How to Effectively De-Risk your IND Process

Music. And a warm welcome to the latest edition of Conversations in Drug Development, brought to you by the team at Boyd's.

This podcast is for our fellow community of scientists and clinicians working in the wonderful world of cell and gene therapy and drug development. Thank you for tuning in, and we hope you enjoy the conversation. Music.

Hello, my name's Nick Myers. I'm VP of Product Development at Boyd's, and today it's my great pleasure to talk to Dr. Eric Hardter, who is Director of Regulatory Affairs in our team. Hi, Eric. Hi, Nick. Thanks for the introduction. Good to be back here. I think the first podcast I did was about a year ago. So excited. And once again, I'm here in the UK. So another... Absolutely. It's great to have you here face to face. So today we're going to talk about de-risking the INDs.

It's a topic we have addressed in the company before, but many of our clients are at the stage where they're moving from preclinical towards the clinic and they need to know how to de-risk their IND. How do they get it right first time? And obviously on the lead up to that is the pre-IND meeting. That's a big part of this and I'm sure we'll touch on that as well.

So without further ado, we'll move into the topic. And I guess there are several aspects to this. You could de-risk your IND by the choice of the studies and what you're actually doing in the program. And within the program, you know, two, well actually probably three quite big pieces of activity. The program is geared to being able to open a specific protocol, clinical protocol with your IND. And so you need to understand what the first clinical study is that you're going to be doing in the US.

And then the non-clinical package and CMC package is geared to making sure that that clinical trial is open to you. Yeah, I often view the clinical trial as almost the context for the CMC, for the preclinical. And it is very important to remember regulation exists for a reason. But part of that reason is to kind of be all encompassing this large umbrella under which a number of different trials are going to fit in.

But because of that, it's not going to be very specific. It's going to tell you that chunk information. So we know there exist other resources, whether they're promulgated by FDA or, as you said earlier, just, getting in a room with FDA, meeting with them, talking about your program, and really thinking holistically about how you're going to de-risk your specific application. That's right. And I guess that the IND opening study can take many different forms.

It could be a traditional first into man safety study, but if it's in a rare disease, it could be in patients or oncology, it could be in patients, or it could be for sponsors outside of the US. It could be that They've done safety studies, and now very often they do a PK-type study to open their I&D. Yeah, and it really is going to be bespoke. I like to say every development program is kind of its own special snowflake.

No two are the same. There's always going to be a little bit of variance there. And I think you had mentioned some of those there, which could be from a downstream perspective. You know, if you've already run a trial XUS, just as one of the examples you noted, a couple thousand more pages in your I&D. Yep, absolutely. And just one more question about the actual clinical study. I guess some people will be aware of this. Some potential sponsors will not.

Does the FDA require a full clinical protocol, detailed synopsis, a study outline? What do they need? So I think it really depends on the deliverable itself. When we touch on the pre-IND meeting, that would actually be frowned upon. It's a little too much information at the time. But at the time of your IND, yeah, we typically like to use something like ICHE6, good clinical practice as your backbone, structure your protocol that way.

Again, we know it's going to differ for any number of things, but that's typically the type of full-length document FDA will be expecting. And oftentimes, they'll even want some ancillary documentation. Independent data monitoring, committee charter, those types of things. So. And again, this is all going to be potentially, if you're holding a really good meeting with FDA, fleshing that out pretty well.

Yeah. And I guess things like endpoints could be quite substantial topics of conversation, particularly if it's not going to be a sort of fairly vanilla safety study. And you're actually trying to look at efficacy in a rare disease population.

The choice of endpoints is a big topic, right? Yeah, exactly. For some of these, you're having kind of hard-hitting meeting on a number of factors, like you said. And the vast majority of programs are probably not thinking about much more than safety and tolerability in your first human study, but rare diseases again. And so it's actually, I think, a podcast when I spoke with Harriet last time, we talked about some of those complexities, that it is going to really be a

huge determinant in what your life cycle development looks like. Okay, great. I wanted to ask you actually about the extent to which for a completely new molecule or treatment modality, what kind of information is required or the extent of information on target validation and validation of the approach and mechanism of action? I feel that's always a big question, especially maybe for sponsors in the UK. They don't know how much they need to tell FDI about.

Right. And so I think since you're referencing a small molecule, I think you're going to need a fairly robust in vitro suite of mechanistic information. The next question is, are you going to need a bespoke animal model? Because if we're talking about a new molecule or a new mechanism of action. The smart money would say you're probably going to need to show to FDA, who again, they are all about reduce, reuse, refine 3Rs mechanism, use animals as little as possible.

But here, it's hard to believe that there could be proper surrogate if you're just looking at something completely novel. So that's going to be not only the information you need to include about the study, but the justification of the species itself. But when we're thinking about first in human, here again, it's all going to be geared towards safety. So I don't think this would likely deviate from your, two different species, you know, what is the dosing regimen?

It's going to help guide how long that study is going to need to go for. And then as you iteratively develop into phase two, start thinking about additional bridging studies. So I know I've rambled a bit there, but it's fine. And it leads on to, I guess, the non-clinical package, which is the key thing that underpins the IND opening study. Species selection always comes up, especially with non-human primates. Should we use them? Should we not use them?

And for novel treatment modalities, I guess people are thinking that may not be covered in full by the guidance.

So, I mean, you know, what do they do? They consult their experts. They try and justify whether they need to use them or they don't need to use them. Yeah. And so I had mentioned earlier about the IND regulations under 21 CFR 312. They're fairly dry, not terribly illustrative, but FDA does promulgate a lot of IMP-specific and indication-specific guidance.

We know that if it's a small molecule versus a biologic versus an advanced therapy like a cellar gene therapy, CRISPR-Cas9-based therapy, something like that, it's going to. Completely differ. And here again, this is why I think in addition to that, you could be searching for what are some of FDA's predicate approvals. Now, the FDA review memorandum, they're really helpful. They are heavily redacted. They are more geared towards summary of the pivotal trial data.

But right up front, they'll give you that regulatory history. They'll say, what did your phase one look like? What did the suite of non-clinical studies look like? It might not be a one-to-one, but this is where you consult your experts, like you said, you consult your regulatory affairs professionals, you start to think, we can leverage this data.

It's not copy and paste, of course, but we can use our intuition from there and then subsequently meet with FDA, hopefully confirm said intuition and get onto the application itself. Yeah, I think that's right. It also seems to me there's a linkage to the timing and the planning here because my experience is quite a lot of times people don't select the CROs for their pivotal TOPS program until quite late on.

And I think in an ideal world, you would select them or work with a number of potential CROs quite early on because those guys have got a lot of experience. I mean, what you have to bear in mind is they're interested in selling studies. So they will often give you a package. And what you actually need to do is within that. But there might be some things that they're saying you could do that you don't actually need to do.

So there's, for me, an iterative process where you look at the input from the CROs, talk to them about it, then you go to your experts, you refine it, you maybe think, well, actually, you don't need to do that study right now. And, you know, over this process, you will come to a package of studies that you're comfortable doing and you think is aligned with the guidance and you can justify that to the agency.

But if you do it in haste and you haven't really had time to consult, there's a risk that that's not a well-thought-out package. And we use phrases like target product profile as an example, thinking backwards from what you believe your approved product labeling is going to look like, what population it's going to support. That's going to be directly influential on the types of non-clinical and clinical studies that you're going to need to run.

And of course, at this very initial step, speaking more to the non-clinical studies, that's then going to be influential, whether it's reputational for who you want to go and work with, who has potentially more experience in those types of studies. But also, you said earlier, what about something like novel, whether it's a cell or gene therapy, a small molecule, it might necessitate a novel animal model. Sometimes the big CROs are not always going to be a great fit.

There might be some smaller bespoke CROs out there who have a little bit more experience with generating these types of models. And this is where it becomes interesting because we've talked about, you know, weaving all of these things together. So you're thinking about how am I going to message this to the FDA? And I've actually done this. We've said we're going to use this laboratory because we believe they're going to be the best with this particular animal model now.

They are not fully good laboratory practice compliant. But we believe where they differ, maybe it's more of a matter of like paperwork when QA is doing their type of oversight. It's not in the practices themselves. They're not cutting corners, but this is going to be the best set of data that we can provide to you. Do you agree? And, you know, we've seen FDA say, That's right. I think we get that. Provide that in your IND, and that's definitely going to be acceptable.

I guess that could be a valid strategy or will be a valid strategy, especially if the data there is related to efficacy and how the product works, as opposed to safety, which is another kettle of fish.

But but you're right i mean i think that could save a lot of time if there's an academic lab or a really small commercial lab that may not be fully you know grp compliant to the level that we would normally expect for safety studies if they have a particular animal model what's the alternative the alternative might be especially if it's a specific mutation or a humanized model you're going to go to somewhere like jackson labs or somewhere get them to generate that

breed those up and then transfer those animals to somewhere else. That's going to take months and months. Yeah. And if we're pushing the boundaries with product approvals, again, we've had the first CRISPR-Cas9-based gene editing cellular therapy approved.

We have to be pushing the boundaries elsewhere, right? That's the reason. Absolutely. Okay. That's really, really useful. Perhaps we should turn our attention to the CMC package because again, I think this is an area of confusion or concern for many potential sponsors where they don't really know how much they need to do on the CMC. Obviously, they've got to have a process for manufacturing their material. They will have had to generate material for their safety studies, et cetera.

But what else do they need to do? Do they need to know the clinical formulation at this point? What level of stability data to think. Right. Are you able to address that? Yeah. And here again, my favorite phrase in regulatory affairs, it depends. Right. So we make some of these broad distinctions, if I was to say, between a small molecule and a biologic.

In graduate school, I was a chemist in this former life. I could have made the same molecule probably 10 different ways, different reagents, number of steps. But if I went to the NMR lab and got my results, it was going to tell me the exact same thing. here's your product, right?

And I say that because this is not to say small molecules are inherently easier, but it could mean that whether you have one CDMO, then you go to another CDMO, it's entirely likely that even if the process drifts a little bit, you're going to wind up having released data that's going to show the exact same thing. So in this case, the life cycle development, I'll call it the trail of breadcrumbs, it's a little bit easier to follow from a regulator's perspective.

And when you're thinking about this in terms of a CMC package in your IND, you're not having to tell this big story about this is when I changed my reagents. This is when I changed my in-process controls. This is when I went from that quasi-GMP to full GMP. Now, if you're thinking about something like a cell and gene therapy, it's just not the same. Outputs reflect inputs. Even small input changes can lead to big changes in outputs.

And this trail of breadcrumbs, suddenly maybe there's a couple of kilometers between breadcrumbs instead of a couple of feet. So this is where it becomes really imperative, not only to be able to show this at the time of your IND, but to de-risk this in something like a pre-IND meeting saying, here's where we started in the lab. Let's call that generation one. Here's where we went to with our first CDMO. Let's call that generation two,

but they were doing feasibility studies. They were doing engineering runs. Now here's our fully GMP clinical trial formulation. We're able to show you that the results from our pivotal talk study are reflective of that formulation. We're moving into the clinic with that same formulation. However, we still believe all this mechanistic data, all this efficacy data that we obtained potentially with earlier generations is still relevant. Here's the data. Does FDA agree?

Yeah, that's absolutely right. And to clear up one question now, people ask me this all the time. Does my material for the pivotal tox need to be manufactured to GMP? Well, it does, doesn't it? But we advise people to basically try and take that material from one of the late engineering runs so that you're not going to see any process changes after you've done the pivotal tox.

Yeah, it's pie in the sky to say, here's our GMP, Alana, is going to support both our pivotal tox study and our first in human clinical trial. But to that point, we know there's maybe always going to be a little bit of drift in a scale up for a complex ATMP. If you can say the process is by and large the same, you're still hitting those same in-process control specs, those release specs, and the stability starts to look the same as well, it's not going to be an issue.

But here again, you want to tell this to FDA prior to your IND so that they already understand that this is coming. Yeah, I guess that's the thing. You don't want any surprises in the IND package that they're not aware of, really. Yeah, and this is interesting because we are speaking to a global crowd here during an IND review, we don't have clock stops.

FDA has 30 days and sometimes less if day 30 is on a holiday, a weekend, right? So they need to get through this information, oftentimes a lot of information, depending on the program. And they're going to come back to you with a lot of questions and you're making your own life a lot easier if you've already messaged this to them in advance. Yeah, indeed.

So before we move away from the CMC process, stability is something you need enough stability on your drug substance or whatever formulation you were using in your safety studies to cover that and you need enough stability data to cover the duration of dosing in the clinical study right so basically and again it's going to depend on the explicit program here what we like to try to do and encourage our clients and sponsors of inds is thinking back to Again, if I'll use an ATMP,

what data do you have in hand for your late feasibility run, your engineering run? How long is your GMP lot going to be available at the time of submission of your IND? But not only that, and this would apply to your small molecules, your biologics as well, can you get some accelerated data? Can you get some stress data? Can you sort of say this is some sentinel information? It's not going to be your real-time stability, right?

So it's not quite the same gravitas, but it can kind of show to the FDA, even though, say, we don't have two years of real-time stability data, we believe, based on the results of the accelerated distress, they're going to have that. And even though we only have one GMP lot on stability, we have the engineering lot, we have maybe a leak feasibility lot. These are the types of assurances I believe the CMC regulators really like to see. Yeah.

I mean, I certainly know from speaking with sponsors and some of my clients that people balk at the cost of stability studies and putting all these batches up. I think it depends how many batches people are making. If you're only making a few batches, and that might be the case with some treatment modalities that a little goes a long way. So if you've only got two or three batches, in my view, they will need to be up on ICH compliant stability studies.

However, I have other companies I work with who make lots and lots of batches, and their strategy can sometimes be to put every third batch up or something, and I think that's fine. Yeah, here again, I think it's going to depend on the explicit program. The other thing I think sponsors need to be cognizant of is the fact that manufacturing at some point in time during your clinical lifecycle development, it's going to change.

So if you've only put a small number of batches on stability or you've only kept retains for a small number of batches then it becomes maybe a little bit more challenging i'll use the word bridging it's a dangerous word right but to bridge that early clinical trial material to the late clinical trial material i think that's good i mean the bottom line is the more batches you have made the better experience you have and the stability and analysis of that, if it is considerable,

that gives confidence to the agency that you have this process under control, you understand your material. So that's all very good. There are cost implications. And in the early stages, maybe more so in places like the UK and US, money is tight. But. There's a lot to be said. You're de-risking. The more experience you have of your manufacturing process and the nature of your materials, the better, really. It can only help to de-risk.

And we've said that, you know, the treatment modality, whether you're in a biologic, a small molecule, an ATMP, the situation is very different.

So, you know, in cell and gene therapy type products, you've got considerations about master cell banks and working cell banks, completely different to the small molecule world. Do you have any sort of particular considerations around how to deal with those things like the cell banks? Yeah, it's interesting. We can get into the concept of the sort of multi-vendor paradigm.

There's a lot of times where you might be getting your master and working cell banks from could be different from who's giving you your plasmids, for example, and like a triple transfection modality could be different from who's making your drug substance.

And so here, this could probably be a discussion in and of its own right, something like a quality agreement in place with any vendor such that they'll inform you of any changes being made over time that you really have, even though they're making something for you, it's going to be too stuck. It's not going to change if there is something like, for example, new excipient that they wind up needing to use, they'll give you advanced notice of that.

Past that, I would say it's really going to be in the approach of what the IND is going to look like. CMC nomenclature, it may sound trifling. It's not. It could wind up being very influential in, for example, how you put together a drug substance package of things that, again, this is speaking at a very broad level, but you need to think about how that's going to impact a build list for your future IND and just the level of information, the level of granularity that's going to need it.

I think that's right. Actually, I know we've moved on from the non-clinical, but the treatment modality and the differences between them have massive implications for the package. So for things like a nanomedicine, you know, the biodistribution data is absolutely critical. And for many gene therapists, viral-off-exammediated gene therapists, where does the material go?

Where do the carriers go? What happens to them? And then you think about, yeah, CRISPR-Cas9, for example, or other forms of gene editing. What's the equivalent to the tox? it's really the off-target effects. And so whichever modality you're developing, you have to think about the specific package which you're going to need.

Yeah. And we tend to think because sometimes folks might have a discipline that is very specific to non-clinical pharmacokinetics or someone might be more on drug substance and CMC as kind of multidisciplinary regulatory professionals. We need to tie this all together.

Yes, they are standalone verticals, but you need to message each one together and then showing how it's going to support that clinical trial, which, as we said earlier, is kind of the context for something, whether it's your applications, a meeting with FDA.

But they all need to sort of exist these data packages in harmony and such that the FDA counterpart reviewers are all able to, whether it's a non-clinical reviewer reviewing a quality overall summary or reviewing just some of the early CMC data, being able to say, oh, that makes more sense. I understand that this batch was used in this study. This batch was used in this study.

This is how the manufacturing between those batches changed over time and how I think it might influence my review of the non-clinical information. I think that's a really good point that have been made there.

And it leads me to perhaps. Agency interactions and meetings themselves and and again thinking about my contacts and my clients we always tell people to try and engage early with the regulators and to message things so that they understand what's coming and what you've done this is all bread and butter stuff but i think there's an area of confusion about the early engagement so i think people are quite familiar now you know before you get to a pre-ind

or a formal scientific advice in the uk and europe You have things like Interact, Innovation Task Force, Innovation Office. But I think people still, some people don't really understand what those meetings are like. Have I done too much? Has my program gone too far to have any value for those sort of early engagements? Maybe you would have a comment on that. Yeah, so I'll use the Interact meeting as the perfect example.

This is relatively new in the grand scheme of things and even newer as of the most recent Purdue for Commitments.

Now the center for drugs are holding these meetings in addition it was classically center for biologics actually started solely and now referred to as office of therapeutic products but ciber otad it was solely for these cell and gene therapies but where we sort of draw an admittedly broad line in the sand is what novel questions do you have that are not answered by regulation by guidance by predicate approvals i've not.

Personally held an interact meeting with CEDR. I've held a number with CBER. And again, we've talked about CRISPR-Cas9 over and over again, right? You talked about the off-target editing. Five, 10 years ago, that was not known, right? It wasn't known very well. It wasn't known what the effect of off-target editing would be or how much fidelity you need in editing.

I think what we saw in the recent Kastchevi approval was that the efficacy was so overwhelming that, you know, we won't say it didn't matter, but it almost sort of mitigated some of those risks. But these are the types of things, you know, thinking back to an interact, these are the types of questions you would want to ask.

If you believe that there's enough predicate out there that you don't have a novel question to ask, but you still want to get some concurrence to de-risk your package, that's when I think you're looking at a pre-IND. Yeah, I think that's really good advice because you don't want to waste that interaction by having an answer, well, that's covering the regulations or the guidance. So it's for things that perhaps where the guidance doesn't really truly cover

what you want to know. It's those type of questions. Yeah. And then as you said earlier, drug development's an expensive process. So if you do have a question early on, maybe again, it's about an animal model of efficacy where you don't want to start running these studies that could cost hundreds of thousands, possibly millions of dollars without having met with FDA and them saying, you know, that's going to be an acceptable model.

So those are the types of things where we just don't have the answers at this point and where you're really de-risking now activities that would wind up supporting not only just your IND, but a pre-IND meeting with FDA as well.

Yeah, yeah, absolutely. So how about the timetable for that? I know it's always going to be different and bespoke to each program, but instead of thinking about months and years, let's say you do take an interact meeting, and you're going to have a pre-IND meeting, then you're going to file your IND. What does that timetable look like? Is that spread over a number of months or a couple of years? Yeah.

And like you said, it's all going to differ. If I was thinking about a complex biologic, your interact could be like four years in advance of your IND submission. If I'm thinking about, because you think about your pre-IND, that could be a six-month GLP top study. And it's not just to six months of study, it's having the QA audit, it's generating the data sets for FDA.

Your top study could be a nine to 12 month process. So. Instead, what you might think about it is in terms of the anticipated level of information at each step. We talked about Interact, maybe you're asking about something like a novel animal model. We talked about pre-IND, and that's classically viewed as having that meeting for support of a first-in-human program just in advance of your GLP talk study, try to gain the agency concurrence on the design of that study and go from there.

And there that's where you're going to introduce drift it's going to depend on how long those studies need to be the the explicit class of molecule again but yeah we could be looking at anywhere from two to four years for an interact maybe anywhere for six months to two years for pre-ind yeah okay yeah that's really helpful and does the agency do face-to-face meetings anymore or is it all sort of teleconference video conference

or written only responses maybe we could speak to that a little bit. All right. So it's interesting because they actually, someone recently in the past couple of years, reclassified the definition of a face-to-face meeting to be inclusive of a teleconference. They call them virtual face-to-face. So in that sense, yes, but it's kind of yes with the NASFERF, right? I've never actually supported a true in-the-room face-to-face interaction.

I can see why for something like an advisory committee meetings. Certainly, you have a wealth of stakeholders, right?

And it's also publicly facing. So you need to sort of have that ability for folks to all be there. But for an interact, for a pre-IND, even for an end-of-phase meeting. The virtual teleconference is perfectly fine. Yeah. Do they ever do written-only responses for those meetings? They do. And these are some of those things that don't always make their way into regulation or guidance. If you're looking to get a meeting at the end of the year, like in Q4,

FDA is going to be swamped. Everybody's got that same metric, right? So something like a teleconference could be shuffled down to a written response only. There do exist avenues to sort of push back on that a little bit and say, I really think we need this virtual teleconference. Here's why. FDA is not obliged to say, okay, that's great. I have seen that happen. But sometimes written responses only...

They're okay. Maybe you only have one or two questions. Maybe you don't feel a full meeting is warranted. Maybe you're seeking clarification from items discussed previously. The meeting, I think, is great for sponsors early in development to begin fostering that relationship, but it's just not always going to be the best, most bespoke format.

Yeah, no, that's true. And even when the meeting is a teleconference or a video conference, The FDA sends you, usually, like the day or two days before, they send you some written responses, don't they, or comments? Yeah, for a pre-IND meeting, it's two calendar days. And I will say they mean two calendar days. I've had meetings on Mondays where we got comments at end of business on a Friday. Yeah, I think we've all had that. Yeah, thanks for a fun weekend, for sure.

Because then you have the interim steps of getting them agenda, telling them what you want to talk about. It can be a very fast-paced and agile couple of days, but you will at least have that preliminary commentary. If you ask 10 questions, maybe you'll find out that seven of the answers you're okay with. You don't need to talk about them anymore. But of course, the other side of that coin is FDA is going to comment on the totality of your briefing package.

You may not have explicitly asked a question. They may provide a comment. So suddenly you might have five or six pages of additional FDA commentary and say, huh, where did this come from? This might be something to talk to them about. Yeah. I remember I have been involved in actual in-person face-to-face meetings at the agency back in the day. And one of the things that could go wrong in those days was that the sponsor would eat up a lot of the meeting, giving lengthy presentations.

And so having experienced a couple of those situations, I always tell people to, if you're going to do an intro, it's got to be very snappy, you know, five minutes. Yeah. And so this is where the planning phase, once you've been granted the meeting, once you receive the commentary, those couple of days, depending on the type of meeting in between, they mean everything.

You're figuring out not only what you're going to talk about, but that's going to then influence who are going to be the respondents for each thing that you're talking about. But you still need that one person. I refer to it as like the MC role who is going to. Keeping everyone on track, you say, we're talking about five issues. Issue number one, we're spending 15 minutes on. Issue number two, 10 minutes, 10 minutes, et cetera, et cetera.

Checking the clock, you know, maybe if you are in the same kind of war room, kicking someone's feet under the table and give them that subtle jab, we got to move on, right? But really just fleshing out the roles and responsibilities of who's doing what, who's speaking when. I have seen those presentations given and be effective.

I have seen them take up way too much time. and that does have the potential because fda is going to cut you off right at 60 minutes yeah that imperils everything that you're hoping to be able to talk about so it's it's like anything in life i think if it works out then it was the right call right but and this can you know go into something like having patient advocates or other stakeholders present where you think you're going to talk for 60 seconds and they go on for five minutes

if you only have 60 minutes right it adds up. Yeah. While we're on meetings, I was going to ask you exactly about that, about taking external parties into these meetings. I guess for very small sponsor companies that we work with clients who've only got two people in the company, they kind of need to do that. But I guess those external people who are coming in need to be managed quite carefully.

Yeah, exactly. And you're bringing them in because they're in some way, shape or form, a key opinion reader. And so you're not telling them what to say, but your understanding and hopefully having them understand, here's how much time you have to talk about it. This is the overarching message of what we're trying to say. It's not a time for cowboys, that's for sure. That could certainly derail the whole thing. Okay, now that's great.

So we've talked about some fairly specific things, but I wanted to get more of a sort of, A free discussion next about in your experience in recent years, what do you think the tips are for people to really de-risk their IND to try and give them the best chance of the IND being open sort of first time up without going on any kind of hole? Yeah, and I can't stress this enough, getting those formal interactions with FDA are of paramount importance.

I've heard the phrase, I don't know how many times I can't count of, I want to get this IND in quickly. And hey, we all do, right? There are external pressures. We're sensitive to that, of course. But the regulatory hurdles you have to meet don't really change at the end of the day. So what happens is you might submit an IND. I'm not saying you cut corners or anything like that. Put things together quickly. Maybe you didn't give it the due diligence.

You didn't think it through enough about all of the totality of this package, the information that's going to need to support it. And unfortunately, you get put on clinical hold. Now, this follows 30 days of FDA review. FDA has another 30 days subsequent to say this is why you're on hold. If it's a non-clinical issue, a CMC issue, that can take time. Another study, more CMC interrogation, that takes the time it takes.

You submit an amendment to FDA. They have another 30 days to review and hopefully approve. So I asked the question, did you save time in this instance by getting it in quickly? Now, again, this is the horror story, right? It's not going to happen for everyone. But to me, just take the 60 days, submit your meeting request, have a decent meeting package in shape at the point of submission of your meeting request. Ask the right questions. Don't ask anything open-ended.

Don't say, FDA, please guide us on this. Here's our viewpoint. Does the FDA agree? Get the information in front of them. Have the hour-long discussion. Hopefully gain some concurrence. But what I've realized is that unless the answer is a non-answer, there's no such thing as a bad answer from FDA because it's prescriptive one way or the other. You're not probably going to hear 100% of the concurrence that you're hoping for. No one does.

But if you can just get some sort of path forward, it then de-risks your IND application. Maybe it was something you didn't think about. And FDA is saying, you know, this is what we want to see in your IND application. But if you don't hold the meetings, you rob yourself of this and suddenly you submit your IND application and you get put on clinical hold and investor funds dry up or the program might not recover. Yeah.

I wonder if that sort of, again, not liking to use the phrase coming corners, but doing things in a very accelerated manner. I wonder if that can happen where a sponsor is, let's say they're planning to open a study in the UK. So they put a clinical trial application in here and then they think, oh, it'd be good to have a couple of US sites. And that triggers a very hasty, you know, putting together of an IND package.

That's not a good thing. I think this is where the integrated, for me, the integrated plan comes into play, you know, much earlier on. The totality of the program, when people even raise the idea of moving to the clinic, where are you going to do? Do you think there's any possibility that you want science in the U.S. So that you actually then start that regulatory warm-up process in parallel with anything you might do here with MHRA or with email in Europe?

I just think sometimes that can happen. I think it's a really important point because the granularity of information, what I might refer to as the formality of information, differs across regions. I think you can take an IMPD that was submitted to the UK or to a member state in the EU and kind of fashion it into an IND application. But for a commercial IND, it's modules one through five. The investigator's brochure doesn't need to be quite as thick, right?

But for something like non-clinical studies, FDA wants to see study reports. And so there are just these types of differences that maybe unless you have some boots on the ground or someone who's seen it, done it, You're just not going to know on the top of your head. I agree. That's a great point. I think that's right.

The thing I remind people of is that you would never dream of submitting a clinical trial application to EMA or to the MHRA that wasn't complete in your eyes, had everything you needed there. So why would you do anything different with the IND? And you can't. It won't work.

Okay, Eric. So that's great. If we turn our attention to the content of the application itself. Are there any tips that you would give people, things they should definitely focus on and get right, things not to do perhaps? Yeah, absolutely. And so my number one rule of thumb for an application is don't make the FDA hunt.

So if you have documentation that you want them to see, whether it's within a cover letter or people think of a reviewer's guide more as supporting like an NDA or a BLA, I've leveraged them for INDs as well. Usually it's like, for example, if I have a pivotal toxicology study that is also a tumorigenicity study that is also a biodistribution study, you're not putting that report in three places, right? So you're going to reference it in multiple sections. Exactly.

So you can hyperlink, but just let them know, I have one study, it serves two to three purposes, this is where we're putting it. Just those types of things so that they're not looking in the anticipated module, seeing nothing and wondering where do I look. This becomes even more important when you have held a pre-IND meeting or an interact meeting or both. This is when in addition to or as part of that reviewer's guide, I refer to it as the response matrix, even if it's just a response saying.

We agree, right? Or if you disagree and provide a rationale, I think everyone thinks that FDA gives you their meeting minutes and you have to agree with what they say. It's formal, it's not binding, is what I'll say. If you have really compelling rationale, just ensure you provide it. But more importantly, ensure that it's part of that response matrix. And then within that response matrix, for each response that you give,

have it hyperlinked to the appropriate section. Again, don't make the FDA hunt, right?

So you're saying we've heard you we're responding to you either we agree or we don't agree and here's the reason why but you click your mouse one time and you're gonna have the information right in front of you yeah that's great advice and i and i guess for companies who put lots of inds in all the time they know there's some people who've worked with people like us they know that but for the you know the naive first time up submission those guys may

not realize this and so that's a great tip And I guess we should just touch on publishing as well, because documentation that goes into the FDA, those packages have to be properly published, and your publisher will be able to help you with the hyperlinking. Yeah, the electronic submissions gateway is where sponsors of commercial INDs will submit the IND application and all subsequent IND amendment information as well.

And it's just not the same as paper. and you're no longer submitting three paper copies to a desk at the FDA. I remember that. Yeah, certain color binders, certain size fonts, etc. The... It's called the Electronic Common Technical Document Format. It's not scary. There's plenty of guidance out there to show you what to do. But this needs to exist all on the same backbone where documents need to talk

to one another. If you are referencing one document in another document, they essentially need to speak to one another. And what that really means is reviewers are going to be able, with a couple clicks of a mouse, go seamlessly from one module to another module to another module or documents within a module. And again, we talked about this being a 30-day review. It's not like you're flipping through paper anymore trying to figure out, you know, where did I leave my bookmark last?

But because of this, you need people who really understand what that technical compliance looks like. And more importantly, you need folks to be agile because during the FDA's 30-day review, they're going to come back to you with requests for more information. During the life cycle of the IND, they may come to you with requests for information.

And for each of these, they're going to predetermine the timeframe for response. Now, for the IND itself, one thing I like to employ is to just ask the regulatory project manager, once we get that first request for information and say, we're anticipating more of these. this one came from the clinical reviewer. They're usually first, right? But we think CMC, non-clinical are likely to weigh in. Can I just send you this response via secure email, first of all?

And then at the end of 30 days, can I consolidate all my responses and do a single submission? I've yet to have an RPM say no to that. And I think it just saves a lot of time, particularly for your publishers, because your publishers are always the ones getting squeezed at the end of the day for time, if you're able to do that. Yeah, I think that's a great channel and one that maybe people think doesn't exist because it's all 100% formal, but I agree with you that is a good channel.

And kind of on that theme, I wanted to ask you, if you've had a pre-IND meeting, and the FDA doesn't agree with your approach and you want to propose an alternative or if you want to strengthen your rationale as to why the approach they disagree with actually is appropriate, you want to somehow nail that down before you actually submit the IND. So is the route to put something into the divisional project manager or is it to ask for another type of meeting before you submit to nail that down?

What would your advice be there? Right. And here again, the answer is it depends. In the most recent iteration of the draft guidance on formal meetings from 2023. FDA included what I might call like a clarification pathway. That is, as it sounds, you're not hitting them with a lot of new evidence. You're maybe trying to clear something up, whether it was potentially a misunderstanding or whether you talked about it at the meeting and wanted to clear something up after the fact.

But if you're coming with new data, supportive information, especially where it's something where you may have disagreed with FDA, I think an initial email to the regulatory project manager is always your first step. Just getting that RPM assigned is huge for your program. You now have a face and a voice at the FDA. Reach out to them and usually try to be prescriptive. Don't ask them, what do I do? Just say, I think this fits a type C meeting.

I think this fits a more narrowly focused type D meeting. This is what we plan to submit and they'll usually say yeah go ahead right the one thing that i will say is everyone's allowed to disagree and the other thing that i'll say to that is a lot of people on the sponsor side view the fda almost as like the regulatory police that if they say something it must be true and and you know they're regulators and so there's a certain level of truth to that but what they've even acknowledged

in some of these meetings particularly with these groundbreaking therapies is, you guys understand this better than anyone else in the world. And then if it's from a clinical perspective, you understand this disease better than most anyone in the world. So... You are absolutely able to say, well, here's some additional data. This is why we disagree. Just try to avoid kind of taking what you said the first time, yelling louder, not providing more information, right?

It needs to be data-driven. It needs to be rationale-driven. But absolutely, in advance of the IND or worst case, within that response matrix or within somewhere else in the IND, pushing back is totally acceptable. Yeah, that's great. So the clarification pathway is really useful if you just really do want clarification as to what they've said. Because sometimes I know the way English is written in the US is a little bit different to the way we write English.

And so there can be areas where you just listen to clarification. But if you have new data, I guess what you were saying is if the sponsor is very, very confident they've done some new studies that really strengthens the rationale, they could include that in their package. But if it warrants discussion, then maybe you need a type C meeting or something to actually deal with that before you put the package in.

And, you know, we talked about the concept of these meetings and the important thing to note is that they are all driven by the questions that you're asking. And what I mean by that is you need to give FDA the data that allows them to then answer those questions. So if you do have a question about some new data that you've unearthed, just make sure that you're providing everything to FDA. Otherwise, you're going to get a non-response or the same response that you got the first

time. Okay. That's great. Just a question here, because we do have a global audience talking about FDA.

How does the agency view packages where potentially a lot or virtually everything has been done outside of the US? And that could include some prior clinical studies. Does that set you off sort of on the back foot or is that completely acceptable? Yeah, I think it's just another way of doing things, to be honest with you. And so we actually know that you can get an application for licensure approved completely on XUS data, but there's the rub, right?

If it's the first time FDA is seeing it, either at like pre-MDA or pre-BLA meeting or at the time of your submission, you need to make sure that when these auditors come, all of your good clinical practices have been adhered to at each site. You have all the documentation in place. Now, if it's more like you had a first in human study XUS and you're going into the FDA for phase two, believe it or not, you can still have a pre-IND meeting. I take that very literally.

A pre-IND meeting is a meeting advanced in an IND, right? So even if it's just going to be supportive of your phase two study. And again, it's written in the investigational new drug regulations. This is totally acceptable, but. Hopefully, these were ICH adopting countries, and hopefully within these clinical sites and these site investigators, they were all doing everything in compliance with good clinical practices.

From there, it becomes fairly straightforward. You're submitting a bit more in your clinical data summaries and potentially even some clinical study reports, like in module five. But past that, the overall pathway is the same. I just think it really highlights sponsor control over the investigational sites. I agree with that completely. I think we're in a different place now. It's 2025, very international world.

People need to be thinking that there can be few sponsors who don't intend to market their drug in the United States, wherever they do the work. And maybe back in the day, there were certain places in the world you might do non-clinical studies or you might do clinical studies and you could get them done very fast and you didn't pay that much attention to what was going on. I think those days are over.

You can't do that if you're going to be filing your IND. As you say, you need to take a great deal of control about how those studies are done, where you do them, because they're going to go to FDA. Right. And, you know, FDA understands that inception may not occur in the US, but whether it's something like comparison of pharmacopoeia to the USP. You know, how are they the same? Or is it comparison of animal study regulations,

like for example, OECD, as compared to GLP? How are they the same? Where do they differ? Can you build those bridges for FDA? And then even past that, and FDA, ICH, EMA all have guidance about this. They understand, as you just said, that drug development is going to occur in a global setting. So then you have to ask your questions, well, if I'm going to the US, and the U.S. is not my first stop, are there any slight differences in population? Could it potentially affect the PK?

Is any sort of bridging non-clinical study necessary? Oftentimes, that won't be the case, but it is something that you'll see in some of their commentary. You started in an Italian population. Can you prove to me that it's the same as your target population in the U.S.? Yeah, good advice. Okay, we've traversed many subject areas. I think we're Coming to the wrap-up, any final comments or tips, Eric, that come to mind for our audience?

Yeah, really just I think the more robust interaction you're able to have with regulators early on, it's better. Obviously, I'm biased because I've done a number of these, but I've also seen firsthand how much they've helped. And honestly, like I said earlier, it doesn't mean that FDA has agreed to everything,

but they are helping you roadmap your immediate next steps. And when you're thinking through phase one all the way through licensure, the more that you do this, again, I know I'm pivoting a little bit from just de-risking your IND, it's de-risking your entire life cycle development. You know, the more you can meet, the better. And then just from that very early setting, I don't think that you can really quantify this, but just socializing your existence to the FDA, the existence of your program.

When they see you for the first time at the IND, you're still going to be held to the same standard as everyone else. But I just think that being able to get in front of them ahead of time, hopefully have some continuity in regulatory project manager and disciplinary reviewers. It just de-risks your lifecycle development a bit more. It means that they might not be hunting for something a little bit more during the 30-day review. And I just overall, I've really only seen it benefit sponsors.

Yeah, that's a great tip. And I guess actually we've talked, podcasts has really talked to as much about de-risking your development program across its entire life cycle, perhaps as much as the IND, but they're integrally linked. And I think my tip would be to think about the timetable early.

Again, I know for smaller companies with limited funding, this is difficult, but I would urge people to engage with CROs, with consultancies like us as early as possible, and then we can help take you through the steps and how long it's going to take. Because I think some people have fairly unrealistic expectations of how long things will take. And the degree to which you need to try and look into the future.

You want your TPP, even if it's you know, fairly light touch in some sections, you want that available early. And you want to think about the disease population, which you're going to be marketing the drug to the patients who are going to be taking this drug. And you need to sort of think about the end game really early on and build a plan towards your IND.

I think if you sort of, well, we want to get into the clinic in the US, but you've got a timetable that you've actually got to have a plan to get to there. And I think that's what I would urge people to do. You know, there are plenty of people like you and I and others who can help people build those plans and get them to where they want to be in a structured fashion. And I think that would be my sort of key message there.

Yeah, there's really no substitute for practical experience at the end of the day. And ideally, you're working with the same folks from the translational phase all the way through licensure, the people who are really going to be able to be influential in helping you with your strategies early on, but more importantly, not someone who's picking it up midstream, learning on the fly.

Obviously, we know that this exists, but if you're taking these de-risking steps and then kind of keeping these stakeholders largely similar, I think, like you said, it's not even just your IND at this point. You're really de-risking the entirety of your life cycle development. Okay. Well, Eric, it's been a pleasure speaking to you today. This is a topic we love to talk about ad nauseum. And I hope that our audience has enjoyed listening and see you again sometime.

Thanks, Eric. Great. Thank you. Goodbye, everybody. Thank you. Music. Thank you for listening to Conversations in Drug Development, the podcast series brought to you by the team at Boyce. Don't forget to follow us on the usual podcast platforms or visit our website to ensure you don't miss out on any of our. Music.