“FDA Gap Analysis: The What, Why, and How” Featuring David Pepperl

Are you working on a drug or device submission? An FDA gap analysis can actually save you time and money by ensuring your regulatory compliance. David Pepperl explains the importance of performing a gap analysis and more in this episode of Insight at Biologics.

Transcript

James: Gap analysis isn’t figuring out how to fix Michael Strahan’s teeth. So what is gap analysis? When do I need it? How do I use it? Hi, I’m James C. Taylor of Biologics Consulting and joining me to answer those questions is David Pepperl, senior consultant and leader of our nonclinical team. This is Insight at Biologics.

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Hi David. Now for people who don’t know you quite as well as I do, why don’t you tell ’em a little bit about who you are and what you do? 

David: Sure. James. My name is David Pepperl. I’m a pharmacologist and toxicologist with Biologics Consulting, and I’ve been with the company for a little over 18 years. I’ve got a background in pharmacology, toxicology, cell and molecular biology, and I’ve been consulting for a little bit over 20 years now in drug development, product development, and regulatory affairs. I’ve been with, again, biologics since about 2004 and heading up the nonclinical team since about 2015. 

James: And now I want to get into gap analysis. I looked up a little bit about it when I found out I was gonna be interviewing you about it. But I don’t really understand a lot about it, so this will be a perfect opportunity for anybody else in that same boat to learn. So just broadly, what is gap analysis? 

David: Well, in the biopharmaceutical industry, we see a lot of projects and a lot of clients and sponsors come to us with either early stage projects, middle stage, late stage projects of all sorts. And a lot of times we need a place to start. They ask for help, assistance with their program, and you need to start somewhere.

You can’t just dive into a specific question and address the finer points of what they’re asking without first reviewing what they have and doing more of a deep dive. Gap assessment is really an early stage in depth evaluation or assessment of any clients or sponsors or company’s development program.

And in our case, it’s usually a biotech development for, say a vaccine or a cell or gene therapy, a small molecule medical device. And again, essentially what we can do and what is done with a gap analysis is an outside group can come in, review all the data, all the information on the product, and provide an assessment of where any critical gaps or holes in the program might be for whatever stage they’re at.

They may be at, filing a regulatory submission with the FDA, or they may be talking to investors, so it’s good to know if there’s any critical omissions or gaps in your program that may lead to stumbling blocks or clinical hold or some adverse finding that may halt your development program. So a lot of what we do is early stage assessments of development programs for biotech companies to see if there’s anything critical missing before they move on to that next step.

And it’s good to have an outside pair of eyes on one’s program because it gives a fresh perspective, a sort of unbiased perspective as to where things stand. And we would look for those gaps, if you will. And the gaps have to be compared to wherever the company or sponsor client wants to be. If they want to file a regulatory submission, an IND with the FDA, or if they want to have a pre IND or again, talk to investors, it has to be against some key milestone in their program. 

So whatever that milestone is, you’re trying to identify where any shortcomings may be and that’s where the gap would be. And then sometimes a client has just about everything they need, and it’s just very minor points that we inform them of. So it can be anything from one to the other. Quite a broad spectrum. 

James: All right, now, who needs a gap analysis? 

David: Typically, it’s any company that’s moving toward a critical juncture in their development pathway or program. In our case, it’s small to mid-size or even large biotech companies, drug companies, or medical device companies that will be looking to make a regulatory submission or something along those lines. 

And then they have to prepare information for regulators and submit that. Of course you want to go into the regulatory agencies with your best foot forward. So you, you have a dossier you would prepare and we would prepare that for them. 

James: Now, you had mentioned that this is done by someone outside of the project itself, so who does perform the gap analysis? 

David: Well, typically what we see is, clients come to us and as an outside consulting company, it’s often consultants or somebody outside the organization who would have that fresh perspective or highly objective perspective.

So usually you wanna have a group or person or persons, depending on the scope of the gap analysis. It could be a very focused gap analysis of one area, like nonclinical in my area, or it could be very broad and then have chemistry, manufacturing, nonclinical, clinical, regulatory. So it really depends on what you need.

So if you need a whole consulting organization, you may just need one consultant or one outside person. Maybe it’s an academic who’s an expert in the field, but it’s usually a group that can provide that broad development and regulatory expertise. And somebody, again, who’s not within the program or within the company, although that could be a case.

In the case of a large company, you might have some people who aren’t familiar with that project and they might look it over, but in general, it’s good to have a fresh, objective set of eyes on the program. 

James: So what determines the scope of a gap analysis? You’d mentioned that it can be very focused or can be very broad. So what determines the breadth of the analysis? 

David: Well, most cases, James, they’re, they’re pretty broad. They’re usually covering all the different disciplines in our, again, in our case, CMC chemistry, nonclinical, clinical, regulatory, and maybe medical device, if a client has a medical device involved with their program. But what really drives the breadth and the diversity of the gap analysis is what they have and what they’re requesting.

It’s best, certainly if you can review everything, if you can have a team involved and review everything that they have. But sometimes companies or clients will come in and they have a good handle on the manufacturing and they just don’t know maybe what they’ll need for the nonclinical, the animal studies, toxicology, pharmacology, or they just need a second perspective on that.

And sometimes it’s the other way around. It may be that they have the nonclinical, but they don’t have any CMC. Over the years I’ve seen most of them are comprehensive, covering all the different areas and that’s often beneficial because we also need to start somewhere. We need to get the information and digest it and take it in, and consider it in relation to where the client wants to be.

So it’s good that we can do that early stage review. But sometimes they only need a very focused assessment. If they might have the other experts in-house already and they’re missing some little aspect or they’re not confident of their data, those kinds of things that really drive the scope of it.

James: Okay. So you perform a gap analysis and you have an idea of where. You could improve things in your project. What do you do with that? 

David: Well, again, what we would typically do is take the time needed to review the material, go back to possibly background material or regulatory submissions that maybe they’ve submitted, or just basic data papers, and we would normally get our notes, our thoughts in order, and again, compare it to what they’re targeting, whether it be a pre IND or a mid-stage regulatory submission or a marketing application, a biologic license application, or a new drug application to the FDA. 

Or typically an IND, an investigation on new drug application, what we’re most accustomed to dealing with, and then we would write up a memo or dossier to the client and say, here’s what we reviewed. We reviewed documents 1, 2, 3, and 4, and we found these shortcomings, we found these findings that might impact your program and indicate how significant they are. A certain finding, number one is minor. It may not cause any problems, but finding number two, you can’t move forward unless you address that.

You may need an animal study or you may need to remanufacture your product or add some additional tests to your product qualification, something along those lines. So we would prepare a memo or a document that lays out what documents were reviewed and then specify comments on specific documents, particularly if they’re larger ones, like regulatory submissions or reports, critical reports, and what comments I might have on those.

And then the client could subsequently use those as a plan or marching orders and say, okay, this is what we need to do. Or let’s talk about this. Let’s consider, do we really need to do that? We may not have the financial wherewithal to do that. So there’s a lot of things that can come out of it, but often we’ll do these analyses and the clients will discuss them and then they’ll move on to address those gaps and move on to their next stage of development.

James: So if I’m understanding this correctly, this is a way of seeing, of preventing future stumbling blocks. You know, it’s seeing that you could run into this issue down the road if you don’t correct the areas identified by the gap analysis and that could end up costing you your time. So taking this little bit of time to do the analysis in the beginning could actually save you in the long run, correct?

David: Yeah, exactly. And I’d say it could be done for any sort of project really, and it’s just a matter of how much resources and time you have to put into it. But again, not only is the gap analysis a great place for somebody like us or a consulting group to start when we’re working with a client, it allows us to identify those key stumbling blocks and certainly save time and money.

You don’t want to go into the FDA and then get a clinical hold, have your IND put on hold because you were missing a study or you missed some endpoint, or you had some adverse finding, or you had some impurity in your manufactured material, that you can identify that and make sure everything is in line. It may cost more down the road. Costs more in the short term, but then it will certainly save time and significant amounts of money potentially. And sometimes we identify clients that are doing more than they need. 

On occasion, they may be performing more or maybe the wrong studies that aren’t really going to address the right questions, and then we can guide them to say, Hey, this study may not be necessary, but you may need to do this other study in another model to properly address what the regulators are looking for. It can get the program on track. It could save clients time and money, maybe help hone the program so that it’s more focused and more efficient in the end. 

James: Right. I was going to say, it looks like you have two different areas where you can find efficiencies, both in avoiding problems and in streamlining your process. So, All right. I have a study and I say, David, I want you to perform a gap analysis. What do I need to give to you and your team? 

David: Well, generally, James, a lot of these are performed on an entire program, so you know, we could look at a single large study, like you mentioned, but they could also be generally on an entire program. So they’ve come up to this point and what they should give us, or what they should provide to any outside group that’s performing these assessments, is everything, essentially as much as you can certainly. Papers that have been published, study reports, batch records for produce, material specifications for producing the drug or the biologic, or anything.

And then animal studies, analytical tests, results, essentially everything that they can afford to give us within reason. The more data that an outside group has to evaluate, the more comprehensive an assessment that can be performed, just like anything else. And you have to be careful. Like if you’re submitting things to the FDA, you don’t wanna bombard them with too much useless detail. You want to provide them what’s salient and succinct. 

James: Right.

David: But at the same time, for us, what we see, we can take everything. We can take reports and even notes or just data and figures, and, and that’s something that helps us too, that if they provide us with some reports or just figures and tables, but they don’t have the data presented in terms of an actual study report, that could be a gap because you need to have study reports, you need to have the data written up in a meaningful fashion that has the results and conclusions and methods presented in a meaningful way. 

So that not only consultants, but then ultimately the FDA can review it. In providing us with everything we can see that, well, they have reports or they don’t have reports, they’re so, they’re lacking something. So it really boils down to getting the reviewing organization or your consultants as much as possible to review on the program so that they can provide the best and most comprehensive feedback. 

James: So you really want to create a broad picture so that you can see in all the possible problem areas. That’s why you want to give everything. Now you had mentioned earlier, a dossier, usually the way that the results are presented to the sponsor. 

David: Yeah, it might be as a memo or a write up or an attachment, or a combined assessment from the different consultants. You may have, again, two or three different people working on this gap analysis for the client. And those can be combined into one overall assessment and then that can be provided to the client and then they can review it and then say, okay, we need to do X, Y, and Z. But otherwise the A, B and C are okay in those areas and we may want to talk about some of these other items and need clarification. So it’s usually a bit of that. It’s a write up that we would provide to the client after completing our assessment. 

James: Okay. And now, and now I have a kind of a slightly weird question, but it happens in the business world, so: Should a sponsor fear a gap analysis? 

David: Fear? No. I mean, wouldn’t you want to know, I guess it’s a little bit like going to the dentist. You mentioned fear, everything may be fine and you wanna find that out, and you have a checkup and you get that checkup where then, you may have a sore tooth and the dentist will tell you what it is and he or she will address it. We don’t know if we’re missing something, are we ready? 

Sometimes the sponsors know a great deal about their product. They may know a great deal about development and all the different areas, but sometimes there’s just something that you might miss, and that’s why it’s good to have that outside perspective and experts working in the field for years and years to look at these, the programs with a fresh set of eyes and with that regulatory perspective and an outside perspective to give you that assessment.

And I think you should welcome feedback. Sometimes it’s welcome, sometimes it isn’t so much, but I think it’s important to know where you’re at and you don’t want to go into, you don’t wanna press forward, with a substandard program, for sure. 

James: You had mentioned in explaining it a little bit about the dentist and they always say about dental problems, you should go in as early as possible because waiting never makes it less of a problem when it comes to the dentist, and I imagine it works similarly for a gap analysis earlier in the process is generally better. Correct? 

David: To a degree, yeah. And that’s a good segue to a point I wanted to make. You really need to have some substantive data, whether, you know, you’re, whether it’s just chemistry or just nonclinical or an overall program, you have to have some good data for an outside group to find gaps. 

If you are too early and you just have some ideas and you have thoughts on where to go, but you haven’t really done any of the studies, you haven’t really manufactured your material. You may not even be in position for a gap analysis because it’s all gaps. It may be too gappy in that sense, so in that case, what a sponsor or client needs is more of a development plan and that’s more of a roadmap on how to get from where they’re at to their final goal, whether it’s an IND submission, BLA, NDA, any of the regulatory submissions or talking to investors getting that funding.

But if you’re too early, we found in our experience that some clients come in and everything is missing, so it’s like, you need a plan to move forward and that can be provided as well, but it’s not really a gap analysis, so it’s really you have to have something substantive to work with and hopefully the gaps are minor and not Grand-Canyon-esque.

James: Thank you to David Pepperl for joining us. If you’d like more information, just email us at insight@biologicsconsulting.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 Kris Kraihanzel. 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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