Talking Biotech 430 - The FDA Regulatory Ecosystem- Expert Panel Discusses the Process

Hi everybody, and welcome to this week's Talking Biotech podcast by Collabora. And thanks to Collabora for sponsoring this work and allowing us to share information with you. Now, one of the big changes we've seen in biotechnology space has been an explosion of potential therapeutics and a pipeline that's based on genetic engineering. And considering that the first approved biotech drug was insulin, what, almost 40 years ago, it's not surprising that genetic engineering would inspire new thinking on how to solve challenging health problems. The COVID pandemic and speedy deployment of RNA-based vaccines, that was another big step forward that was rather recent, but put concepts like mRNA and PCR into the general vernacular, which I thought was really cool, and showed the public that biotech approaches can be used to quickly and very effectively address public health issues. But the unfortunate moniker of Project Warp Speed, it meant that the public started to question how the FDA and other regulatory bodies considered the safety and effectiveness of new drugs. And what does that process look like? So I wanted to provide more insight into that regulatory process and talk about how it evolved and how it's changing or how it changed, if it has, to meet the contemporary pace of drug development. And so we have 3 experts with us today. We have Dr. Deborah Webster. She's the Vice President of Regulatory Affairs at Aditum Bio. So welcome, Deborah.

Happy to be joining you, Kevin. Thank you.

Yeah, this is cool. And then Dr. Julia Marais, she's the Associate Director of Scientific and Regulatory Affairs at Pocket Naloxone Corporation. So welcome, Julia.

Thank you for the invitation, Kevin.

Yeah, we'll talk about Pocket Naloxone in a minute. And then Michael Matthews, Director of Regulatory Affairs at Sabin Vaccine Institute. So Welcome, Michael.

Hi, pleasure to meet you.

Yeah, this is great, and I really appreciate it. It's really the first time we've had a panel in the discussion, and looking forward to see how this works. So one of the fun parts about this is that all 3 panelists share is a common thread of moving from the Food and Drug Administration to industry, or having some experience in regulatory policy. And so first, I'll ask the easy question, and any one of you can dive in and answer this. Do companies recruit or otherwise pursue getting folks who worked with the FDA on their team? I mean, does it really help to have someone on staff that can tell you about, you know, the man behind the curtain before you navigate the yellow brick road?

So I'll jump right in because when I was with Cardinal Health, was my prior organization before, well, 2 organizations back, that was certainly something we looked for when we were looking to hire consultants. is we wanted someone with FDA background. And similarly, when I was at BlueRock, it was looking for, you know, people who had the experience, particularly in CMC, with respect to, you know, cell and gene therapies, seen as a very valuable asset. And so much to the point that this happens so much that I think Dr. Marks, in a remark at one point, said, Please stop poaching our people.

Yeah, I mean, I would echo that. I first was recruited as a consultant after I had left FDA. So I think there's, there's a lot of ethics rules about, you know, being recruited while you're actively at the FDA. But, you know, after I left FDA, that was one of the ways that I got into the company I'm at now was that they were looking for a specific consultant with a background at FDA that was a microbiology expert. So I think, you know, having that on your resume gives you a big leg up. And I think it also makes a difference because when you're reading language from the agency that's coming in information requests or other correspondences, you can, you can speak the FDA language, right? Deborah and Michael, you know what I mean, right?

Yeah.

There are, there are things to read in between the lines.

Yes. And we know how to pull out from the guidance documents the, you know, because they're very long and a lot of words, and FDA has to be very precise when they're writing those documents. We know how to pull out, you know, the important information from there, condense it down, so to speak, into regulatory speak instead of reg speak.

Oh, very good. And Michael, maybe you can answer this one for me about You know, during that transition, when you're going from FDA to industry, what was particularly surprising? And maybe like particularly how regulatory strategy or submissions are approached differently on each side? Like what lessons or practices from FDA review do you think are the most valuable for regulatory teams in industry to understand or adopt to be more effective?

But yeah, my experience at FDA is a little bit unique. I actually had worked in industry for about 8 years. And then I went to work at FDA for 4, and now I'm back in industry. So not too much surprising personally, but I guess it just reinforced my understanding of FDA going into working at the agency. Basically the focus on data.

Yeah.

I would say that prior to FDA, I would push, I would consult and say data runs product development, you know, and when I was at FDA, that seemed to be the case. And so I just continue that perspective.

Yeah, I've noticed, you know, being out of FDA, I've noticed that even very experienced regulatory affairs professionals, if they haven't worked at FDA, there is a bit of an underst— misunderstanding of how communication travels within the agency and, and how communication Like, like, um, guidance from the agency differs depending on the stage of development that you're at, right? So if you're at the IND stage, you're going to get guidance that's specific to the IND stage, but then you can't take that as the gospel truth for your full application. And, you know, I'll oftentimes explain to people, hey, that was true for your IND, but now the, the level of what you need to provide is going to be increased when we—

So Yeah, phase-appropriate— understanding of phase-appropriate approaches to drug development is really important. One of the things that I saw in working with a lot of small biotechs or small companies that were like a man and a molecule even is that really a lack of understanding of how the review process works, the timing of the review, how reviewers are arranged in the assigned and how they work together really just sort of seemed to be a black box. Even though FDA has generated a document called the 21st Century Review, you know, it's out there for people to read, but I don't think people read it. It's very, very dense and it's very hard to get through, but it does outline exactly what the review process is. And I think that there is a— that's what I saw was a little bit of a lack of understanding of what that whole process was.

No, very good. And we've also been joined Hi, Jonathan. We've been joined by Jonathan Elfgot, and he's a program coordinator and senior lecturer at the Johns Hopkins Center for Biotechnology Education. Hi, Jonathan.

Hello.

Yeah, we got rolling here and already just got through the first question, but I really appreciate your feedback on any of these topics as we roll here. And we were talking about the idea of what this regulatory process looks like and some surprises as you would transition. from FDA to industry, and it turns out from industry to FDA. We also came across the acronym of IND, which is an investigational new drug for those who are listening, just to kind of clarify that. So along that line, the FDA has these rules of what they call an investigational new drug. And can you tell me what happens at the beginning of that process of looking at an investigational new drug? How much work has to be already done? maybe, or what we have to know before the FDA gets involved? And is there a pre-consultation process or anything like that that can help smooth that initial contact with FDA?

Yeah, I can start with that one. I think the best thing to understand prior to going into working on IND is understand your product. It's surprising how many organizations I've worked with that don't understand their product. Um, and also understand your target indication. What are you going to— why are you going to run a clinical study? What are you planning to find out? And then understand your study design. So my whole focus is on clinical, but there should be people with focus on the chemistry, manufacturing controls, and then what non-clinical data do you need to support the IND.

Yeah.

One of the— so one of the best approaches is to prepare your IND and then find out where your gaps are to do a pre-IND meeting with FDA. Okay, so once you have a good— oh, go ahead, Deborah.

I was going to say, just to get back to basics and for the audience, if you, you know, are unfamiliar with the term of what is an IND, this is the, as we said, the Investigational New Drug application. It consists of All of the information that FDA is going to review to determine whether your product is safe to proceed to administer to patients. And that can vary depending on whether you're going into patients first, whether you're going into healthy volunteers to just evaluate the pharmacokinetics of a drug. But basically, the IND consists of 3 components: all the information you need to know about chemistry, manufacturing, and Controls, i.e., the manufacture of your product and whether it's safe, introduces any risks. The nonclinical studies that were done to conduct and support the clinical study that you propose. So, as Julia had mentioned earlier, that's phase-appropriate at your IND level. You may need only a 2-week study in 2 species to be able to enter— have your IND-enabling study. Those are your IND-enabling studies to support whatever your clinical protocol is. It depends on what your clinical protocol is and what the patient population is. And then, of course, the final section is the clinical, which at the IND stage simply consists of a protocol and investigator's brochure that would help you describe to the FDA how— what you intend to develop and how you intend to develop it. And that's what they review in order to make that determination.

Yeah, I think that's a great background. And I think to expand on the patient population note, we in CMC would also have different levels of scrutiny based on the number of patients that would be in the clinical study. So, you know, occasionally I would review an IND for, you know, one patient and, you know, and then compare that to if 1,000 patients are going to be dosed, right? So understanding the, you know, as you said, healthy volunteers, if it's going to be neonates, you know, the level of scrutiny is going to be shifted depending on that.

And the IND itself is an application to the US FDA to conduct research within the US and occupied territories. So depending on which phase of product and clinical development the product is undergoing. That will also dictate the type of engagement that industry or an applicant or sponsor of an IND would consider submitting to the agency. It's noteworthy as referenced, there are the opportunities for what's called pre-IND submissions and meetings, whether that's what are called in-person or written response only. Ideally, those are reserved for questions that fall beyond the scope of traditional considerations, that which has applied to any predicate products. And it's also important to consider whether it's at a later stage of development, perhaps introduced internationally, and the data is going to be leveraged to jump in at a later phase, perhaps at a Phase 2A, B, or even potentially a Phase 3 for obtaining marketing authorizations. And it's noteworthy as well that the FDA does not regulate the practice of medicine. Products used by physicians outside of the scope of labeling uses are not under the jurisdiction Or the enforcement of the agency. The gray areas are when products are used under non-investigational use, under clinical practice, and they're retrospectively analyzed with, with a concept called real-world data, real-world evidence, to potentially then be utilized to support either expanding marketing claims or even introducing initial Yeah, we'll come back to real-world application in a second here.

Oh, Julie, did you have something else to add to that?

Yeah, I just, I wanted to remark on the— Jonathan mentioned the pre-IND meeting, and I think that that's something that is underutilized by a lot of sponsors because that's your opportunity super early in development to start Mm-hmm. Teaching the agency what you're working on and getting some feedback. I think especially if you're working on a novel dosage form or something that's a little bit complicated, or even if you're, you know, a new small company and you need some basic feedback on, hey, you know, I want to apply for this type of full application, this is the strategy I'm going to use, the agency is very receptive to giving you that guidance. And a lot of times you'll get kind of like free advice. I know when I was a reviewer, I would— I loved all the new applications that would come in, all that, because they're interesting, right? It's kind of sometimes wacky ideas, right? And so I, I loved that. And so I would, I would review kind of a little bit extra and give additional comments. A lot of times the meeting minutes that you get back, they'll have additional comments and it'll be, you know, some more clues. Hey, in the eventual NDA, make sure you think about this, that kind of thing. So, you know, the earlier interaction, the better from my perspective.

Yeah, you always hear FDA saying interact with us early and often. And if you're working on the cell and gene therapy space, the— actually, it's now been made a PDUFA meeting, which is When it's— when I say something's a PDUFA meeting, that means it's part of the law. And so it has to be held to certain timelines, but it's called the Interact meeting, and it's an early engagement meeting for companies that are really early in development and have not done their IND-enabling studies or even their dose range-finding studies. And they really want to engage with FDA about what is our whole approach. With respect to nonclinical development. And it started as basically a nonclinical development meeting and then eventually became this PDUFA meeting. So you can have an interact meeting when you're not quite ready for your pre-IND meeting. At your pre-IND meeting, you should be ready to propose to the FDA, these are my GLP tox studies that I intend to conduct, and here's the protocols for them. At the interact meeting, you're like going like, well, I think we want to do the development in just rats and not in monkeys or not in dogs? Do you agree with that? More of that kind of question. And then, you know, this is how we intend to demonstrate, you know, mechanism of action, that kind of thing. So then— and then, of course, there are many, many other ways to interact with the agency throughout drug development, but I'm not sure that we're at that question yet.

Well, it would seem like that whole process would save you a lot of time and money, especially when you're talking about further trials in animal models, or even potentially how you may move to a clinical setting, that just engaging in that consultation is a good idea. What are some of the other big mistakes people make?

If I can just add on to that.

Sure.

In fact, FDA, the reviewers at FDA have actually combed through documents, and you can look these— I don't have the references on the top of my head, but they actually show that we When you engage and have these pre-IND meetings, you are less likely to be put on clinical hold. And this is documented from the, you know, as I said, CMC reviewers, a number of reviewers looking at all the people that— did they have a pre-IND meeting? Did they not? And then what were the issues for their clinical holds? And could it have been avoided if they had had a meeting?

Yeah, to address your question, Kevin, with respect to some of the pitfalls pitfalls to avoid. If we were to summarize the 3 main areas with respect to clinical, nonclinical issues in development, the safety, and the biostatistics, then what we— and what needs to be addressed is ensuring that the total product lifecycle is taken into consideration. is just as much as it is a science to not treat the agency as a consultative body. You have to craft the questions and select them in a very meticulous manner, and that is really the key to success. But what I've seen as a reviewer are signals that the applicant and sponsor themselves are simply not ready. They're asking open-ended questions as opposed to specific questions.

Yeah.

Regarding, we've narrowed it down to these approaches, we're defending with confidence. Do you see any issues with respect to this approach? It's a little different than what's outlined in the guidance or in the ICH standard, but it's really tackling it from that angle. And we're really focusing really on the early stages, kind of the first-in-human. But it's also important to recognize when the IND is first being filed, can also be towards the later stages. And that's a little different than the considerations that we're really talking about pre-IND. So it's really focusing, just like it was mentioned earlier by my colleague, former colleagues, reverse engineering the complete sections and how it's manufactured, what the clinical, nonclinical information is, and your biostats to make sure it's safe for use. And I think if you follow that and Avoid asking obtuse questions and sticking to the value-added endpoints that will guide the optimal process for agency approval, that those are really the key ingredients.

Yeah, developing the pre-IND questions or the even, yeah, the pre-IND especially, you really want to keep the end goal in mind, right? The end goal for these products almost always is to get a marketing application to sell the product for the business to make money. So keeping that BLA or NDA in mind, as Jonathan said, you want to reverse engineer that development path and find out again where those gaps are to ask the agency direct questions that you can get answers.

I guess one of the things that's come up in this conversation that I would've never anticipated is that, all right, so say I'm a research laboratory, I come up with a new drug that shows some efficacy in animals, appears to be safe. I also have to demonstrate that I have a way to manufacture it safely in order to be considered for further tests in an IND application.

But they're basic. It's basic. Yes, you do.

Yeah, the quality, you know, in fact, this is where FDA has really implemented quality by design, and they've really implemented that in the manufacturing space in terms of, you know, having you test a lot up front. And this is very important for cell and gene therapies. They want you to test a lot up front and refine as you gain greater understanding of your product and manufacturing. As Michael had pointed out earlier, understand your product. There are so many— it's in the Code of Federal Regulations that your product has to be safe. And that includes impurities, mycoplasma testing, sterility, and Matt, Michael, I'm sure, and Julia, you can add more things to that as well as Jonathan. But you definitely have to have the CMC information showing that you can manufacture it safely and consistently.

But I would also add to that, that it's, you know, it is not to the level of a full application again, right? So I— Right. And it— so I mean, Kevin, if you're a recent— you know, there are also research and commercial INDs. That's, that's a distinction, right? So I've seen INDs from professors at a university, right? Um, and so, you know, what you're expecting at that level is going to differ too between something that's commercial, and you're going to get more commercial-appropriate comments, right? Um, but so yeah, it's, it's It's not the sort of thing that it's, you would be unable to produce, especially at the IND phase.

I would add for clarification to the audience, the IND itself is found under 21 CFR, part under the Code of Federal Regulations. And this applies to both drugs, biologics, as well as combination products. And speaking from a compliance GMP perspective, as a former officer, inspection agent, the sponsors themselves are really married to that manufacturing process once they couple it with their clinical data and their research. And so even if it's done in an academic setting, it needs to be scalable. And they should have in mind the ultimate commercial end goal. in the ability to mass produce under GMP conditions. And so I think it's really ensuring from upfront, as mentioned, quality by design, whether we're talking clearly articulated endpoints or we're talking about how it's made, where it's made. The manufacturers and the sponsors early on need to understand the consequences of And I've seen talk about pitfalls, trying to cut corners, trying to save money early on. And when there's a signal, right, it's one of those good problems to have. Great, we have to move up. We have to make hundreds of batches. We have to make thousands now. Wow, it's going to cost a lot more than we thought. Well, hopefully the way it's manufactured— and we brought up, and Deborah brought up cell and gene therapies, which are considered really its own domain.

Yeah.

Especially the way the agency, through a team called Team Biologics, evaluates these manufacturing facilities. The biologics license application itself is issued upon approval to both the facilities that are corroborated by the field auditors, as well as the— ultimately the BLA application as a result of a successful IND study. But this is just a confirmation to the audience that this applies Equally, the IND studies to biologics, cell and gene therapies, and drugs, as well as combinations thereof, and drug device delivery systems, so that the manufacturing as well as other considerations can be addressed successfully throughout the development process.

It seems like a lot of the approval process, or at least in initiating the application process, I should say, is it lies in design of clinical trials. And so what are some of the considerations of designing clinical trials correctly to meet regulatory standards that really expedite the approval process? So in other words, you know, what do companies have to do from day one and what should companies be investing more of in the beginning rather than in the later phases?

I think quality by design applies equally to your clinical trial design, as well. What is your patient population? Are you going to be able to enroll them? Getting patient input is huge, particularly in rare disease cases. These clinical trials should be designed so that they are not a burden on the patients who are participating. I'm not going to talk about the Phase 1/2 studies where you're just looking at pharmacology— sorry, pharmacokinetics, or the level of the drug in your blood, but about when you're going right into patients. And you need to be very thoughtful about that and implement this quality design. What is your outcome? What are your endpoints? Do you have any biomarkers that you can evaluate that could support an accelerated approval? Are you including an appropriate number of patients that is like the diversity of the population. FDA just issued guidance on this that's out for comment right now. And it's really important because if you don't have enough appropriate amount of people in that population, you may be asked to do, as a post-marketing requirement, a study in that population that you may have not adequately captured in your— your clinical trials. So, you really have to be thoughtful.

I would say you definitely want to talk to the division, especially since Deborah brought up rare diseases. You definitely want to talk to the division about the study design and definitely get agreement on the primary endpoint that you're targeting.

Yeah, and Deborah also brought up, you know, the agency puts out a lot of guidances. So, I mean, that's always where you should start from, right? looking at the exact kind of product that you're trying to market and then thinking around, you know, for example, if you have a combination product, then you're going to have to do human factor studies for the device portion of your product, right?

Yeah.

And so I always begin with the guidances. FDA has a great website where you can, you know, search different keywords. And then there's also So, you know, you can look at reviews, parts of reviews from other applications. So you can either do a Freedom of Information Act request to get the actual FDA review of a product that might be similar to yours, or there are some that are already published on Drugs@FDA. So I use all of those as ways to get clues into where Absolutely.

Always look at predicate products to see how they can help you. Don't reinvent the wheel if you don't have to.

Yeah.

And with respect to keeping the common thread on approaching this holistically, I break it up into 3 key consideration areas. Number one is what is called your MCID, which stands for your minimally clinical important difference. And this is ideally going to identify whatever signal it is that you're looking to evaluate. And as Michael and Julia had mentioned, you know, we have to really think about whether it's combination drugs or combination biologics or combination products themselves. And from, from these values, though, of what we're identifying as our primary safety and efficacy endpoints, that's where we're deriving our sample size calculations.

Right.

What do we know about the standard deviations? What are what's called least burdensome approaches that we can take to ensure that we're deriving the most useful information possible with a smart— notice I didn't say small sample size, but this is going to be driven upfront by the decisions that are made regarding the nature of the product itself, the patient population, what it is that's being evaluated. And then there's also the concept of what's called spending your alpha. What I've seen is, and I was, as a former reformed recovering researcher, I could say I loved the idea of having multiple different secondary endpoints, even a lot of exploratory endpoints, a lot of imaging biomarkers. I love learning about the mechanisms of action. Enriching the population, but they all costed money. A lot of times I wished I could have just, you know, if I would have just picked the most important thing, focused on everything afterwards, once I get the approval, I might have given myself a little more runway. And so I think it's really thinking strategically about how your product will fit within the standard of care. And then it was mentioned the different tools, like making it more patient Whether we're talking about later phases leveraging decentralized clinical trials, remote-based technologies, telemedicine, these are all factors I think that are going to improve the quality of research when built and implemented.

And I'm going to talk about the least burdensome way to keep our sponsor happy. And we'll take a brief break here. We're speaking with Dr. Deborah Webster, Dr. Julia Murray, Jonathan Helfgott, I'm sorry, Jonathan, Jonathan Helfgott, and Michael Matthews. We're speaking about the regulatory climate and how you begin to navigate the regulatory climate with investigational new drugs that are potential therapies. This is a Talking Biotech podcast by Collabra, and we'll be back in just a moment. And now we're back on the Talking Biotech podcast by Collabra, and we're talking about the process of at least initiating the application on an IND, so an investigational new drug with the FDA, and what that process looks like. And really what I hope to do is do 2 things today. One is to provide for folks listening a little bit more about that process and understand it from a side where if you're interested in moving a drug through, how some of the pitfalls that you may encounter and some of the things you do better, but also at the same time to build a sense of trust in the system for the average person who questions, is this really a process that is rigorous? And does it take time? And are there different levels that need to be satisfied? And the ultimate goal, of course, is for all of us to be better at understanding and communicating what this process is and isn't to the folks who are curious. And that's really important. So, you know, Jonathan, You mentioned earlier something about real-world evidence. And so what is real-world evidence and how is— it's an unusual term. How is real-world evidence being utilized in the regulatory submission and what challenges and opportunities does that present?

Yes.

As we summarize our discussions from the first half of the podcast, we come to the conclusion that the shift of focus as you go early stage is more on safety and slowly progress towards, okay, now that we know it can be used, is it really, really working in my patient population? Who is my patient population? And now do I have enough evidence to prove some of the marketing claims or labeling claims that the sponsor is looking to make? And this is where the concept of what's known as real-world data and/or real-world evidence comes into play before consideration. It's important of utilizing these concepts. Traditionally, folks like myself have been guarded with respect to you're just looking to compromise the way you're collecting information because the only way I really know whether a product works is whether you evaluate it through a double-blind randomized controlled trial, 2 of them to be specific. And this is all under the 21 CFR provisions that identify adequate and well-controlled as being interpreted for those 2 RCTs, whereas really the ability to do hypothesis testing still exists in a real-world study. All you're really capturing is was there exposure exposure to the product? And do you have clinical outcomes that are meaningful that can be collected? As a former paranoid FDA compliance officer, the biggest consideration is, is there bias introduced? How do I know the information— the sponsor's or the manufacturer's information— to look superior? And it's the ability to demonstrate really beyond any scientific That the approach and the validation of whatever that— whether it's— and there's multiple ways, again, of deriving it through registry studies, through electronic health records, through retrospective analyses. I mean, it really can be confusing for folks. And so maybe I'll pause there and just try to—

Yeah.

Galvanize the discussion with regards to we're still having to determine whether this concept would apply in the first place. And this is typically once the molecule, once the product's already on the market, and just to be clear. And then how do you convert that real-world data to real-world evidence? There's a strategy how to employ that. And so I'm sorry, Dr. Webster, please.

Yeah, so I think it might be helpful for the audience to understand that real-world— there are 2 different terms at play here. Real-world data, and that's data relating to a patient's health status, the delivery of the healthcare that's routinely collected from a variety of sources. They can be electronic records, medical claims data, and registries. And that's from the FDA definition of what they consider to be real-world data. Real-world evidence is the clinical evidence about the usage and the potential benefits of the risks derived from the analysis of real-world data. So whether a real-world data set or source is appropriate to develop real-world evidence that can serve as confirmatory evidence for efficacy depends on a lot of different things: the reliability and reliance of the data source, how it was collected— was it 21 CFR compliant in its collection— and the quality of the study design, and then the statistical analysis methods. One of the things that has been a problem with using real-world data as real-world evidence has been built-in biases. Nonetheless, it's becoming increasingly important and being discussed that the accumulation of this data can be used in terms of creating a control group for a rare disease. It's, you know, treating rare diseases is very hard. You have very few patients.

Right.

You don't want to have a placebo group. The patients don't want it. The parents don't want it. It's— but it's like there was still this RTC, randomized clinical trial, that's just hanging over things. But recently we've seen an approval of a gene therapy based off of real-world data that came from a natural history study. And so you can create these arts, almost like an artificial control group. control group. And, you know, this isn't something that's like really brand new. I mean, we know in oncology that, you know, we know what, you know, the advancement of, you know, survival and time to remission and those sort of things. Those are things that have been collected and used, and drugs have been approved in oncology based on You know, already know about the progression of that disease.

And to add really to the poignant points, which are, does the data itself have the richness, the robustness, the clinically meaningful information for it to convert from RWD to RWE? And it depends on the question being asked. And in my experiences, When you drill down to it, unfortunately, a lot of the electronic health records just don't have that level of detail because they're primarily used for billing purposes. At best, you have 1 out of 100 records, even with patients that are diagnosed with that population, really have all— even when you try to trim it down and use a less is more approach, do they have that bare minimal information that I would need to determine outcomes? We have to be judicious with ensuring it's still a complete and accurate set of records for the outcome, as mentioned, whether it's what's called the use of digital twins that I've seen also driving some of the later-phase studies, right? As a lot of the OncoOutcomes, when you know what some of the time spans are, why have to enroll controls You know, placebo groups, where sometimes even a randomization of 2:1:1, you can replace the 1:1 ratios while still getting that statistical power, as well as the concept of synthetic control arms, even possibly trying to replace placebo control arms as a whole in certain circumstances for rare disease and populations that really need to benefit from these types of trials. Yeah.

Another topic that came up earlier today was the idea of diversity in a clinical population. And this is an interesting concept for me as someone who thinks about how you design experiments, that yes, it's important that we understand diversity and that we understand how different could have different effects based upon the many factors in a diverse population. But at the same time, doesn't that also take away potentially from our ability to be able to identify the effects or safety because we're not looking— we're looking at a heterogeneous population that we really should be looking in a very focused population first, or maybe many different significantly large populations in that clinical trial. You see that where that trade-off is, and is that something we really have to think about?

I like to give the standard regulatory answer to most questions. It depends. It depends on the target indication you're going for. We talked about rare diseases a bit. You still want to include diversity in a rare disease population study, but if you only have, you know, 300 known subjects or patients in the United States that have the disease, you're probably not going to get the diversity you want.

Yeah.

But if you're developing a vaccine that All studies are gonna be in healthy volunteers. There's no reason you can't have the appropriate level of diversity that the population—

No, very good. That was just one that came to mind as we were talking. But I guess the other question along the same line is that diseases and health problems are global, but regulation is regional or national, whatever that works. And it's confined to some sort of geographically defined regulatory And so how do regulatory challenges differ when you bring a drug to market in different global regions? And how do you, as a developer, adapt your strategies to meet these different varied requirements?

So from my perspective, maybe it helps to understand just at the basic level what it takes to start like an investigation of a new drug in the US versus Europe. So in the US, you file an IND application for your drug for that one indication, and then that IND allows you to continue development of that drug through to its IND— I mean, NDA or BLA. In Europe— and I'm only going to address Europe and MHRA England. I'm not a great expert at China or Asia. But basically there, and this is for Canada as well, Well, every clinical trial has to be approved through a clinical trial application. So you do your Phase 1 study, that has to be approved. There's a process that goes through where it gets reviewed, and then you have to get your IRB approvals, and then you go, and then you do the next study, and you have to do the same sort of thing, the same filing, and wait the days for it to get approved. Whereas in the US, you start your trial and then the The safety of the subjects are overseen by IRBs. And so you can start your Phase 1 study, submit your Phase 2 study, and essentially start right away. Most people wait the 30 days to give FDA a chance to react to it. But basically, it's the IRB then is that making sure that the patient's protected.

Yes.

So that's just a fundamental difference between the two. To get into the specifics The differences about what's required in an IND for each of those is a whole other topic of conversation.

As someone who's currently learning the African regulations, a couple countries in Africa, I second that. It does turn out those 2 countries, Kenya and Uganda, do also buy clinical trials as well. I've been learning that on the fly. But I would say that to give a broader answer to the question, You're going to want to find a local expert for that particular region. If we wanted to run a study in another country in Africa, I'm not going to be looking at the regulations for it. I'll be learning them, but we'll be having— we'll have someone else help out with that.

I think, yeah, I think it's also important to understand that there's something called the ICH, the International Council on harmonization, and that is an effort between— you guys correct me if I'm wrong— I know it's at least Europe, Japan, and the US. I can't remember if there's more in that, but it's essentially a consensus between several global regions on what requirements are needed for certain aspects of application. So there's a lot of CMC information, especially on stability and, you know, when you need to look at qualification of impurities and things like that. So there is an effort to make it easier for sponsors to be able to reach approval in multiple regions based on, you know, it's— they put out these guidances kind of like FDA.

Yeah.

And so then you can, You can at least know, all right, in these regions, if I follow this, then I'm on the right path.

Yeah, I was, when I was at FDA, that was when, this is really gonna date me, that's how old I am, but that was when we were doing the ICH guidance documents. And so we actually formed committees around that to come up with the documentation and, you know, align with that. And we did, they did, doing a really great job of it and so forth, but you've probably noticed that there haven't been a lot of ICH harmonization documents of recent. There's been a big push, I think, by Dr. Marks to come back to that with respect to CBER because of the complexity of these products. You know, they're called ATMPs in Europe, they're called cell and gene therapy in the United States. They have— this is where we're starting to diverge diverge again, and then we need to come back and have more convergence so that it makes it— because diseases are global. They're not one country-specific usually.

And the ability to compare apples to apples with respect to the patient population, there are differences. The standard of care, as I referenced earlier, with regards to how the product would fit within the US context, can often be different Depending on where medicine is being practiced globally. So when you look at the cumulative clinical evidence that's presented, you have to ensure that it reflects the heterogeneity that—

which—

that of the US population. And when you're doing research in certain pockets of the globe, you have a tendency for the population to be a little more homogeneous. So that sensitivity analysis with regards to how the totality of evidence does compare US exclusively with the rest of the world can often be a factor that the agency uses to drive some of its decision-making as well.

Well, that's a really good explanation of how these things can differ by place. But what about through time? It seems like the rules are always— well, I shouldn't say rules, but the Standards may be always adjusting to better accommodate or to be, you know, perhaps have more rigor in different ways. But how can companies best adapt to changes in regulatory policy and be most updated to ensure continuous compliance throughout the entire drug development lifecycle?

That's a tough one. You know, when you see that the things— when things change and when guidances get updated, it's Because FDA now becomes familiar with the product. You can, as the most recent example, you can look at autologous CAR T-cells and the journey that they've been on. And the data that was— that's in the information that was needed to support the first one, as FDA got experience, now they knew what to ask of other sponsors to be able to provide a similar product that has similar safety. Because the You know, they, now we have several of them, right? So it evolves and you, probably the best way is engagement with FDA because as Matthew, Michael pointed out, it depends. It's a case-by-case. I mean, these are terms that FDA uses all the time, weight of evidence. So you need to keep up, you know, with what the guidance documents are saying. Follow what other companies are doing. Predicate products are great ways to be able to accelerate your development pathway and interacting with FDA early and often.

Go ahead, Jonathan.

I think an appropriate visual that would serve as a good analogy is playing pin the tail on the donkey. No matter what, everyone gets spun around. The question is, when you don't have the right navigator or navigators, it's like having the blinders on. But even the experts themselves have to spend as a full-time job and profession keeping up to speed with the rapid evolutions and development of— it's not just recommendations from agency guidances and policies and the way they interpret things and what the competitors are, what the landscape is. It's also the technology itself, the tools, the industry best practices. And the key is, as Charlie Munger said it best, knowing what you don't know is more useful than brilliance. So the ability to ensure that you have the right integrated interdisciplinary team supporting the product development process, that's really the best way to mitigate the risks. of not following the most up-to-date and valuable information that the agency is providing to the industry and the stakeholders to accelerate the development of these products to fill these unmet clinical needs.

Yeah. And I think also understanding that if you're trying to do something new, there is this phase in which you, you have to To teach the agency what you're doing. And right, it's good to have this regulation, right? There's, it's these checks and balances. The agency has this wealth of knowledge from other products and they know what kind of risks to think around. But if you're doing something new, then you have to have that conversation back and forth and say, okay, I didn't think about that aspect, but hey, FDA, did you know this about my product? Right? And I think that, you know, Deborah, you were just mentioning this, right, that the agency is slow to move, which is a good thing because they're careful and it takes time to move the guidances and the thinking on something. So I think being willing to engage in that conversation and kind of push back on the agency, and then they'll push back on you, right?

And everything by data.

I think, Michael, you said that initially, right? If you can defend your perspective based on data, they're scientists, they're fine with that.

Absolutely. It is data-driven, and FDA is not there to be a roadblock, but to be, you know, the map. They, you know, they're not, you know, there was when I first started at FDA, there was this sort of feeling, I think, within industry is like, oh, it's just a roadblock. We have to get over this regulatory hurdle. And I just didn't find that to be the case. I feel like, you know, everyone should take a step back and realize that they're your partner in getting drugs, much-needed drugs to patients.

I'm going to go out on a limb here and say with data, you can pretty much do whatever you want. Yep.

With the right data.

Got to have the right data. Yeah, that's it.

Let's just say, yeah, with good reproducible, well-obtained data, right?

I would add— I'm sorry, I'm sorry, Michael.

No, I was happy.

You know, reflecting on the numerous training programs that I went through as a premarket evaluator, field investigator, the training programs that I developed for the reviewers as well, the theme was we're a risk-based agency. Do the Benefits outweigh the risks. That's really the fundamental questions, and it's not really a quantifiable answer as reference. It all depends right on the particular product, how it's aligned right. The level of risk tolerance for terminally ill cancer patients can be much higher than products you know that are nominally you know treating minor aches and pains. And so understanding the relevance. that not all clinical evidence is equal and that each particular indication and product has its own nuances. And how to effectively address that is, is really the key to not just staying on top of whatever's coming on a day-to-day basis, but making sure you have the right foundation. That, that's really what's most important.

I think in terms of that risk estimate, what I've seen an evolution in is FDA's listening to the patient voice and the risk patients are willing to evaluate. So they were, I think, you know, in the past, you know, very, very conservative. It's a conservative group, right? It's a conservative organization. You know, it was okay, you know, we're looking at it in isolation of, you know, the indication and the overall population. But there's more of an understanding now that some patients are willing to accept more risk. and some diseases are willing to accept more risks. I'm willing to accept the risk of cancer if I have an incurable rare disease that I'm only gonna live to be 2 years old. Right.

Now that's a really important change in that regard that now you have opportunities to do these tests previously where it was considered completely out of bounds. And it's a great example of how things have evolved in the biopharma space. And Are there any changes that you think will significantly impact the biopharma industry next? So what are some other changes like, and then this is maybe the magic wand question to wrap up, is that if each of you could create some sort of change in that regulatory environment, what would you want it to be?

Well, I think less about what would I want to be and more as I was leaving the agency, there was this move to combine different disciplines into groups so that each application you got, each IND you got, you were reviewing with the same group of other reviewers. And I think that made a big difference the last— in the last year that I was there because you had a rapport with the other disciplines.

Mm-hmm.

You knew the same people. Before, I mean, it was just selected from this massive group of people, right? So I felt like at the end that made it so that the information being conveyed to sponsors was more connected, and I think that made for a better review of the, of the application itself. So that's— the agency already did that, so props to them.

I'm not sure I can think of something that I would want the agency to do. I mean, I just think there's so— I think they're really on the forefront of a lot of emerging technologies. They're really on the forefront of how are we integrating AI into manufacturing. They've been on the forefront of incorporating real-world data and real-world evidence, having done their own studies on it and whether it correlates with doing retrospective evaluation. Does that data correlate with the data that they had approved the drug on? And then the digital digital health technologies. That's a huge— that's going to be a huge leap forward. So all of these, you know, really incredible technologies that are coming through, I feel like FDA is really on top of it. A lot of different programs to allow for platform— to work with FDA to allow for evaluation of platform manufacturing. A lot of different programs, the iStand program, the Cures program. I mean, I really I really feel like they're doing a great job.

They are. I think it's good to note, to remember, the agency doesn't collect data. They don't manufacture products. It's the companies, the organizations that develop these products do that. My magic wand answer would be data transparency. I know the agency only has so much they can do with that. We were talking earlier about drugs at FDA. And other means that FDA has to release their review documents, albeit they're still redacted. But if I had the magic wand, I would require all organizations to be transparent with all clinical data and preferably non-clinical data, but especially—

Yeah.

I know clinicaltrials.gov has been trying to push for that in some ways.

It's been okay, but That reminds me, or triggers in me, I would like to have more access to what the nonclinical development plans were for everything. So much of that is redacted, and it would be like, oh, this would be such a nice roadmap if I could just see it.

We all want more data.

To echo the comments made, I think our former agency colleagues are doing a fantastic job fulfilling the dual mission of not just protecting, but promoting public health, trying to be proactive. And I think the key concepts that I'm seeing are technology and automation, especially the use of generative AI. I think that's going to be transformative with respect to driving decision-making and a lot of convergence with respect to where products fall under FDA jurisdiction. A lot of elements, right, of supporting physicians decision-making and then facilitating the phenomenon known as deskilling of healthcare, right? Giving the tools what physicians may otherwise use today, what ideally a nurse practitioner could use in a decade or two, and so on and so forth. So I think you're going to have to think about smart ways of doing research, answering the questions in economical fashion to determine the signals are there. And I have some very intimidating statistics. Remember, it's only 1 out of 10 INDs that end up either as an NDA or BLA, and that's at best.

Yeah.

And it's just to get to the IND filing phase is a Herculean task in and of itself. So recognizing there's no margins for error and that it's going back to building quality into the process, ensuring that you have clear clearly articulated endpoints, a product pathway, and how that meets up with the commercial plan. Think about also what's called market access— the coverage, the coding, the reimbursement, the payment. A lot of folks that I've seen go through the proverbial, what's known as the valley of death— they get the FDA approval, but then they don't have the level of evidence that they need to drive It's not just the payers, it's also adoption at the prescriber level. So it goes back to evidence, publications at the best journals possible, the RCTs. But how do we do this in a way that allows patients at the end of the day, because that's what we all are, to access these meaningful technologies, these meaningful solutions? Whether they're investigational or for marketing uses, it goes back to the agency should be applauded for setting up the infrastructure to allow all the stakeholders. It's the academic research institutions, it's the community care, it's the medical associations, really a space for everyone to contribute. And I think it's really the burden is on all of us as patients to ensure that the best medical care is being delivered to hopefully not just those in the US, but globally? How do we share this evidence together? How do we make decisions? How do we harmonize this so that the innovators can bring these technologies in cost-effective ways across the globe? And hopefully we can help fulfill these goals together.

Oh, very good. That's a beautiful point to go out on. Well, I guess you're just saying that it's not the rubber rubber stamp that the guy in the bunker claims it is on Twitter. So that's very enlightening. Well, thank you very much everybody for joining me today. I really appreciate your expertise and I learned a lot about this process. So thank you for joining me.

Thank you for inviting us.

Thanks.

Yeah. And for all the listeners, thank you for listening to another episode of the Talking Biotech Podcast. Write a review on iTunes, talk to friends, share this media because you And by amplifying what we're doing here through your networks, help us grow and help us reach more people to answer their quick questions about biotechnology, about the regulatory process, and how all these things work together to serve them. So build confidence in the very good system. This is the Talking Biotech Podcast, and thank you for listening, and we'll talk to you again next week.