Regulatory Open Forum

Some basic questions here for an ophthalmology, academic research project advancing a gene editing therapeutic for an inherited retinal disease. For each answer, you please say how do you know this, or where I can find a reference?

The FDA requires 2 species for toxicology and biodistribution studies. Most INDs use rats and NHP. Can mice replace rats for toxicology?

Can rabbits be considered as a large animal for ophthalmology?

May rabbits replace NHP and dogs for AAV testing?

Thank you very much!

Eric Nelson, Ph.D.
enelson@ncebiotech.com



------------------------------
Eric Nelson, Ph.D.
Independent Business Development Consultant
enelson@ncebiotech.com
919-332-9080
Chapel Hill, NC
------------------------------

I am sure you are aware there are no gene editing guidances yet available, however, you can apply the gene therapy guidances. 

To answer your specific questions:
*The FDA requires 2 species for toxicology and biodistribution studies. Most INDs use rats and NHP. Can mice replace rats for toxicology?
  A:  In our experience for gene therapy and gene editing programs we use 2 species, a relevant diseased mouse or diseased dog or cat model, and a NHP.  We have also used a combination of in vitro and in vivo studies non-clinically to support the FIH trial.  BioD may only need to be performed in the relevant species (in our case NHPs) and only in 2 species if there is something new, such as a new AAV capsid.

Can rabbits be considered as a large animal for ophthalmology?
A:  Yes rabbits are considered a large animal in toxicology studies, you just have to justify the use including the ability to use the same route of administration as proposed in the clinical trial and ability to scale doses accordingly.

May rabbits replace NHP and dogs for AAV testing?
A:  I would say yes with adequate justification.

For gene therapy/gene editing products there are no specific requirements regarding species (number or type) and it is up to the IND Sponsor to justify the selection and endpoints.  For gene editing there will be the need to measure off-target toxicity and have long-term animal data to measure both durability of effect and off-target to support the FIH trial.  How off-target toxicity will be measured and length of the study for both nonclinical and clinical will need to be discussed with the Agency.  Early pre-IND interactions are strongly encouraged and having some initial pharmacology (PD) in the species you propose will be helpful to justify your species.  Although be advised that meetings with CBER are usually WRO now and they are scheduling up to 5-9 months after the pre-IND meeting request submission.  Also feedback is rarely "we agree" but more along the lines of "maybe, if you do this, or "address that" so do not be surprised if you walk away with little clarity.  However, even with that being said, if they disagree they clearly make you aware of this fact.

------------------------------
Suzanne Thornton-Jones
Executive Director
Philadelphia PA
United States
------------------------------

Original Message:
Sent: 23-Aug-2021 17:40
From: Eric Nelson
Subject: Animal IND-Enabling Studies for Ophthalmology Gene Therapeutic

Some basic questions here for an ophthalmology, academic research project advancing a gene editing therapeutic for an inherited retinal disease. For each answer, you please say how do you know this, or where I can find a reference?

The FDA requires 2 species for toxicology and biodistribution studies. Most INDs use rats and NHP. Can mice replace rats for toxicology?

Can rabbits be considered as a large animal for ophthalmology?

May rabbits replace NHP and dogs for AAV testing?

Thank you very much!

Eric Nelson, Ph.D.
enelson@ncebiotech.com



------------------------------
Eric Nelson, Ph.D.
Independent Business Development Consultant
enelson@ncebiotech.com
919-332-9080
Chapel Hill, NC
------------------------------

Dear Susanne,

 

Thank you for your expert answers on animal selection for ophthalmology gene therapy IND-enabling studies. We are also looking at any publications of comparable gene therapeutics where the pre-IND studies data have been published. And we are hiring a professional regulatory consultant. FYI, I do business development consultant work for start-up biotechnology companies and foundations, in various gene therapy disease fields, such as ophthalmology, CNS, and hematology. If you know of any team that wants to establish a pharma partnership or get venture capital funding these are my consulting service areas. My Linked-In profile is here, www.linkedin.com/in/drericnelson.

 Eric

___________________

Eric M. Nelson, Ph.D.

Biotechnology Business Development Consultant

Chapel Hill, NC

+1 919 332 9080  

enelson@ncebiotech.com

 

------------------------------
Eric Nelson
Managing Director
Chapel Hill NC
United States
------------------------------

Original Message:
Sent: 24-Aug-2021 07:53
From: Suzanne Thornton-Jones
Subject: Animal IND-Enabling Studies for Ophthalmology Gene Therapeutic

I am sure you are aware there are no gene editing guidances yet available, however, you can apply the gene therapy guidances.

To answer your specific questions:
*The FDA requires 2 species for toxicology and biodistribution studies. Most INDs use rats and NHP. Can mice replace rats for toxicology?
  A:  In our experience for gene therapy and gene editing programs we use 2 species, a relevant diseased mouse or diseased dog or cat model, and a NHP.  We have also used a combination of in vitro and in vivo studies non-clinically to support the FIH trial.  BioD may only need to be performed in the relevant species (in our case NHPs) and only in 2 species if there is something new, such as a new AAV capsid.

Can rabbits be considered as a large animal for ophthalmology?
A:  Yes rabbits are considered a large animal in toxicology studies, you just have to justify the use including the ability to use the same route of administration as proposed in the clinical trial and ability to scale doses accordingly.

May rabbits replace NHP and dogs for AAV testing?
A:  I would say yes with adequate justification.

For gene therapy/gene editing products there are no specific requirements regarding species (number or type) and it is up to the IND Sponsor to justify the selection and endpoints.  For gene editing there will be the need to measure off-target toxicity and have long-term animal data to measure both durability of effect and off-target to support the FIH trial.  How off-target toxicity will be measured and length of the study for both nonclinical and clinical will need to be discussed with the Agency.  Early pre-IND interactions are strongly encouraged and having some initial pharmacology (PD) in the species you propose will be helpful to justify your species.  Although be advised that meetings with CBER are usually WRO now and they are scheduling up to 5-9 months after the pre-IND meeting request submission.  Also feedback is rarely "we agree" but more along the lines of "maybe, if you do this, or "address that" so do not be surprised if you walk away with little clarity.  However, even with that being said, if they disagree they clearly make you aware of this fact.

------------------------------
Suzanne Thornton-Jones
Executive Director
Philadelphia PA
United States

Original Message:
Sent: 23-Aug-2021 17:40
From: Eric Nelson
Subject: Animal IND-Enabling Studies for Ophthalmology Gene Therapeutic

Some basic questions here for an ophthalmology, academic research project advancing a gene editing therapeutic for an inherited retinal disease. For each answer, you please say how do you know this, or where I can find a reference?

The FDA requires 2 species for toxicology and biodistribution studies. Most INDs use rats and NHP. Can mice replace rats for toxicology?

Can rabbits be considered as a large animal for ophthalmology?

May rabbits replace NHP and dogs for AAV testing?

Thank you very much!

Eric Nelson, Ph.D.
enelson@ncebiotech.com



------------------------------
Eric Nelson, Ph.D.
Independent Business Development Consultant
enelson@ncebiotech.com
919-332-9080
Chapel Hill, NC
------------------------------

This message was posted by a user wishing to remain anonymous

This is the question that should be addressed to your pre-clinical development toxicologists/scientists prior to coming in here for a regulatory assessment! You need a scientific rationale first, based on your gene editing therapeutic characteristics, and the proposed animal models versus applicability to humans. 
Good luck!
Original Message:
Sent: 23-Aug-2021 17:40
From: Eric Nelson
Subject: Animal IND-Enabling Studies for Ophthalmology Gene Therapeutic

Some basic questions here for an ophthalmology, academic research project advancing a gene editing therapeutic for an inherited retinal disease. For each answer, you please say how do you know this, or where I can find a reference?

The FDA requires 2 species for toxicology and biodistribution studies. Most INDs use rats and NHP. Can mice replace rats for toxicology?

Can rabbits be considered as a large animal for ophthalmology?

May rabbits replace NHP and dogs for AAV testing?

Thank you very much!

Eric Nelson, Ph.D.
enelson@ncebiotech.com



------------------------------
Eric Nelson, Ph.D.
Independent Business Development Consultant
enelson@ncebiotech.com
919-332-9080
Chapel Hill, NC
------------------------------

Yes, we agree with your reminder that the FDA needs from the Sponsor all of these details and background information in the proposal. Luckily, we have a very thorough and technically exact team. Thank you. 

Eric M. Nelson, Ph.D.

Biotechnology Business Development Consultant

Chapel Hill, NC

+1 919 332 9080  

enelson@ncebiotech.com

------------------------------
Eric Nelson
Managing Director
Chapel Hill NC
United States
------------------------------

Original Message:
Sent: 24-Aug-2021 00:59
From: Anonymous Member
Subject: Animal IND-Enabling Studies for Ophthalmology Gene Therapeutic

This message was posted by a user wishing to remain anonymous

This is the question that should be addressed to your pre-clinical development toxicologists/scientists prior to coming in here for a regulatory assessment! You need a scientific rationale first, based on your gene editing therapeutic characteristics, and the proposed animal models versus applicability to humans.
Good luck!
Original Message:
Sent: 23-Aug-2021 17:40
From: Eric Nelson
Subject: Animal IND-Enabling Studies for Ophthalmology Gene Therapeutic

Some basic questions here for an ophthalmology, academic research project advancing a gene editing therapeutic for an inherited retinal disease. For each answer, you please say how do you know this, or where I can find a reference?

The FDA requires 2 species for toxicology and biodistribution studies. Most INDs use rats and NHP. Can mice replace rats for toxicology?

Can rabbits be considered as a large animal for ophthalmology?

May rabbits replace NHP and dogs for AAV testing?

Thank you very much!

Eric Nelson, Ph.D.
enelson@ncebiotech.com



------------------------------
Eric Nelson, Ph.D.
Independent Business Development Consultant
enelson@ncebiotech.com
919-332-9080
Chapel Hill, NC
------------------------------