Regulatory Open Forum

This message was posted by a user wishing to remain anonymous

Outside of devices, is there use of recent Real World Evidence data helping to identify biomarkers and/or surrogate endpoints that either support Inclusion/Exclusion criteria or a  surrogate endpoint for a "harder endpoint" for studies that will be used for the basis of approval?
Any experience with Maccabi (Israel's extensive RWE database) ? How does FDA feel about extrapolation of single country data (from Israel) to apply to a larger study?
Thank you!

Biomarkers for surrogate endpoints generally require a robust demonstration that the biomarker predicts the outcome of a "harder endpoint." I would be surprised if RWE could provide sufficient evidence that could satisfy regulators to approve a product under accelerated approval. It could be that in my limited experience with discussion of surrogate endpoints with FDA there are possibilities that I have not considered before. Of course, if you can make the case, it would be worth the discussion.

On the other hand, I could imagine RWE data being used to define a patient population that could benefit from a therapy and fine tune the inclusion/exclusion criteria.

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Glen Park PharmD
Vice President, Regulatory Affairs and Quality Assurance
New York NY
United States
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Original Message:
Sent: 23-Mar-2021 10:51
From: Anonymous Member
Subject: RWE data to identify biomarkers

This message was posted by a user wishing to remain anonymous

Outside of devices, is there use of recent Real World Evidence data helping to identify biomarkers and/or surrogate endpoints that either support Inclusion/Exclusion criteria or a  surrogate endpoint for a "harder endpoint" for studies that will be used for the basis of approval?
Any experience with Maccabi (Israel's extensive RWE database) ? How does FDA feel about extrapolation of single country data (from Israel) to apply to a larger study?
Thank you!

This message was posted by a user wishing to remain anonymous

"is there use of recent Real World Evidence data helping to identify biomarkers and/or surrogate endpoints that either support Inclusion/Exclusion criteria or a  surrogate endpoint for a "harder endpoint" for studies that will be used for the basis of approval?"

Let me rephrase your question so its clear for everyone. You wish to use RWE data to identify biomarkers/possible surrogate endpoints first, that can then be later used to design pivotal or registration trials using either a harder endpoint/surrogate endpoints based on your RWE data analysis for either full or accelerated approval?

Yes. Since you did not provide whether its a NCE/NBE or previously marketed product I am assuming that you have taken care of/addressed all the developmental program/studies for your test drug if its an NCE/NBE before you arrived at the stage described above in your question? 
Original Message:
Sent: 23-Mar-2021 10:51
From: Anonymous Member
Subject: RWE data to identify biomarkers

This message was posted by a user wishing to remain anonymous

Outside of devices, is there use of recent Real World Evidence data helping to identify biomarkers and/or surrogate endpoints that either support Inclusion/Exclusion criteria or a  surrogate endpoint for a "harder endpoint" for studies that will be used for the basis of approval?
Any experience with Maccabi (Israel's extensive RWE database) ? How does FDA feel about extrapolation of single country data (from Israel) to apply to a larger study?
Thank you!

Thank you for your answer. Can you please list a few examples of that?

"You wish to use RWE data to identify biomarkers/possible surrogate endpoints first, that can then be later used to design pivotal or registration trials using either a harder endpoint/surrogate endpoints based on your RWE data analysis for either full or accelerated approval?"


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Yuwei Zhang
Waltham MA
United States
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Original Message:
Sent: 24-Mar-2021 12:02
From: Anonymous Member
Subject: RWE data to identify biomarkers

This message was posted by a user wishing to remain anonymous

"is there use of recent Real World Evidence data helping to identify biomarkers and/or surrogate endpoints that either support Inclusion/Exclusion criteria or a  surrogate endpoint for a "harder endpoint" for studies that will be used for the basis of approval?"

Let me rephrase your question so its clear for everyone. You wish to use RWE data to identify biomarkers/possible surrogate endpoints first, that can then be later used to design pivotal or registration trials using either a harder endpoint/surrogate endpoints based on your RWE data analysis for either full or accelerated approval?

Yes. Since you did not provide whether its a NCE/NBE or previously marketed product I am assuming that you have taken care of/addressed all the developmental program/studies for your test drug if its an NCE/NBE before you arrived at the stage described above in your question? 
Original Message:
Sent: 23-Mar-2021 10:51
From: Anonymous Member
Subject: RWE data to identify biomarkers

This message was posted by a user wishing to remain anonymous

Outside of devices, is there use of recent Real World Evidence data helping to identify biomarkers and/or surrogate endpoints that either support Inclusion/Exclusion criteria or a  surrogate endpoint for a "harder endpoint" for studies that will be used for the basis of approval?
Any experience with Maccabi (Israel's extensive RWE database) ? How does FDA feel about extrapolation of single country data (from Israel) to apply to a larger study?
Thank you!

Dear Anonymous,

RWE tools are being used to gather data to understand patient insights, what outcomes are meaningful to the efficiency and even quality of care, and other things that patients care about. Its a tool to look for gaps and unmet need and provides input into designing patient-centric trials. It basically informs the decision making process across drug development continuum.  There is RWE helping to identify biomarkers and possible surrogate endpoints to be studied in a clinical trial if it can be defined and supported by data as a true surrogate.  These are the types of discussion with FDA, early on and at milestone meetings such as EOP1, EOP2, etc.  

Your question about how does FDA feel about extrapolation of single country data to apply to a larger study depends on a lot of factors, the indication, treatment paradigm, clinical manifestation and other factors including whether or not the population represents the US population.  Also depends if it is an unmet medical need or if it is serious and life threatening, orphan or rare disease, etc. 

In the above context, Glen is correct, it is being used to define a patient population that might benefit from the treatment and help to define study specific criteria and study design.  On the extrapolation of single country data, from Israel, to apply to a larger study, I can't comment.

Best,

Dar 


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Darlene Rosario MBA, RAC
Principle Consultant
Ventura CA
United States
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Original Message:
Sent: 23-Mar-2021 10:51
From: Anonymous Member
Subject: RWE data to identify biomarkers

This message was posted by a user wishing to remain anonymous

Outside of devices, is there use of recent Real World Evidence data helping to identify biomarkers and/or surrogate endpoints that either support Inclusion/Exclusion criteria or a  surrogate endpoint for a "harder endpoint" for studies that will be used for the basis of approval?
Any experience with Maccabi (Israel's extensive RWE database) ? How does FDA feel about extrapolation of single country data (from Israel) to apply to a larger study?
Thank you!

As the other responses make clear, this is a complex topic where the tension for FDA arises from the fact that RWE databases are rarely seen as comparable to a clinical trial, natural history study, disease registry, or anything else one can find on clinicaltrials.gov or https://euclinicaltrials.eu/

I would recommend looking at FDA's extensive materials in this area, some of which were formalized after a 2016 US law (called 21st Century Cures Act) required the FDA to issue more guidance on RWE.  Here's the FDA's stated RWE framework:  https://www.fda.gov/media/120060/download.

When you're done reviewing that, pick the most relevant materials to match your situation from this list:  https://www.fda.gov/science-research/science-and-research-special-topics/real-world-evidence 

As for a specific example, I would suggest following "accelerated approval" drug examples, such as Biogen's pending ALS drug, where a neurofilament biomarker will be used to (hopefully) demonstrate efficacy even though the Phase III failed to meet its primary endpoint:  https://investors.biogen.com/news-releases/news-release-details/fda-accepts-biogens-new-drug-application-and-grants-priority

While I've supported teams in Israel, I'm sorry to say I'm not familiar with the database you mentioned.  Hopefully the materials above will help you assess whether it's possible to leverage existing RWE data for a larger study.



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Roger Cepeda, JD, MBA, RAC
MedTech Law LLC
roger@medtech.law
Mobile: 847-421-8361
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Original Message:
Sent: 23-Mar-2021 10:51
From: Anonymous Member
Subject: RWE data to identify biomarkers

This message was posted by a user wishing to remain anonymous

Outside of devices, is there use of recent Real World Evidence data helping to identify biomarkers and/or surrogate endpoints that either support Inclusion/Exclusion criteria or a  surrogate endpoint for a "harder endpoint" for studies that will be used for the basis of approval?
Any experience with Maccabi (Israel's extensive RWE database) ? How does FDA feel about extrapolation of single country data (from Israel) to apply to a larger study?
Thank you!