Regulatory Open Forum

This message was posted by a user wishing to remain anonymous

We are conducting in vitro ADME experiments as well as in vivo experimentation moving into canine studies on our current drug. The goal for these studies is IND enablement. We are conducting this through a CRO company who is well validated in putting together IND packages. Some team members want to modify some of the protocols and reagents used in some of these assays to answer some discovery related questions using the current studies we are conducting for IND enablement. 

I worry there is a risk here as this could potentially lead to problems down the line if the FDA decides that the change we made to the standard validated protocol requires justification or if they decide it could have impacted the resulting data, regardless of how small or large the change is. However, I am not sure where to verify and confirm this, I feel this is more rule of thumb and hope to draw on the expertise of the community for guidance. 

Thank you 

Dear inquirer,

Based on my prior experience with IND filing and response to FDA , a comparability study based on ICHQ5e guidance 'Comparability of Biotechnological/Biological Products Subject to Changes in Their Manufacturing Process' would be a good start to determine what would be the best course of action.

If there is a change in formulation, a risk assessment can provide guidance to determine the degree of effect it may have on the drug safety and profile. Depending on your findings, for minor risks, a written rational may be sufficient to address those changes. For medium to significant risks, a comparability study on the drug activity may be requested by the FDA to show that those changes in formulation did not impact the targeted drug product profile or safety- this could be performed based on your defined analytical targets and/or potency assays. 

I hope this answer will help you guide a little bit in the direction of the most optimal decision for your inquiry.

Elena

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Elena Toth
Sr Scientist
Irving TX
United States
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Original Message:
Sent: 10-Jan-2023 20:42
From: Anonymous Member
Subject: Changing assay protocols for validated and standard IND enabling studies

This message was posted by a user wishing to remain anonymous

We are conducting in vitro ADME experiments as well as in vivo experimentation moving into canine studies on our current drug. The goal for these studies is IND enablement. We are conducting this through a CRO company who is well validated in putting together IND packages. Some team members want to modify some of the protocols and reagents used in some of these assays to answer some discovery related questions using the current studies we are conducting for IND enablement.

I worry there is a risk here as this could potentially lead to problems down the line if the FDA decides that the change we made to the standard validated protocol requires justification or if they decide it could have impacted the resulting data, regardless of how small or large the change is. However, I am not sure where to verify and confirm this, I feel this is more rule of thumb and hope to draw on the expertise of the community for guidance.

Thank you

This article may be useful as well: https://www.cellandgenecollaborative.com/doc/cell-gene-comparability-fda-s-recommendations-for-coping-with-change-0001

------------------------------
Elena Toth
Sr Scientist
Irving TX
United States
------------------------------

Original Message:
Sent: 10-Jan-2023 20:42
From: Anonymous Member
Subject: Changing assay protocols for validated and standard IND enabling studies

This message was posted by a user wishing to remain anonymous

We are conducting in vitro ADME experiments as well as in vivo experimentation moving into canine studies on our current drug. The goal for these studies is IND enablement. We are conducting this through a CRO company who is well validated in putting together IND packages. Some team members want to modify some of the protocols and reagents used in some of these assays to answer some discovery related questions using the current studies we are conducting for IND enablement.

I worry there is a risk here as this could potentially lead to problems down the line if the FDA decides that the change we made to the standard validated protocol requires justification or if they decide it could have impacted the resulting data, regardless of how small or large the change is. However, I am not sure where to verify and confirm this, I feel this is more rule of thumb and hope to draw on the expertise of the community for guidance.

Thank you

You are at IND enabling stage of drug development (specifically nonclinical studies). If those changes are relevant and justified please document those changes and if possible add addendum/errata to the final study reports when you reach the IND submission stage.
I am sorry to disagree the below suggestions which are mostly CMC related changes but your question is related to changes to the assays/protocols for nonclinical studies. Your statement "Some team members want to modify some of the protocols and reagents used in some of these assays to answer some discovery related questions using the current studies we are conducting for IND enablement."
You have already provided some relevancy (bolded part) as to why your team members wish to make changes so please elaborate on those and document those changes with appropriate approvals and attach to the final study reports! You will be fine in my experience. Reach out to me privately if you need further help! These things happen all the time!
Good luck!

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GRSAOnline
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Original Message:
Sent: 10-Jan-2023 20:42
From: Anonymous Member
Subject: Changing assay protocols for validated and standard IND enabling studies

This message was posted by a user wishing to remain anonymous

We are conducting in vitro ADME experiments as well as in vivo experimentation moving into canine studies on our current drug. The goal for these studies is IND enablement. We are conducting this through a CRO company who is well validated in putting together IND packages. Some team members want to modify some of the protocols and reagents used in some of these assays to answer some discovery related questions using the current studies we are conducting for IND enablement.

I worry there is a risk here as this could potentially lead to problems down the line if the FDA decides that the change we made to the standard validated protocol requires justification or if they decide it could have impacted the resulting data, regardless of how small or large the change is. However, I am not sure where to verify and confirm this, I feel this is more rule of thumb and hope to draw on the expertise of the community for guidance.

Thank you

Anonymous and Narayan,

I have severely misread the question, so I would like to rectify that.

Narayan is spot on with his/her response. For discovery purposes, there is flexibility for changes as long they are documented and appropriately rationalized for the intended application. The final matrix of assays selected for commercial lot release need to be fully validated before applying for licensure. 

Elena

------------------------------
Elena Toth
Sr Scientist
Irving TX
United States
------------------------------

Original Message:
Sent: 12-Jan-2023 22:55
From: Narayan Rao
Subject: Changing assay protocols for validated and standard IND enabling studies

You are at IND enabling stage of drug development (specifically nonclinical studies). If those changes are relevant and justified please document those changes and if possible add addendum/errata to the final study reports when you reach the IND submission stage.
I am sorry to disagree the below suggestions which are mostly CMC related changes but your question is related to changes to the assays/protocols for nonclinical studies. Your statement "Some team members want to modify some of the protocols and reagents used in some of these assays to answer some discovery related questions using the current studies we are conducting for IND enablement."
You have already provided some relevancy (bolded part) as to why your team members wish to make changes so please elaborate on those and document those changes with appropriate approvals and attach to the final study reports! You will be fine in my experience. Reach out to me privately if you need further help! These things happen all the time!
Good luck!

------------------------------
GRSAOnline

Original Message:
Sent: 10-Jan-2023 20:42
From: Anonymous Member
Subject: Changing assay protocols for validated and standard IND enabling studies

This message was posted by a user wishing to remain anonymous

We are conducting in vitro ADME experiments as well as in vivo experimentation moving into canine studies on our current drug. The goal for these studies is IND enablement. We are conducting this through a CRO company who is well validated in putting together IND packages. Some team members want to modify some of the protocols and reagents used in some of these assays to answer some discovery related questions using the current studies we are conducting for IND enablement.

I worry there is a risk here as this could potentially lead to problems down the line if the FDA decides that the change we made to the standard validated protocol requires justification or if they decide it could have impacted the resulting data, regardless of how small or large the change is. However, I am not sure where to verify and confirm this, I feel this is more rule of thumb and hope to draw on the expertise of the community for guidance.

Thank you