4. Assembling Your Non-Clinical IND, with Emily Noonan Place

The regulatory agency doesn't get a lot of time with your IND submission. To figure out how to make the most of that time, we talk with Emily Noonan Place.

Episode Transcript

James C. Taylor (00:01):
So you want to submit a non-clinical IND
to the regulatory authority.
How do you put it all together?
Well, Emily Noonan Place knowshow, and we're going to talk
with her about it right now.
This is Insight at Biologics.

(00:23):
Welcome, Emily.
If you would please tell thepeople a little bit about yourself.

Emily Noonan Place (00:28):
So my name is Emily Place and I am a senior
consultant at Biologics Consultant.
I just started here this past May, 2022,and I'm coming from the FDA and from CDER
in the Office of New Drugs, and that'sthe Center for Drug Evaluation Research.

(00:49):
I worked in the Office of OncologyProducts for eight years, reviewing
both hematologic malignancies andsolid tumor applications and spent
about an equal amount of time on each.
I have an expertise in oligonucleotidetherapeutics and also have reviewed

(01:10):
just a full gamut of different types ofmolecules from small molecules, biologics,
uh, which would include monoclonalantibodies, antibody drug conjugates,
fusion proteins, biosimilars,trispecifics, bispecifics, you name it.
We see all the flavors there andoligonucleotides and oncology, and got to

(01:33):
participate in some of the different farmtalk sub committees while I was there.
Before FDA, did thestandard post hoc purgatory.
I was over at Stanford and UCSF andalso at the NIH in their NCI's Cancer
Prevention Fellowship program..
I also have a master's in public healthepidemiology, and I teach biostats

(01:56):
at UC Berkeley as a side hustle.
So it's a little bit about me.

James C. Taylor (02:03):
(laugh)

Emily Noonan Place (02:03):
A lot of it.

James C. Taylor (02:04):
Interesting side hustle.
Yeah, you you have a impressiveresume there for sure.
Technically CV since we are in theindustry that we're in, but let's talk
about nonclinical submission of an IND.
So, what's the most critical elementsto submitting your nonclinical IND?

Emily Noonan Place (02:24):
Right.
So when I was at FDA, I did a lotof IND review and, really depends
on who you ask and what type ofIND it is, if the product, the
indication, who's reviewing it.
And at the agency, when somebody isreviewing an IND, they're all going to

(02:44):
approach that IND review differently.
And in each IND submission, therewill be differences in the submission,
in the breadth of data and thetype of data in the submission.
So if I had to isolate some keycomponents, I would say the critical
components in the non-clinicalsubmission would be the IND enabling

(03:05):
toxicology studies because they'reused to set starting dose if it's
a first in human clinical trial.
They're also used to establishsafety monitoring for any type of
clinical trial and, and then ofcourse, understanding the mechanism
of action, and you would get that fromthe different pharmacology studies.

James C. Taylor (03:26):
Okay.
All right, so let's, let's accessyour knowledge a little bit.
Let's hearken back to whenyou were doing the reviewing.
If you were an FDA reviewer, how mightyou approach your, your beginning, how
might you start looking at the IND?

Emily Noonan Place (03:44):
All right, so when you have all that data and you have a, a
submission like this, it's, it's a lot.
And so, There are different approaches tohow you might tackle this type of data.
And again, it's going to be individual,depending on all that different, um,
all these different caveats, right?
But the first thing you're going to wantto do is determine what type of product

(04:08):
you're dealing with, whether it's asmall molecule or monoclonal antibody.
You know, what are you looking at here?
And then once you do that, you want toknow, What is the mechanism of action?
So what is the drug?
You know, what does the small molecule do?
Is it a kinase inhibitor or is it a smallmolecule, or is it a monoclonal antibody?

(04:29):
Then what does it target?
What is it binding to?
And.
Once you know that mechanismof action, you can identify
what the relevant species are.
And once you know what the relevantspecies are, then you can kind
of determine what toxicologyprogram they're going to have.
Because then you can identify what studiesthey're going to need because you'll

(04:53):
know what animals they're going to use.
And so once you have that, youcan start thinking about the,
um, the, the clinical protocol.
That's something you're always goingto want to look at because it's going
to help you understand the durationof the studies, and it's going
to help you understand the dosingand the schedule so that you can

(05:15):
consider that non-clinical packagein regards to the clinical protocol.
And then, and then from there,you're going to start looking at the
toxicology study that is going to be theIND-enabling study for the start dose.
And so that's, that'swhat I would start with.

James C. Taylor (05:37):
Okay.

Emily Noonan Place (05:37):
And, and then I would move into the other toxicology study.
And from there, you know, you, youcould move to pharmacology and PK
and, and spend a few days on that.
So...

James C. Taylor (05:50):
Well, talking about spending a few days.
Reviewers are on a timeline, correct?

Emily Noonan Place (05:56):
Oh yes.

James C. Taylor (05:56):
So-

Emily Noonan Place (05:57):
For sure.

James C. Taylor (05:58):
About how much time is the reviewer going to
end up spending with your IND?

Emily Noonan Place (06:04):
So this is interesting because I think that when
clients submit, sponsors submit tothe FDA, they submit with a 30 day
timeline, and they may be under the falseimpression that that a reviewer sees
the- sees their package for 30 days.

(06:24):
But this is, this is prettyinaccurate because as a reviewer
you'll, you'll get the IND packagemaybe two or three days, especially
if it gets, comes in on a Friday.
You might not see it until Tuesday onceyou get the assignment, 'cause it'll go
into an RPM and then a project managerand then, it'll get to a supervisor

(06:48):
and then the supervisor checks theworkload, and then you may get it that
following Tuesday, and you might noteven look at it for a few days because
you are reviewing somebody else'sIND and the safety meetings not until
Thursday, and you're not thinking aboutdoing anything else until that's over.
So it might not be almost awhole week until that reviewer

(07:09):
even looks at your IND.
And then they'll start crunching intothe data maybe the following week, and so
the timeline is a little bit ambiguous.
Uh, Should I say misleading , butyeah, so, and then you have a
safety meeting that's set and thesafety meeting is usually set not

(07:32):
right before that 30 day deadline.
A safety meeting is when the, theteam that's reviewing your application
meets to discuss major safety issues,major hold issues or non hold issues
that they need to communicate to you.
And they're not going to wait theday before that 30 day deadline to
communicate with you because theyneed to make sure that they give

(07:53):
you enough time to communicate back.

James C. Taylor (07:54):
Right.

Emily Noonan Place (07:55):
So let's say your 30 day deadline is on a Friday.
And they have safety meeting on Thursday.
They're going to have the safetymeeting a whole eight days
before that 30 day deadline.
So that means a reviewer has to beready with their review, not that
Thursday, not the eight days beforeyour deadline, but maybe 15 days before

(08:19):
your deadline because they have togive it to their supervisor who needs
to have at least five or six days toreview it before the safety meeting.
So, it's...They may not, and if theydidn't start for a week, that means that
they only have maybe five business days-

James C. Taylor (08:35):
Right.

Emily Noonan Place (08:36):
-to look at your review.
So if you think about it in that way,they are going to spend about 40 hours
at the most with your IND package.
And so it's very important that things inthe IND package are very clear, especially

(08:56):
the summary sections of the IND.

James C. Taylor (08:59):
Right.
You want to make it as easyon the reviewer as possible to
understand what you're trying to do.

Emily Noonan Place (09:05):
That's right.

James C. Taylor (09:06):
So how can a sponsor strengthen their IND to avoid holds?
What can you learn from what has gone
before?

Emily Noonan Place (09:16):
I would say things that have resulted in hold
issues in INDs would be a startdose, an issue with a start dose.
So let's say the start dose orthe dose escalation is too high.
Now you can always lower the startdose and you can change the dose
escalation, especially if there'san information request that comes

(09:36):
from the nonclinical team or theclinical team asking you to change it.
And that, you know, usually comeswith a good amount of time giving,
giving the sponsor a good amount oftime to, to have that discussion.
And one of the ways this can befacilitated by the sponsor is to create
a very clear, a very clear languagein the IND with the start dose,

(10:03):
with the start dose, with the sar.
I don't say this, creating a very clearoutline of the start dose protocol in
the IND submission, within either thesummary section of the toxicology or

(10:25):
in a general introduction section rightup front so that the reviewer sees it
and they understand right away what theanticipated start dose rationale is.
And that's one of the first thingsthat a reviewer's going to look for,
especially in a first in human IND.
The other thing that would put asponsor on hold would be missing

(10:47):
studies in the non-clinical section.
So if you know, if you need two GLPtalk studies and you only have one, you
really can't get around that requirement.
So making sure that you have all therequired studies is very important.
And those are based on guidances.
And then the other thing that I thinkhas put sponsors on hold in the past

(11:11):
would be severe, unexplained toxicity.
So if you have some severe toxicity inone of your animal studies and you can't
explain it and it can't be monitoredand it's causing death, then there's
not a lot of ways around it, especiallyif it's in that range that you intend

(11:35):
to treat, um, that could put you onclinical hold or if it's in the nervous
system, the cardiovascular system.
Any of the safety farm measurements,then that could be a real issue.
Now, one of the, the best ways toclearly communicate in the IND is
to have a very clear section two.

(11:55):
One of the, one of the ways that thesupervisors look through submissions
quickly is are the tabulated summaries.
So having a very cleartoxicology tabulated summary,
pharmacology tabulated summary, thepharmacology written summary, and even
having that start dose rationale inthe toxicology written summary, all of

(12:18):
which we do at Biologics, are excellentways to make sure that you're clearly
communicating in your application, andthose are the parts of the review that
the reviewers at FDA and OND use themost and upfront to get the review done.

James C. Taylor (12:38):
So properly setting all of that up will help the reviewer
get to the heart of what you areattempting to illustrate, correct?

Emily Noonan Place (12:49):
That's right.
And I think that, um, when I wasat the agency, we did have sponsors
that never submitted section twos.
And I don't know, in our office,you know, you can get by without
submitting a section two.
It's not recommended.
And I think in other offices you mayget put on hold for that, but yeah,

(13:12):
for sure you could get, I mean, reallyyou need the safety from the toxicology
GLP talk studies to understand what'shappening and to make sure that
the, the drug is safe in humans.
But module two, it is important to makesure that we understand the program and to
make sure that the program's clear, right?

(13:32):
So-

James C. Taylor (13:33):
Right.

Emily Noonan Place (13:33):
We, like I said before, we only spend 40
hours with your development programand you spend years with it.
Right?
Even as a consultant we spend, youwould spend less time understanding
the development program.
But if we have a well constructed, Moduletwo with all the summary information
that really guides the reviewers.

(13:53):
It's a tool for the sponsors to aid thereview be, and it benefits everybody.
It doesn't lead people off trackso that they understand the drug.
You know, you really know the drug.
You have years of experience versusthat 40 hours, the reviewer's
going to take tops really topsto understand that information.

(14:13):
So it's, it's best way to capture that
information.

James C. Taylor (14:17):
And not only does the regulatory agency prefer a well-structured
document, but the electronicpublishing department would also
appreciate a well-structured document.
That's me making a little plugfor making my life easier.
But thank you, Emily, for-

Emily Noonan Place (14:32):
You're welcome.

James C. Taylor (14:33):
-talking with us about that.
I really do appreciate it.
And if people want to know more,they can contact you, correct?

Emily Noonan Place (14:40):
That's right.
Yep.
Or anyone on my non-clinical team.
Everybody's doing a great job here.
Cranking those module twos andthe rest of the applications out,
so we're always happy to help.

James C. Taylor (14:51):
Thank
you again to Emily for joining us.
If you'd like more information, just emailus at [e-mail].
That's Insight at BiologicsConsulting (all one word) dot com.
Also, we'd love it if you'dlike, subscribe to, and
rate and review our show.
The executive producer of Insightat Biologics is Kris Krainhanzel.
This episode is producedand edited by James C.

(15:11):
Taylor.
Technical supervisor is Jeff.
Wease.
The Insight at Biologicstheme is by Tom Rory Parsons.
I'm James C.
Taylor.
Thank you for joining us.
Please come back for moreInsight at Biologics.