Regulatory Open Forum

This message was posted by a user wishing to remain anonymous

I'm hoping someone can help me understand the process.

There is an approved NDA (OTC product) for a product and subsequent approved ANDAs.  What happens to the ANDAs if the branded NDA product is discontinued?

If the ANDA product remains, what happens if there is a desire for a label change, either marketing or safety driven.  If there is no reference product to get the label change approved, can the ANDA holder create a change through a filing?  Who ultimately is responsible for the label?

Thank you in advance for any information you can provide.

​Hi A!

I am by no means an "expert" in this area but this is my understanding:

Once a drug product that has been approved via NDA is withdrawn from the market, and assuming that it was not withdrawn for safety or efficacy reasons (read as it was withdrawn because we don't have enough sales or it is now too costly to manufacture or whatever other reason you might think of) the FDA will then assign one of the ANDA applicants as the "reference" drug.  The assigned ANDA holder would then become essentially responsible for the duties that have been previously performed by the NDA holder including the expectation to provide samples for other ANDA applicants to perform their testing with as well as working through any necessary labeling changes that might occur.  The big difference is that because the ANDA holder is not the NDA holder and the products were approved through modified (and therefore different) approval pathways, I don't believe the ANDA reference drug manufacturer is allowed to ever unilaterally change labeling to improve warnings and other areas of the product label.  These changes all are discussed with and previously approved by FDA before they are made and then all of the other ANDA approved products are expected to manage the update to their labeling as normal.  I believe FDA maintains somewhere on the website the list of approved reference drugs that would list which company is the current reference drug material for each active ingredient or potentially each combination that has been approved via (A)NDA.

Hope some of this helps (and that I am not completely wrong in my understanding!).

------------------------------
Victor Mencarelli
Director Regulatory Affairs
United States
------------------------------

Original Message:
Sent: 17-Jul-2018 09:51
From: Anonymous Member
Subject: NDA/ANDA label changes

This message was posted by a user wishing to remain anonymous

I'm hoping someone can help me understand the process.

There is an approved NDA (OTC product) for a product and subsequent approved ANDAs.  What happens to the ANDAs if the branded NDA product is discontinued?

If the ANDA product remains, what happens if there is a desire for a label change, either marketing or safety driven.  If there is no reference product to get the label change approved, can the ANDA holder create a change through a filing?  Who ultimately is responsible for the label?

Thank you in advance for any information you can provide.

Hi All,

This topic has been the subject of many discussions at various generic drug events, and it is still confusing.  The FDA published a draft guidance in July 2016 titled "Updating ANDA Labeling After the Marketing Application for the Reference Listed Drug has been Withdrawn".  Take a look (attached), but I doubt it will answer all your questions.  If you feel there is a need for labeling changes to your ANDA, I would definitely contact your PM and the Labeling group for a discussion.  Any change deemed to be safety-related would be FDA driven as it would affect all the other ANDAs for the product.  Unfortunately, it's not as simple as just submitting a labeling supplement. 

Good Luck!

------------------------------
Lisa Apolis RAC
Regulatory Affairs
Dublin CA
United StatesRAC
------------------------------

Original Message:
Sent: 19-Jul-2018 08:21
From: Victor Mencarelli
Subject: NDA/ANDA label changes

​Hi A!

I am by no means an "expert" in this area but this is my understanding:

Once a drug product that has been approved via NDA is withdrawn from the market, and assuming that it was not withdrawn for safety or efficacy reasons (read as it was withdrawn because we don't have enough sales or it is now too costly to manufacture or whatever other reason you might think of) the FDA will then assign one of the ANDA applicants as the "reference" drug.  The assigned ANDA holder would then become essentially responsible for the duties that have been previously performed by the NDA holder including the expectation to provide samples for other ANDA applicants to perform their testing with as well as working through any necessary labeling changes that might occur.  The big difference is that because the ANDA holder is not the NDA holder and the products were approved through modified (and therefore different) approval pathways, I don't believe the ANDA reference drug manufacturer is allowed to ever unilaterally change labeling to improve warnings and other areas of the product label.  These changes all are discussed with and previously approved by FDA before they are made and then all of the other ANDA approved products are expected to manage the update to their labeling as normal.  I believe FDA maintains somewhere on the website the list of approved reference drugs that would list which company is the current reference drug material for each active ingredient or potentially each combination that has been approved via (A)NDA.

Hope some of this helps (and that I am not completely wrong in my understanding!).

------------------------------
Victor Mencarelli
Director Regulatory Affairs
United States

Original Message:
Sent: 17-Jul-2018 09:51
From: Anonymous Member
Subject: NDA/ANDA label changes

This message was posted by a user wishing to remain anonymous

I'm hoping someone can help me understand the process.

There is an approved NDA (OTC product) for a product and subsequent approved ANDAs.  What happens to the ANDAs if the branded NDA product is discontinued?

If the ANDA product remains, what happens if there is a desire for a label change, either marketing or safety driven.  If there is no reference product to get the label change approved, can the ANDA holder create a change through a filing?  Who ultimately is responsible for the label?

Thank you in advance for any information you can provide.

Hello,

My understanding aligns with Victor's. You can search for the Reference Standard in the Orange Book: https://www.accessdata.fda.gov/scripts/cder/ob/index.cfm 

The discontinued product will have "RLD" in the RLD column, usually with the phrase "Federal Register determination that product was not discontinued or withdrawn for safety or efficacy reasons" next to any discontinued strengths. The product(s) (down to the specific strength, if applicable) you'll base any future labeling changes on will have an "RS" in the RS column. 

EDIT: "withdrawn" vs "discontinued" - ANDA holders of RLDs that are discontinued are theoretically meant to update their labeling if their product is not withdrawn, though this labeling may not be as readily available as the RS labeling would be. Assuming the RS labeling is aligned with a discontinued RLD labeling (that is being maintained), it would be appropriate to base your labeling updates on the RS labeling. 

Good luck!
Courtney

------------------------------
Courtney Portik
Atlanta, GA

------------------------------

Original Message:
Sent: 17-Jul-2018 09:51
From: Anonymous Member
Subject: NDA/ANDA label changes

This message was posted by a user wishing to remain anonymous

I'm hoping someone can help me understand the process.

There is an approved NDA (OTC product) for a product and subsequent approved ANDAs.  What happens to the ANDAs if the branded NDA product is discontinued?

If the ANDA product remains, what happens if there is a desire for a label change, either marketing or safety driven.  If there is no reference product to get the label change approved, can the ANDA holder create a change through a filing?  Who ultimately is responsible for the label?

Thank you in advance for any information you can provide.

ANDA holders can not solely change the labeling content without any reference.

In your case, voluntarily you can not propose safety changes on the label, unless you received deficiency letter from FDA for label change.

Anything you change in the label that needs to be justified with reference, supporting study and scientific literature.

------------------------------
Gaurang Bhavsar, MS, RAC
Manager, R&D and RA
Sunrise Pharmaceutical, Inc.
Rahway, NJ 07065
USA
------------------------------

Original Message:
Sent: 17-Jul-2018 09:51
From: Anonymous Member
Subject: NDA/ANDA label changes

This message was posted by a user wishing to remain anonymous

I'm hoping someone can help me understand the process.

There is an approved NDA (OTC product) for a product and subsequent approved ANDAs.  What happens to the ANDAs if the branded NDA product is discontinued?

If the ANDA product remains, what happens if there is a desire for a label change, either marketing or safety driven.  If there is no reference product to get the label change approved, can the ANDA holder create a change through a filing?  Who ultimately is responsible for the label?

Thank you in advance for any information you can provide.