMAs

• Panel Track, 180 day, and Real Time PMA Supplements

We recommend you provide similar patent and 

exclusivity information in submissions with and 

without RTA checklists
11

IDENTIFICATION OF COMBINATION 

PRODUCTS
12

New Statutory Provisions

• Accurately self-identify the product as a 

combination product

FD&C Act sec. 503(g)(8)(C)(v))

“In seeking agency action with respect to a 

combination product, the sponsor of such product shall 

identify the product as a combination product”
13

Identification of Combination 

Products

• Sponsors of combination products must self identify as 

such

• CDRH will verify the sponsor’s identification of their 

combination product

• Failure by the sponsor to identify a submitted combination 

product as a combination product is grounds for refusal to 

accept (i.e., RTA1 decision)
14

Types of Combination Products

• Drugs/devices/biologics that are:

• Physically or chemically combined into a single entity 

(21 CFR 3.2 (e)(1))

• Copackaged/kit (21 CFR 3.2 (e)(2))

• Sold separately but labeled for use together (21 CFR 

3.2 (e)(3),(4))

• May be submitted in separate drug/biologic and 

device applications or in one single device 

application if device PMOA

• Select “N/A” for containing approved drug as a 

constituent part question if application only contains 

a device
15

Classification of Products

• Refer to final Classification Guidance

• Provides interpretation of “chemical action” and “primary 

intended purposes” in the device exclusionary clause

“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”
16

Combination Product 

Assignment

• CDRH regulates combination products with a 

device primary mode of action (PMOA)

– PMOA is the single mode of action (MOA) of a 

combination product that provides the most important 

therapeutic action of the combination product (21 CFR 

3.2 (m), 3.4 (a))

OR

• That are assigned to CDRH based on the product 

assignment algorithm (21 CFR 3.4 (b))

– Center that regulates products raising similar questions 

of safety and effectiveness

– Center with most expertise to evaluate the most 

significant safety and effectiveness questions raised by 

the product 
17

Drug Eluting Stent

• PMOA – stent opens artery 

(device)

• Secondary MOA – drug 

prevents inflammation and 

restenosis 

• Assigned to CDRH 

Drug Eluting Disk

• PMOA – chemotherapy for 

brain tumor (drug)

• Secondary MOA – local 

delivery of drug by the 

device

• Assigned to CDER

PMOA Examples
18

Example CDRH Combination 

Products

• Oral/dermal wound 

dressings with drugs

• Sutures with 

antimicrobials

• Heparin/antimicrobial 

coated catheters

• Steroid-eluting leads

• Drug-eluting stents 

• Surgical mesh with 

antimicrobials

• Breath tests

• Lock flush solutions

• Bone void fillers with 

antimicrobials

• Dermal fillers with 

lidocaine
19

Classification of Combination 

Product Procedures

• Recommend including the following statement in cover letter and 

product description:

• We are identifying [insert product name] as a combination product.

• Recommend in product description clearly identifying the drug 

constituent parts

• CDRH may refuse to accept (RTA) applications for combination 

products that do not self identify as such

• If you have questions about the classification of your product contact 

CDRHProductJurisidiction@fda.hhs.gov or the Office of Combination 

Products at combination@fda.gov
20

PATENT PROVISIONS
21

New Statutory Provisions

• Provide patent certification/statement if product 

contains an approved drug 

FD&C Act sec. 503(g)(5)(A)

“If an application is submitted under section 515 or 510(k) or a 

request is submitted under section 513(f)(2), consistent with any 

determination made under paragraph (1)(D), for a combination 

product containing as a constituent part an approved drug

• the application or request shall include the certification or 

statement described in section 505(b)(2); and

• the applicant or requester shall provide notice as 

described in section 505(b)(3)”
22

Patent Procedures 

• Sponsors of combination product applications should 

determine whether the drug component (active ingredient) 

has been previously approved by CDER

• If yes, the sponsor should identify a listed drug (LD) under 

an NDA in the Orange Book for which they rely

• Sponsors should provide appropriate patent certification or 

statement to all patents listed for the LD

• Right of reference from the NDA holder may be provided 

in lieu of patent information

• Recommend stating in cover letter that a right of reference is 

included and identify its location in the submission
23

Patent Certifications 

• For each RLD that is relied on, sponsors should provide 

either a statement that there are no relevant patents or 

one of the following certifications based on the Orange 

Book to each listed patent (21 CFR 314.50(i)): 

• Paragraph I: The patent information has not been 

submitted to FDA

• Paragraph II: That the patent has expired

• Paragraph III: The date on which the patent will expire

• Paragraph IV: That the patent is invalid, 

unenforceable, or will not be infringed by the 

manufacture, use, or sale of the drug product for which 

the application is submitted
24

Patent Certifications 

• When providing a paragraph IV certification, 

sponsors must provide notice to each owner of 

the patent and to the NDA holder and include a 

statement of such certification (21 CFR 

314.52(b)(3))

• Owner/holder has 45 days to file infringement 

suit
25

Patent Certifications 

• CDRH plans to RTA combination product submissions that 

do not contain appropriate patent certifications or 

statements

• If a Paragraph III certification is provided, CDRH cannot 

grant final clearance or approval until the patent has 

expired

• If a Paragraph IV certification is provided, CDRH must wait 

45 days before granting final clearance or approval

• If an infringement suit is filed within the 45 day period, 

CDRH must delay clearance or approval for up to 30 

months
26

Patent Certifications 

• Patent provisions are met/ no delay on approval/ 

clearance/ granting when:

• The submission does not contain an approved drug, or

• A right of reference to the NDA is provided, or

• a complete data set to establish safety and 

effectiveness of the drug is included in the submission 

such that reliance on a LD is not required, or

• An appropriate ‘no relevant’ patent statement or 

Paragraph I or II certification is provided
27

EXCLUSIVITY PROVISIONS
28

New Statutory Provisions

• Consider whether the drug constituent is 

covered by exclusivity 

FD&C Act sec. 503(g)(5)(C))

“The following provisions shall apply with respect to an 

application or request... to the same extent and in the same 

manner as if such application or request were an application 

described in section 505(b)(2) that referenced the approved 

drug:

• (i) Subparagraphs (A), (B), (C), and (D) of section 505(c)(3)

• (ii) Clauses (ii), (iii), and (iv) of section 505(c)(3)(E). 

• (iii) Subsections (b) and (c) of section 505A, Section 505E(a), 

Section 527(a).”
29

Exclusivity Provision

• Sponsor does not need to provide information related to 

exclusivity 

• FDA will be checking for exclusivity, so we do recommend 

being aware of any unexpired exclusivity and contacting 

us with questions

• Contact CDRHProductJurisdiction@fda.hhs.gov for any 

questions on exclusivity
30

IMPLEMENTATION PROCEDURES
31

Implementation Procedures

• CDRH will evaluate information related to these provisions 

at RTA phase and issue RTA1 if provisions are not 

met/submission or marketing authorization is blocked

• CDRH will also conduct evaluation of patent and 

exclusivity information prior to clearance/approval

• If clearance/approval is blocked, CDRH may not issue a 

“clean” clearance/approval decision

• Evaluation prior to clearance/approval applies to 

submissions received on/after Dec 13, 2016

• RTA updates apply to submissions received on/after 

4/2/2018
32

CASE STUDIES
33

Case Studies

• Just a reminder, considerations for evaluating your 

obligations in addressing these provisions:

• Self-Identification as a Combination Product

• Listing in the Orange Book

• Patents listed in the Orange Book

• Exclusivities listed in the Orange Book 
34

Case Study 1: No patents or 

exclusivities for drug

• Product Description: Combination Product (Device coated 

w/Drug A)

• Background:

- LD for Drug A was approved under NDA 012345

- No unexpired patents and no unexpired exclusivities 

affecting Drug A

• Sponsor Obligation:

• Self-Identify as a combination product

• Provide a Paragraph I or II Certification (or ROR) to 

NDA 012345 in cover letter:

“Paragraph I Certification to NDA 012345 - To the best of our knowledge no 

patent information has been submitted to the FDA.”
35

Case Study 2: Drug with 

unexpired patent

• Product Description: Combination Product (Device coated 

w/Drug B)

• Background:

- LD for Drug B was approved under NDA 543210

- No unexpired exclusivities affecting Drug B 

- Patent does not expire until 2/2/2020

• Sponsor Obligation:

• Self-Identify as a combination product

• Provide a ROR from holder of NDA 543210 and 

identify in cover letter its location in your submission 

OR

• Provide a PIII or PIV certification (delays 

clearance/approval)
36

Case Study 3: Drug not listed

in Orange Book

• Product Description: Combination Product (Device coated 

w/Drug C)

• Background:

- Drug C not listed in Orange Book

• Sponsor Obligation:

• Self-Identify as a combination product

If drug is not listed in Orange Book, it would be helpful to note 

this in the cover letter. 
37

Case Study 4: Product 

with 2 Drugs

• Product Description: Combination Product (Device coated w/Drugs D 

& E)

• Background:

- LD for Drug D was approved under NDA 102345

- LD for Drug E was approved under NDA 543201

- No unexpired patents and no unexpired exclusivity affecting Drug 

D or Drug E

• Sponsor Obligation:

• Self-Identify as a combination product

• Provide a Paragraph I or II Certification (or ROR) to NDA 102345

• Provide a Paragraph I or II Certification (or ROR) to NDA 543201

“Paragraph II Certifications to NDAs 102345/543201 - To the best of our 

knowledge patent information that has been submitted to the FDA has 

expired.”
38

SUMMARY
39

Summary

• Provisions do not apply if

• Product is not a combination product

• Provisions are met if

• Sponsor identifies product as combination product and

• Product contains a drug component that has not 

been previously approved by CDER, OR

• A right of reference is provided to the NDA holder, 

OR 

• A complete data set to establish S + E of the drug is 

included, OR

• No unexpired patents for the relied-upon LD(s), no 

unexpired exclusivity and the sponsor provides an 

appropriate patent statement or certification
40

• Provisions are not met/ marketing authorization delayed if

• Sponsor does not identify product as combination 

product

OR

• Product contains a drug listed in the Orange Book and

• Sponsor does not provide an appropriate patent 

certification, statement, or right of reference, OR

• Sponsor provides a Paragraph III or IV certification 

to unexpired patent(s) listed for the relied-upon LD, 

OR

• There is unexpired exclusivity that affects the 

submission

Summary
41

• Approved Drug Products with Therapeutic 

Equivalence Evaluations (Orange Book)

• FAQs on the Orange Book

• Frequently Asked Questions on Patents and 

Exclusivity

• Classification Guidance

Resources
42

Questions?

If you have questions please contact 

CDRHProductJurisidiction@fda.hhs.gov

Slide Presentation, Transcript and Webinar Recording will be available at: 

http://www.fda.gov/training/cdrhlearn

Under the Heading: How to Study and Market Your Device; 

Subheading: Cross-Cutting Premarket Policy

Please complete a short survey about your FDA CDRH webinar 

experience. The survey can be found at www.fda.gov/CDRHWebinar

immediately following the conclusion of the live webinar.