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FDA Webinar: Combination Product Updates for “Acceptance and Filing Reviews for 

Premarket Approval Applications” and “Refuse to Accept Policy for 510(k)s”

Moderator: Irene Aihie

March 20, 2018

3:00 pm ET

Coordinator: Welcome and thank you for standing by. Today's call is being recorded. If 

you have any objections, you may disconnect at this time. 

All participants will be on a listen-only mode for the duration of the call. 

During the question and answer period if you would like to ask a question 

please press Star one. I would now like to turn the call over to (Irene Aihie).

(Irene Aihie): Hello...and welcome to today's FDA webinar. I am (Irene Aihie) of CDRH's 

Office of Communication and Education. On January 30th, the FDA updated 

two final guidances. Refuse to accept policy for 510(k), and the Acceptance 

and Filing of Use for Pre-Market Approval Application. 

The purpose of the guidances is to explain the procedures and the criteria the 

FDA intends to use in accepting or refusing a 510(k) or PMA submission. It 

includes checklists to identify the necessary elements and content of a 

complete application. 

Today, James Bertram, Policy Analyst from the Office of Device Evaluation 

here in CDRH, will present an overview of the updates to the final guidances. 

Following the presentation, we will open the line for your questions related to 

information provided during the presentation. 
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Additionally, there are other Center subject matter experts here with us today 

who will assist with the Q and A portion of our webinar. Now I give you 

James...

(James Bertram): Thank you Irene for the opening comments and introduction. My name is 

James Bertram and I'm a Policy Analyst in CDRH's Office of Device 

Evaluation. 

As Irene just informed you -- if you were not previously aware -- on January 

30 of this year we updated two guidances as it pertains to our continued 

implementation of the statutory provisions associated with the 21st Century 

Cures Act. Specifically, the acceptance and filing a review for PMA 

applications guidance and the Refuse to Accept policy for 510(k) guidance. 

All right, the intent of today's webinar is to explain the agency's 

recommendations regarding recent updates to these guidances. Twenty-first 

Century Cures -- or Cures -- amended the Federal Drug and Cosmetic Act to 

now require sponsors of combination products to appropriately self-identify 

their product as such. 

Furthermore, if the product is a device-led combination product and it 

includes a drug constituent that has been previously approved by CDER --

which means the drug is listed in the orange book -- the sponsor must provide 

the appropriate patent certification, or statement as well as consider whether 

any new drug applications -- or NDA -- is protected by any exclusivity. 

If so, this may affect the agency's ability to approve or clear the submission. 

As articulated in the two aforementioned guidances, FDA has updated its 

Refuse to Accept -- or RTA -- checklist to take into account these provisions, 

helping us to ensure the necessary information is present for the agency to 
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initiate review of your submission. I want to remind our listeners; these 

provisions only apply to combination products. 

Today's webinar will begin with an outline of a number of provisions enacted 

under 21st Century Cures on December 13, 2016. After a brief introduction to 

these provisions we will provide an overview of your responsibility to 

accurately self-identify your product as a combination product, the need to 

include appropriate drug patent information in your submission, and

ultimately the need to consider drug exclusivities that may have been 

previously granted by the agency for your drug constituent part. 

We will then identify our intended review practices considering these 

provisions, provided - provide four case studies as examples, and take things 

home with a summary of what we've heard today. At that point we'll open the 

webinar up for participant questions.

Let's start with introductions. First a little history on the existence of the 

patent and exclusivity provisions currently in Section 505 of the Federal Food 

and Drug Cosmetic Act. 

In 1984 Congress enacted the Drug Price Competition and Patent Term 

Restoration Act, which many know as the Hatch-Waxman Act. This included 

the first statutory provisions expressly pertaining to generic drugs, which 

created the basic scheme under which generic drugs are approved today. 

Overall, Hatch-Waxman intended to encourage and speed the entry of generic 

drugs to market while at the same time providing additional protections to 

innovators of the listed drug. While we could arguably hold a separate 

webinar to discuss the Hatch-Waxman Act, for our interests with today's 

webinar it provided clarity regarding two aspects. 
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Drug exclusivities granted by the agency as well as patent protections and 

associated duties of both the innovator and subsequent applicants. Exclusivity 

is unique from patent protections and provides certain innovators limited 

protection from new competition for a prescribed period of time. 

Meaning it could preclude submission of an NDA under Section 505(b) (2) or 

an NDA under Section 505(J). Regarding patent protections, Hatch-Waxman

allowed innovators to submit relevant patents to the FDA for listing in the 

orange book. The orange book being a public repository that includes drug 

products approved by the agency. 

It also includes listings of any applicable exclusivities and submitted patents 

for the listed drug. In turn, applicants of 505(B)(2) applications and ANDAs 

must certify to the patents listed for the relied upon listed drug. 

For those new to this concept, patents and exclusivity work in a similar 

fashion but are distinct from one another and governed by different statutes. 

Patents are a property right granted by United States Patent and Trademark 

Office any time during the development of a drug and can encompass a wide 

range of claims. 

Exclusivity refers to certain delays and prohibitions on approval of competitor 

drugs available under the statute that attach upon approval of a drug or of 

certain supplements. Periods of exclusivity and patent terms may or may not 

run concurrently. 

Exclusivity was designed to promote a balance between new drug innovation 

and greater public access to drugs that result from generic drug competition. 

So, what did Cures do? It applied a number of these Hatch-Waxman
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provisions -- of particular note those associated with drug patent and 

exclusivities -- to device-led combination products which contain a drug 

constituent. 

As such we have updated our PMA and 510(k) RTA checklists helping to 

ensure that we have adequate information to not only initiate a review, but 

also helping to ensure consistency with these new provisions. Please note --

while the RTA updates apply to submissions received on or after April 2, 

2018 -- the provisions have been in effect since December 13, 2016. 

Since that time the agency has been considering appropriate processes for 

implementation. During this process -- to ensure consistency with the law --

CDRH has been checking submissions to determine if the drug constituent has 

unexpired patents or exclusivities for which an appropriate right of reference 

has not been provided. 

Going forward CDRH is implementing processes to correct the necessary 

patent certifications -- and when appropriate patent statements -- from

sponsors. These processes are believed to be consistent with the provisions in 

Cures. For purposes of our discussion and focus, the specific amended 

sections of 503 G are included here for reference. 

Just to remind you, the first bill applies to all combination product types, not 

just those with a drug constituent part. Said another way, if you submit a 

combination product you are responsible for accurately self-identifying your 

product as a combination product. 

Where Cures becomes a little more nuanced is the applicability of the second 

and third bullets to device-led combination products which include a quote 
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unquote approved drug. And approved drug is uniquely defined in Section 

503(G). It is an active ingredient that meets all of the following criteria. 

First, it must have been previously approved under Section 505(C). In other 

words, it was previously approved under a New Drug Application -- or NDA -

- and thus is a listed drug in the orange book. Second, the sponsor submitting 

the application must rely upon the listed drug. A sponsor is believed to rely 

upon a listed drug if the sponsor themselves does not conduct and provide full 

reports of investigations that have been made to show whether the drug is safe 

and effective. And for which a right of reference is not obtained from the 

NDA holder for the listed drug. 

As a general matter, if the drug is listed in the orange book we anticipate the 

sponsor submitting the application for the combination product would not 

provide a complete data set to reestablish all aspects of the safety and 

effectiveness of the drug. And therefore, would be relying upon the listed 

drug.

So, what submission types for your combination product should you consider 

the provisions? This would be all 510(k) types, de novo requests, original 

PMAs as well as PMA supplements including panel track, 180-day, and Realtime. As you probably realize, this includes submission types without an RTA 

checklist. 

Section 503(G) is not limited to those submission types with RTA checklists. 

Therefore, we recommend you provide similar patent information and 

consider exclusivities for submissions with and without an RTA checklist. 

For submissions without RTA checklists, staff will be evaluating whether 

these provisions are addressed and may request information accordingly. 
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Identification of combination products. The cited language from Section 

503(G) is included here for reference as it pertains to a sponsor's 

responsibility to accurately self-identify their product as a combination 

product. 

According to Section 503(G), whenever seeking agency action with respect to 

their combination product, a sponsor must identify the product as a 

combination product. Again, just a reminder, unlike the provisions associated 

with drug patents and exclusivity, this applies to combination products 

comprised of any combination of a drug, device, or biologic constituent part. 

Although this is ultimately the responsibility of the sponsor, the agency will 

be verifying to ensure the sponsor's identification is accurate. If (such) 

identification is not included or is inaccurate -- for submissions with an RTA 

checklist -- this will be grounds for an RTA1 decision. For submissions 

without an RTA checklist, this would likely result in a request for additional 

information. 

Now for a quick refresher on combination product classification and 

jurisdictional assignment. According to 21 CFR 3.2 there are technically four 

different types of combination products. The most common types being those 

that are physically or chemically combined or co-packaged together. 

Less common are those that are sold separately but uniquely labeled for use 

together. While such classes of combination products may be submitted under 

a single application, it is somewhat common place for concomitant 

submissions to be submitted one to CDRH and then one to CBER or CDER. 

In instances where there are concomitant submissions to two centers, 

reviewers of the device alone submission will select Not Applicable in the 
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RTA checklist for the question as to whether the product contains and 

approved drug as a constituent part. 

If you are uncertain as to whether your product contains a drug constituent 

part and is potentially a combination product, in September of 2017 -- in 

collaboration with the centers -- the Office of Combination Products -- or 

OCP -- finalized its guidance on classification products such as drugs and 

devices. 

This guidance provides clarity regarding the device exclusionary clause in 

Section 201(H)(3) of the Food and Drug and Cosmetic Act, cited here for 

reference. Notably this guidance provides the agency's interpretation of 

chemical action as well as primary intended purposes. 

The Office of Combination Products is the agency entity responsible for 

adjudicating product classification and jurisdiction. Classification here 

meaning device, drug, biologic, or combination product. Not Class One, Two, 

or Three, which our audience here may be a little more familiar with. 

If determined to be a combination product, the agency will first look to 

ascertain the primary mode of action of the product. This is the single mode 

of action of the combination product that provides the most important 

therapeutic action of the combination product. 

For combination products regulated in CDRH based on PMOA, the device 

would be considered to provide the primary mode of action. However, in 

some instances the PMOA cannot be determined. And in such cases, we turn 

to the assignment algorithm. The first tier being center assignment based on 

which center regulates products rating similar questions of safety and 

effectiveness. 
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When there's no similar products OCP will then look to the second tier of the 

algorithm and assign the product to the center with the most expertise to 

evaluate the most significant safety and effectiveness questions raised by the 

product as a whole. Included here are a couple examples of combination 

products assigned based on PMLA. 

The first example is a product that most of our audience is likely aware of, a 

drug-eluting stent. This is a combination product assigned to CDRH based on 

PMOA being that of the device, with the role of the coated drug in preventing 

(restenosis) being secondary. 

The second example is a drug-eluting disc. The product is assigned to CDER. 

The PMOA was concluded to be that of the chemo-therapeutic drug, with the 

device being secondary as simply a means to ensure the sustained local 

delivery of the drug. 

I'm not going to go through this list in totality, but included here for reference 

are some of the more common combination product types seen in CDRH. 

Assigned either on PMOA or via the assignment algorithm. 

In summary, to ensure compliance with the provisions set forth in Cures --

regarding combination product self-identification -- we recommend that you 

include a statement in your cover letter and product description that basically 

states that you identify your product as a combination product. 

This also facilitates our staff's review and effort to verify this expeditiously

during the RTA phase. To further facilitate our review of the other 

provisions, if your product contains drug constituent parts we recommend you 

identify each of them in your product description section as well. 
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Ultimately, if unable to locate and identify the self-identification language in 

your submission, CDRH may RTA1 your submission or request additional 

information accordingly. If you have any questions as to whether your 

product is a combination product under CDRH purview, please feel free to 

reach out to CDRH at the cited inbox or the Office of Combination Products 

at combination at FDA dot gov. 

Now on to an overview of the patent provisions. The cited language from 

Section 503(G) is included here for reference as it pertains to a sponsor's 

obligation to provide an appropriate patent certification or statement if their 

product contains an approved drug as previously defined. 

With regard to responsibility to provide an appropriate patent statement or 

certification, you should first determine whether your active ingredient has 

been previously approved by CDER. This can be ascertained by searching the 

orange book. If listed, then the answer would be yes and you should identify 

a listed drug under an NDA for which you rely. 

Depending on the status of any listed patents you should provide an 

appropriate statement or certification for each of the patents listed for the 

particular listed drug. Alternatively, a right of reference from the NDA holder 

may be provided in place of a patent statement or certification. 

If you include a right of reference we ask that you state such in the cover letter 

of your submission, include or identify its location in the submission. This 

will greatly facilitate our review of ensuring compliance with these 

provisions. 
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You may be wondering what exactly patent certifications are. For each relied 

upon listed drug you provide either a statement that there are no relevant 

patents -- if appropriate -- or you provide one of the following four 

certifications to each listed patent in the orange book for the particular listed 

drug. 

Paragraph One Certification may be appropriate if there are no patents listed 

in the orange book for the listed drug. A Paragraph Two Certification may be 

appropriate if there's either no patent listed -- as sometimes patents are 

delisted from the orange book after a period of expiration -- or the listed 

patent has expired. 

A Paragraph Three Certification applies to situations when a sponsor intends 

to submit their application for review but fully appreciates the product won't 

be able to be fully approved for marketing authorization until the patent has 

expired. Finally, a Paragraph Four Certification is basically an assertion by 

the sponsor that the unexpired patent is invalid, unenforceable, or will not be 

infringed upon by the product for which the application is submitted.

When providing a Paragraph Four Certification a sponsor must provide notice 

to each owner of the patent and the NDA holder and include a statement of 

such certification. The Paragraph Four Certification is further described in 

Section 50 (B)(2) of the Federal Food and Drug Cosmetic Act. 

After such notification each owner or holder of the patent has up to 45 days to 

file infringement suit. If the infringement suit is filed, this may stay the 

approval for up to 30 months. From an implementation standpoint, CDRH 

intends to RTA1 applicable combination products with submissions that do 

not contain appropriate patent certifications or statements. 
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As alluded to in the previous slide, if a Paragraph Three Certification is 

provided, CDRH cannot grant final clearance or approval until the patent has 

expired. And if a Paragraph Four Certification is provided, CDRH must wait 

45 days before rendering a Marketing Authorization decision in case a suit is 

filed within the 45 days of notice. As previously stated, if an infringement 

suit is filed within the 45-day window, CDRH will delay clearance or 

approval for up to 30 months. 

Recapping the patent provisions. If these provisions are met this means there

is no attributed delay in approval or clearance when either the submission 

does not contain an approved drug -- that is it's not listed in the orange book --

or a right of reference by the NDA holder is provided in the submission. 

Or a complete data set to establish safety and effectiveness of the drug is 

included in the submission. Again, we believe this scenario to be rare if the 

drug is listed in the orange book. Or an appropriate No Relevance statement 

patent or Paragraph One or Two Certification is provided. 

Very briefly, the exclusivity provisions. The cited language from Section 

503(G) is included here for reference as it pertains to the agency's obligation 

to consider any existing exclusivities for the approved drug as previously 

defined. 

With regard to to roles and responsibilities with drug exclusivities, you do not 

need to provide information related to exclusivity. The onus is on the agency 

to check for any existing exclusivities that may apply to your drug constituent. 

That being said, we do recommend you be aware of any unexpired exclusivity 

that may be associated with your relied-upon listed drug. These too would be 

listed in the orange book under the NDA for the listed drug. Just a reminder --
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as touched on in the introduction -- patents and exclusivity work in a similar 

fashion but are distinct from one another. If you have any questions or 

concerns regarding potential exclusivities, please don't hesitate to contact us at 

the listed inbox. 

Here's CDRH’s planned implementation procedures. From an implementation 

standpoint, CDRH will evaluate information related to these provisions at two 

stages in the review. At the beginning -- in the RTA phase -- as applicable. 

And then prior to clearance or approval. The second check -- prior to 

clearance or approval -- is necessary as the orange book is updated regularly 

and the patent and exclusivity landscape for the listed drug may change over 

the course of the product's review. 

In addition, this practice is consistent with CDER's consideration of the 

orange book and the context of the review of NDAs and ANDAs. If 

determined to be inadequate during the RTA phase -- meaning the provisions 

are not met -- submission will likely not be accepted and an RTA1 decision 

will be made. 

An RTA1 outcome may also occur if it's determined that the submission or 

ultimately marketing authorization is blocked by existing patents and 

exclusivities. If determined to be inadequate at the end of the review --

meaning prior to clearance or approval -- CDRH may not be able to issue a 

clean clearance or approval. 

And the product could not be marketed until you either submit to the agency 

appropriate information addressing the outstanding patent -- or for exclusivity 

-- a letter of reference. Or the blocking conditions expire. And again, please 

remember that -- while RTA updates apply to submissions received on or after 

April 2, 2018 -- evaluation of the patent and exclusivity provisions prior to 
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clearance or approval has been in effect for submissions received on or after 

December 13, 2016. 

So here are a few theoretical case studies that may represent combination 

products in CDRH. Just a reminder, the following are considerations that will 

influence your obligations as a sponsor and CDRH will be evaluating for 

adequacy. This includes your self-identification as a combination product and 

if inclusive of a drug constituent, whether it is listed in the orange book and 

subject to any unexpired patents or exclusivities. 

The first case study, you have a combination product that includes a device 

coated with Drug A. Relevant background regarding Drug A is that the listed 

drug was approved under NDA let's say in this case zero one two three four 

five. Most notably there are no unexpired patents and no unexpired 

exclusivities. 

As a sponsor your responsibility is to self-identify your product as a 

combination product, preferably in the cover letter and product description. 

Next you would be required to provide either a Paragraph One Certification, a 

Paragraph Two Certification, or a right of reference to the NDA holder. This 

too would be preferably identified in the cover letter. 

Included here is example language say for a Paragraph One Certification. 

This could include the following. Paragraph One Certification to the specific 

NDA, to the best of our knowledge no patent information has been submitted 

to the FDA. 

Case study two. You have a combination product that includes a device 

coated with Drug B. Relevant background regarding Drug B is that the listed 

drug was approved under NDA five four three two one zero. Notably there 
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are no unexpired exclusivities for Drug B, however there is a patent that does 

not expire until February 2, 2020. 

Similar to Case Study One, your responsibility is to appropriately self-identify 

your product as a combination product. However, unlike the previous 

example, because of this unexpired patent you would now be required to 

provide a right of reference from the holder of the listed NDA. Or you will 

need to submit a Paragraph Three or Four Certification. Please be reminded 

though, submission of a Paragraph Three or Four Certification may delay 

clearance or approval of your product.

Case Study Three. You have a combination product that includes a device 

coated with Drug C. Relevant background regarding Drug C is it is not listed 

in the orange book. Therefore, your only obligation is to technically selfidentify your product as a combination product. 

A list of the extent of your obligation ensuring compliance with provisions 

discussed today, we recommend that you go one step further by not only 

identifying the drug constituent but also clarifying in your cover letter that the 

drug is not listed in the orange book. This too will assist staff in our review of 

your submission during the RTA phase. 

All right, we're almost done. So maybe people on the East Coast will be able 

to get home before the roads get too bad. So Case Study Four. You have a 

combination product that includes a device coated with Drugs D and E. 

Relevant background (of) Drug D is the listed drug was approved under the 

listed - the cited NDA. For Drug E, this was approved under another NDA. 

For both drugs there are no unexpired patents and no unexpired exclusivities. 
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As a sponsor your responsibility is first, again to self-identify your product as 

a combination product. 

Next you will be required to provide either a Paragraph One Certification, a 

Paragraph Two Certification, or a right of reference to both NDAs. This too 

would preferably be identified in the cover letter. So example language for 

say a Paragraph Two Certification could include the following. 

Paragraph Two Certification to the cited NDAs -- again noting both of them --

to the best of our knowledge. Patent information that has been submitted to 

the FDA has expired. In summary, the aforementioned provisions do not 

apply to your product if it is not a combination product. 

However, if it is the provisions would be met if you first appropriately identify 

your product as a combination product and one of the following criterion 

apply. Your product contains a drug component that has not been previously 

approved by CDER -- i.e. not listed in the orange book -- or a right of 

reference is provided the NDA holder on your behalf. 

Or a complete data set is included that establishes the safety and effectiveness 

of the drug. Again, we believe this to be rare if the drug is listed in the orange 

book. Or finally, there's no unexpired exclusivity for the relied upon listed 

drugs, there are no unexpired patents, and you provide an appropriate patent 

statement or certification for each of the listed patents. 

On the contrary, if provisions are not met and or marketing authorization may 

be delayed if you do not appropriately identify your product as a combination 

product. Or your drug contains a drug listed in the orange book and you do 

not provide an appropriate patent certification statement or right of reference. 
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Or you provide a Paragraph Three Certification or Four Certification to 

unexpired patents listed for the relied upon listed drug. Or there's unexpired 

exclusivity and that affects the submission. 

As you research further responsibilities and considerations associated with a 

future combination product submission, these resources may prove helpful 

and potentially answer some questions that that came to mind during the 

presentation. Please note, CDRH is looking into developing a CDRH website 

for stakeholders consolidating applicable combination product information 

and linkages to already existing FDA resources. 

As I noted throughout the presentation, please don't hesitate to reach out with 

any questions to the CDRH (product jurisdiction) inbox. With that, this ends 

the presentation portion of the webinar. And I believe we'll be opening the 

line for questions. 

Thank you for your attention and I hope this information proves useful in your 

upcoming combination product submissions.

Coordinator: We will now begin our question and answer session. If you would like to ask 

a question, please press Star one from your phone and unmute your line, 

speaking your name clearly when prompted. If you would like to withdraw 

your question, please press Star two. 

Again, if you would like to ask a question please press Star one from your 

phone and speak your name clearly when prompted. One moment while we 

wait for the first questions.

(James Bertram): For the Q and A portion I want to introduce my colleagues in the room. I 

have Dr. (Andrew Yeatts), Policy Analyst and Jurisdictional Officer for 
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CDRH. I also have with me Ms. (Nisha Shah), who's a Regulatory Counsel in 

the Office of Regulatory Policy from the Center for - Drug Evaluation 

Research. 

Also while we're waiting for questions to come into the queue, here's some -

we'll go through some questions that we've received to date. So one being 

what if there is an unresolved patent or exclusivity issue at the end of the 

review? 

CDRH would not be able to issue a clean approval or clearance. And the 

product could not be marketed until you either submit to the agency 

appropriate information addressing the outstanding patent. Or -- for 

exclusivity -- the right of reference. Or the blocking conditions expire. 

Another question has been, my combination product was approved after 

December 13, 2016, but I did not provide a patent certification statement. 

Why now? Since December 2016 the agency has been considering 

appropriate processes for implementation of the respective provisions. 

During this process to ensure consistency with the law, CDRH has been 

checking submissions to determine if the drug constituent has unexpired 

patents for which an appropriate right of reference has not been provided. 

Going forward, CDRH is implementing processes to collect the necessary 

patent certifications and where applicable statements from sponsors consistent 

with the Cures provisions. 

Another question. Are patents and exclusivities approval clearance issues if I 

do not rely upon a listed drug in the orange book? No, because the patent 

exclusivity provisions apply only if you relied upon a listed drug or an active 

ingredient. 
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However -- as a general matter -- if the drug is listed in the orange book we 

recommend that you provide the appropriate patent certification or statement 

or right of reference as we anticipate that the application would not provide a 

complete data set to reestablish all aspects of the safety and effectiveness of 

the drug. 

A complete data set to establish safety and effectiveness of the drug or right of 

reference would however obviate the need to certify to patents or wait for 

exclusivities to expire. 

(Irene Aihie): Well take the other questions. We'll take our first question.

Coordinator: (Rhona Shanker), your line is now open.

(Rhona Shanker): Thank you. If - your - you keep saying that the product has to be declared as a 

combination product. If we have gone to the Office of Combination Product 

and FDA said it's a device but CDER will weigh in on the review process, is 

that considered a combination product?

(James Bertram): No. Technically if you have a determination from the Office of Combination 

Products that has clarified that you only have a device that would not be a 

combination product. It is relatively regular practice for the centers to reach 

out to the other centers for subject matter expertise. 

So if you have a determination from OCP that your product is just a device 

then you would not be a combination product and would not be subject to 

these provisions.

(Rhona Shanker): Thank you.
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Coordinator: As a reminder if you would like to ask a question please press Star one from 

your phone and unmute your line. If you would like to withdraw your 

question, please press Star two. One moment while we wait for any further 

questions.

(James Bertram): Well as we wait for other questions, another question that we've received. 

What if the drug is listed in the orange book under an ANDA? Can I certify 

to the ANDA? Very simply, no. You must certify to one approved under 

NDA. All right, looks like that may have stimulated another question?

Coordinator: One moment please. Our next question comes from (Liz Diamotto). Your 

line is open.

(Liz Diamotto): Hi. We currently have a device right now that's filed with CDRH. It's a 

device but it's classified as a combination product with CDRH. 

It does not technically contain a drug but you can only use this device with a 

drug that's been reviewed on the CDER side. But the device doesn't come -

it's not packaged with this drug. So will this fall into this classification for 

having to include patent certifications?

(James Bertram): May I ask a clarifying question?

(Liz Diamotto): Sure.

(James Bertram): It sounds like you have a separate NDA approval for the drug that your 

device is intended to be used with?

(Liz Diamotto): Yes.
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(James Bertram): And it's not technically part of your product, so it's not co-packaged and not...

(Liz Diamotto): No.

(James Bertram): ...physically or chemically combined? Then...

(Liz Diamotto): No.

(James Bertram): ...no, these provisions would not apply. And that I believe I attempted to 

speak to that in an earlier slide.

(Liz Diamotto): So if we currently have a 510(k) already on this device and we need to submit 

another - basically an - another 510(k) for the same product -- because we're 

changing maybe the indication -- we don't have - it's not - I don't have to 

consider this a combination product? Even though the original 510(k) is 

classified as a combination product with CDRH?

(James Bertram): So technically your only obligation here would be to appropriately identify 

your product as a combination product.

(Liz Diamotto): Okay. So I would just state in the cover letter that we are combination 

product and that's it.

(James Bertram): Yes. 

((Crosstalk))

(Liz Diamotto): Okay.
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(James Bertram): ...it may help to further clarify your situation specifically to help the reviewer. 

But...

(Liz Diamotto): Okay.

(James Bertram): ...your only - from what you said it sounds like your only obligation here 

would be to appropriately ID.

(Liz Diamotto): Okay. And there's no requirements for any type of patent certifications to be 

submitted? Is what...

(James Bertram): Correct.

(Liz Diamotto): ...I understand. Okay. Great. Thank...

(James Bertram): Because it was separately submitted to CDER under an NDA.

(Liz Diamotto): Okay. Thank you.

Coordinator: Again, if you would like to ask a question from the phone please press Star 

one from your phone.

(Irene Aihie): Looks like we have one question...

Coordinator: Our next question comes from (Lena Cantos). Your line is open. (Lena)? 

Your line is open. 

One moment while I get the next question. And our next question comes from 

(Nancy Cameron) with Medtronic.
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Page 23

(Nancy Cameron):Hello. I'm wondering, if you do the orange book search and all of the NDAs 

that come up with your drug are listed as D-I-S-C-N -- which I'm assuming 

means discontinued -- do you still have to make any designation? Or can you 

just state that in your cover letter that all your - all the applicable NDAs are 

discontinued?

(James Bertram): Thank you for the question. So you would still appropriately identify as a 

combination product. You would still need to provide the appropriate 

certification. So that would be you identify one of the NDAs, that is identified 

as discontinued and that you relied upon. And that you would provide either a 

Paragraph One or Paragraph Two Certification statement.

(Nancy Cameron):Okay. Thank you.

(James Bertram): Yes.

Coordinator: And our next question comes from (Simir Shah), your line is open.

(Simir Shah): I wanted to clarify what I thought I heard you tell a previous speaker. Did you 

say that if it's a single entity combination product or a co-packaged 

combination product then one has to do the patent certification? But if it's a 

cross-labeled combination product -- where they're sold separately -- then one 

does not have to do the patent certification?

(James Bertram): Correct. Because arguably if you're doing a cross-labeled that's assuming that 

there were concomitant submissions. You would have had CDER who would 

have considered the appropriate patents and exclusivities in the context of the 

NDA.

(Simir Shah): Okay.
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Page 24

(James Bertram): Does that answer your question?

(Simir Shah): Yes, that does.

Coordinator: Next we have a question from (Anne Leonard). (Anne), your line is open.

(Anne Leonard): Hi. I'm going to try to articulate this clearly, but this is looking forward. And 

it's kind of - well it does involve biologics. And potentially impacts to 

combination products that contain a device and a biologic and not necessarily 

a therapeutic biologic. But a biologic maybe such as insulin. 

I'm aware that you know, most of these biologics, some of them that were 

approved under NDAs will be converted to BLAs around 2020. And I think --

with this legislation and another piece of legislation -- we now have the follow 

on biologics element. 

And I was wondering if you can speak to something that might be emerging 

that is similar to like the use of the 505 (B)(2) in the RLD scheme for drugs. 

If that's going to evolve in some manner for biologics? I'm not sure if you 

heard me.

(Irene Aihie): We heard you. Just one second while we get that answer for you.

Coordinator: While we're waiting again if you would like to ask a question from the phone 

line please press Star one from your phone.

(James Bertram): Okay, can you hear me? Hello, (Anne), can you...

((Crosstalk))
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Page 25

(Anne Leonard): Yes, I can hear you.

(James Bertram): ...okay. Hi, thank you...

(Anne Leonard): Yes, I can.

(James Bertram): ...sorry. Thank you for your patience. So we'll probably likely recommend 

you follow up to the CDRH product jurisdiction inbox with your question. 

But our current thinking right now -- just on a quick discussion -- is that you

would likely comply with the provisions. 

Given that these biologics that are currently under NDA, you would provide 

the appropriate sort of patent certification statements. Regarding the point at 

which they become BLAs, then these provisions do not apply. Again to 

biologics as these provisions are exclusive to drug constituents. 

I think your question regarding sort of future plans for 505(B)(2) et cetera is 

somewhat out of the scope of this discussion. But again I would ask that you -

include that in your email and reach out we can either clarify our response or 

provide additional information as we've had a little more time to think about 

what you have.

(Anne Leonard): Okay. Thank you.

Coordinator: Our next question comes from (Xin Wong), your line is open.

(Xin Wong): Yes, hi. My question is so we have a combination product approved under 

PMA. The question is if we make changes to this product that there's - that's 
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03-20-18 / 3:00 pm ET

Page 26

not drug related, do we need to include patent certification in the PMA 

supplement?

(James Bertram): So, thank you for your question. That depends on the modification and the 

supplement type. So yes if let's say the modification you're making just to the 

device constituent necessitates a 180-day supplement. Then arguably you 

would need to provide that information in that submission, even if it's not a 

change to the drug constituent.

(Xin Wong): Okay. So but if it's like RTR or 30-day notice do we still need to do that? Or 

it's only limited to 180 day PMA?

(James Bertram): Sorry, that's correct. That's what the - I forgot the exact number on the slide. 

But so for example if you were making a modification say 30-day notice...

(Xin Wong): Yes.

(James Bertram): ...you would not need to provide that information.

(Xin Wong): Okay, thank you.

Coordinator: At this time I would like to turn the call back over to (Irene Aihie).

(Irene Aihie): Thank you. This is (Irene Aihie). We appreciate your participation and 

thoughtful questions. Today's presentation and transcript will be made 

available on the CDRH Learn web page at W-W-W dot F-D-A dot gov 

forward slash training forward slash CDRH Learn by Wednesday, March 28. 

If you have additional questions about today's presentation, please use the 

contact information provided at the end of the slide presentation. 
NWX-FDA OC

Moderator: Irene Aihie

03-20-18 / 3:00 pm ET

Page 27

As always, we appreciate your feedback. Following the conclusion of today's 

webinar please complete a short 13-question survey about your FDA CDRH 

Webinar experience. The survey can be found at W-W-W dot F-D-A dot gov 

forward slash CDRH webinar immediately following the conclusion of today's 

live webinar. 

Again, thank you for participating. This concludes today's webinar.

Coordinator: Thank you for your participation in today's conference. You may disconnect 

at this time.

END