INSIGHT AT BIOLOGICS EPISODE 4
On this episode of Insight at Biologics, Senior Consultant and industry expert Dr. Emily Noonan Place from Biologics Consulting chats with James Taylor about IND submissions and the review process. The fact is that the regulatory agency doesn’t get a lot of time with your IND submission. How, then, does one optimize their IND submission to make the most of the allotted time in the review? And, how do you avoid the most common pitfalls? Find out all of this and more on this episode of Insight at Biologics.
James: So you want to submit a nonclinical IND to the regulatory authority. How do you put it all together? Well, Emily Noon in place knows how, and we’re gonna talk with her about it right now. This is Insight at Biologics.
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James: Welcome, Emily. If you would please tell the people a little bit about yourself.
Emily: So, my name is Emily Place, and I am a senior consultant at Biologics Consulting. I just started here this past May, 2022, and I’m coming from the FDA, from Cedar in the Office of New Drugs, and that’s the Center for Drug Evaluation Research.
I worked in the Office of Oncology products for eight years, reviewing both hematologic malignancies and solid tumor applications and spent about an equal amount of time on each. I have an expertise in oligonucleotide therapeutics and also have reviewed just a full gamut of different types of molecules from small molecules, biologics, which would include monoclonal antibodies, antibody drug conjugates, fusion proteins, biosimilars, try specifics, bispecifics, you name it.
We see all the flavors there and oligonucleotides in oncology and got to participate in some of the different farm talk subcommittees. While I was there before FDA I did the standard post purgatory. I was over at Stanford and UCSF, and also at the NIH in their NCIS Cancer Prevention Fellowship program.
I also have a master’s in public health epidemiology, and I teach biostats at UC Berkeley as a side hustle. So, that’s a little bit about me – or a lot of it.
[James and Emily laugh together.]
James: Interesting side hustle. Yeah, you have an impressive resume there for sure. Technically CV since we are in the industry that we’re in, but let’s talk about nonclinical submission of an IND. So, what’re the most critical elements to submitting your nonclinical IND?
Emily: Right, so, When I was at fda, I did a lot of IND review and, really, it depends on who you ask and what type of IND it is, the product, the indication, who’s reviewing it. And at the agency, when somebody is reviewing an IND, they’re all gonna approach that IND review differently. And, in each IND submission, there will be differences in the submission, in the breadth of data and the type of data in the submission.
So, if I had to isolate some key components, I would say the critical components in the non-clinical submission would be the IND enabling toxicology studies because they’re used to setting a starting dose if it’s a first inhuman clinical trial. They’re also used to establish safety monitoring for any type of clinical trial, and then of course, understanding the mechanism of action, and you would get that from the different pharmacology studies.
James: Okay. All right, so let’s access your knowledge a little bit. Let’s harken back to when you were doing the reviewing. If you were an FDA reviewer, how might you approach your beginning, how might you start looking at the IND?
Emily: All right, so when you have all that data and you have a submission like this, it’s a lot. And so there are different approaches to how you might tackle this type of data. And again, it’s gonna be individual, depending on all these different caveats, right?
But the first thing you’re gonna wanna do is determine what type of product you’re dealing with, whether it’s a small molecule or monoclonal antibody. What are you looking at here? And then once you do that, you wanna know, What is the mechanism of action? So, what is the drug? What does the small molecule do? Is it a kinase inhibitor or is it a small molecule, or is it a monoclonal antibody?
Then, what does it target? What is it binding to? And once you know that mechanism of action, you can identify what the relevant species are, and once you know what the relevant species are, then you can kind of determine what toxicology program they’re going to have, because then you can identify what studies they’re going to need, because you’ll know what animals they’re gonna use.
And so once you have that, you can start thinking about the clinical protocol. That’s something you’re always gonna wanna look at because it’s going to help you understand the duration of the studies, and it’s gonna help you understand the dosing and the schedule so that you can consider that nonclinical package in regards to the clinical protocol.
And then, from there, you’re gonna start looking at the toxicology study. That is going to be the IND enabling study for the start dose. And that’s what I would start with.
Emily: And then I would move into the other toxicology study. And from there, you could move to pharmacology and PK, and spend a few days on that.
James: So, well, talking about spending a few days, reviewers are on a timeline, correct?
Emily: Oh yes, for sure.
James: About how much time is the reviewer gonna end up spending with your IND?
Emily: So this is interesting because I think that when clients, sponsors submit to the FDA, they submit with a 30 day timeline, and they may be under the false impression that a reviewer sees their package for 30 days. But this is pretty inaccurate –
[James and Emily laugh.]
Emily: Because, as a reviewer, you’ll get the IND package maybe two or three days, especially if it comes in on a Friday, you might not see it till Tuesday. Once you get the assignment, cuz it’ll go into an RPM and then go to a project manager and then it’ll get to a supervisor and then the supervisor checks the workload.
And then, you may get it that following Tuesday, and you may not even look at it for a few days because you’re reviewing somebody else’s IND and the safety meetings not until Thursday and you’re not thinking about doing anything else until that’s over. So, it might not be almost a whole week until that reviewer even looks at your IND, and then they’ll start crunching into the data maybe the following week.
And so, the timeline is a little bit ambiguous. Or, should I say misleading, but yeah, then you have a safety meeting that’s set, and the safety meeting is usually set not right before that 30 day deadline.
A safety meeting is when the team 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 gonna wait for the day before that 30 day deadline to communicate with you because they need to make sure that they give you enough time to communicate back, right?
Emily: So let’s say your 30 day deadline is on a Friday. And they have a safety meeting on Thursday. They’re going to have the safety meeting a whole eight days before that 30 day deadline. So that means a reviewer has to be ready with their review, not that Thursday, not the eight days before your deadline, but maybe 15 days before your deadline, because they have to give it to their supervisor, who needs to have at least five or six days to review it before the safety meeting.
So they may not, and if they didn’t start for a week, that means that they only have maybe five business days-
Emily: -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 in the IND package are very clear. Especially the summary sections of the IND.
James: Right. You wanna make it as easy on the reviewer as possible to understand what you’re trying to do.
Emily: That’s right.
James: So how can a sponsor strengthen their IND to avoid holds? What can you learn from what has gone before?
Emily: I would say things that have resulted in hold issues in INDs would be a start dose, an issue with a start dose. So, let’s say the start dose or the dose escalation is too high. Now you can always lower the start dose, and you can change the dose escalation, especially if there’s an information request that comes from the nonclinical team or the clinical team asking you to change it.
And that, usually comes with giving the sponsor a good amount of time to have that discussion. And one of the ways this can be facilitated by the sponsor is to create a very clear, a very clear language in the IND with the start dose…I don’t know how to say this, creating a very clear outline of the start dose protocol in the IND submission. Within either the summary section of the toxicology, or, in a general introduction section right up front, so that the reviewer sees it and they understand right away what the anticipated start dose rationale is.
And that’s one of the first things that a reviewer’s gonna look for, especially in a first in humans IND. The other thing that would put a sponsor on hold would be, missing studies in the non-clinical section. So if you need two GLP talk studies and you only have one, you really can’t get around that requirement.
So, making sure that you have all the required studies is very important. And those are based on guidances. And then the other thing, that I think has put sponsors on hold in the past, would be severe, unexplained toxicity. So if you have some severe toxicity in one of your animal studies and you can’t explain it and it can’t be monitored, and it’s causing death, then there’s not a lot of ways around it, especially if it’s in that range that you intend to treat.
That could put you on clinical 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 best ways to clearly communicate in the IND is to have a very clear section two. One of the ways that the supervisors look through submissions quickly are the tabulated summaries.
So having a very clear toxicology tabulated summary, pharmacology tabulated summary with the pharmacology written summary, and maybe even having that start dose rationale in the toxicology written summary, all of which we do at biologics, are excellent ways to make sure that you’re clearly communicating in your application. And those are the parts of the review that the reviewers at FDA and OND use the most and upfront to get the review done.
James: So properly setting all of that up will help the reviewer get to the heart of what you are attempting to illustrate. Correct?
Emily: That’s right. And I think that, when I was at the agency, we did have sponsors that never submitted section twos, and I don’t know. In our office, you can get by without submitting a section two, and it’s not recommended. And I think in other offices you may get put on hold for that.
But yeah, for sure, really you need the safety from the toxicology GLP talk studies to understand what’s happening and to make sure that the drug is safe in humans.And module two is important to make sure that we understand the program and to make sure that the program’s clear, right?
Emily: Like I said before, we only spend 40 hours with your development program and you spend years with it, right? Even as a consultant, you would spend less time understanding the development program.
But, if we have a well constructed module two with all the summary information that really guides the reviewers, it’s a tool for the sponsors to aid the review better, and it benefits everybody. It doesn’t lead people off track, so they understand the drug, really know the drug. You have years of experience versus that 40 hours the reviewer’s gonna take, tops, to understand that information. So it’s it’s best way to capture that information.
James: And not only does the regulatory agency prefer a well-structured document, but the electronic publishing department would also appreciate a well-structured document. That’s me, making a little plug for making my life easier.
James: But thank you, Emily, for-
Emily: You’re welcome.
James: -talking with us about that. I really do appreciate it. And if people want to know more, they can contact you, correct?
Emily: That’s right. Yep. Or anyone on my nonclinical team, everybody’s doing a great job here. Cranking those module twos and the rest of the applications out, so we’re always happy to help.
James: Thank you again to Emily for joining us. If you’d like more information, just email us at email@example.com. That’s Insight, @ Biologics Consulting, all one word, .com. Also, we’d love it if you’d like, subscribe to, and rate and review our show.
The executive producer of Insight at Biologics is Chris Kraihansel. This episode is produced and edited by James C. Taylor, technical supervisor is Jeff Weis. The Insight at Biologics theme is by Tom Rory Parsons. I’m James C. Taylor. Thank you for joining us. Please come back for more Insight at Biologics.
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