A Discussion on CMC Strategy and Submissions with Ed Narke, Brian Lihou & Meranda Parascandola

A Discussion on CMC Strategy and Submissions with Ed Narke, Brian Lihou & Meranda Parascandola

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Episode Summary

Edward Narke is a Principal and Regulatory Managing Director, Brian Lihou is the Head of Operations and Meranda Parascandola is the Head of Business Development & Marketing at Design Space InPharmatics. Today, Ed, Brian and Meranda join the show to discuss CMC marketing application strategies and submissions. Specifically, they speak to the important role regulatory reviewers play in deciphering data and ensuring all authors are following one cohesive story. They break down other CMC issues they’ve encountered with projects they’ve worked on and provide insights and protocols clients can follow to yield a successful program.

What We Covered

  • 01:16 – Ed, Brian and Meranda take a deep dive into analyzing CMC strategy and submissions
  • 11:26 – Ed, Brian and Meranda discuss resources required for compiling CMC dossiers and the importance of understanding roles and responsibilities within this process
  • 20:09 – Essential aspects of putting together an effective authoring team
  • 25:25 – Brian speaks to the importance of respecting the experience of those that have been working on projects from the jump
  • 28:28 – Ed, Brian and Meranda discuss what sponsors should know about CMC regulations to prepare for a marketing application

Tweetable Quotes

I think the experience level of that regulatory point person during the submission is really critical. Click To TweetOftentimes we find that clients are also looking for a submission to be a learning opportunity for their own people. Click To TweetWhen you’re preparing to undertake this preparation to write this, the first and probably the most critical step is to engage across disciplinary teams. Click To TweetOne of the things that I think is often a recipe for anxiety and stress is not understanding roles and responsibilities. Click To TweetOne of the areas that’s really essential when you’re putting together your authoring team is to have somebody at the client that truly understands where the skeletons are. Click To TweetOver the years we’ve worked to build in efficiencies that take a lot of the guess work out of compiling the submissions. Click To TweetI think respecting the experience of the people that brought the project to this point is critical. Click To TweetPlanning is probably a better option than chance. Click To TweetTypically what I would do if I was moving on from an IND and starting to develop an NDA, I would start from ground zero, making sure I at least have an outline chart with all of the ECTB sections outlined in that manner. Click To TweetI think it’s important to note that the cost of doing an incomplete filing is monumental. Click To TweetRegulatory authorities are part of the team. They’re your friends. Seek advice, ask for their advice and also educate them. Click To Tweet

Links Mentioned

Design Space InPharmatics – LinkedIn

Design Space InPharmatics – Twitter

Edward Narke on LinkedIn

Brian Lihou on LinkedIn

Meranda Parascandola on LinkedIn

A Discussion on CMC Strategy and Submissions With Ed Narke, Brian Lihou & Meranda Parascandola

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Full Transcript

Ed Narke 

“I think the experience level of that regulatory point person during the submission is critical.”

Hey guys, it's Ed Narke. Welcome to CMC Live. I'm here to play another round of “what are your thoughts around regulatory and other CMC issues” with my co-hosts, Meranda and Brian. Today, we'll be talking about strategy and submissions- two of my favorite things. There are various types of submissions today, and I'm not talking about NDAs or BLAs. In particular, we're going to be the industry version of the investigative reporter. So we're going to investigate the requirements and the data necessary to report back to put a submission together, discuss any likely scenarios and some examples that we've dealt with, and what's jumping off the pages for us these days as we watch and build and review submissions.

For those just joining us unfamiliar with the marketing application, an NDA is a new drug application, and a BLA is a biologics license- similar to an NDA, but it's for a biologic. Together, combined, they're called a marketing application. So a marketing application, in my opinion, and for most people, is a way of telling us something; it's a way to tell the reviewer something about your process and product. The data in there is really important. It's always trying to tell a story. So our job as regulatory reviewers, authors, CMC experts, or whatever you want to call us is to decipher what that data is in that module and what it's saying and how it's saying it. So the marketing application is speaking a language, essentially. Are we able to interpret this language and what the data is saying in every application? Sometimes the data is light. Sometimes there's more of it. There's always a question on how to provide the data or how much data to provide. Sometimes the data is a little bit standoffish. Sometimes the data can be coy. So it's an art to put this together, to write this, and to present it. It can go out and apply one thing to a reviewer on the surface, and then he/she looks closer into the data, and it says something else. So consistency and cohesiveness are really important. Again, it's evidence; everything in the application changes evidence; in fact, everything it doesn't contain is evidence.

We can talk about some of those examples now. I wanted to just open it up here with Brian; as far as I just said, some of the experiences we've had- certainly have a lot of background in regulatory submission authoring- welcoming questions and those types of things now. Maybe we can get into this. This is a two-part episode. The first part we wanted to cover is the availability and the quality of the content- dossier and what that means. The second piece of that would be the resources. There's variability in how you produce this and how you write this. It's not necessarily written by one person. It shouldn't be. There's a lot of background on that one- compiling a full dossier- not just for marketing but for producing a good submission. And then lastly, for part one, what the sponsors out there need to know about regulatory CMC when they're preparing for the application. Our experiences, essentially, with not just the FDA, but EMA, not just during a drug development process, but during a submission, during a review, and then some of the things that crop up after. We'll have part two that talks in-depth more about Module 3, the quality overall summary, some of the reasons for that, and then we'll wrap it up with some conclusions and pull it all together. So Brian, good morning.

Brian Lihou 

Good morning. That was good. One of the things I think is important to stress as we go into this is the marriage between the technical and the regulatory. Often we'll see clients or companies that have that one person charged with writing and the entire submission. And while it's sufficient, you're talking basically coordinating with yourself. But what I find is that the CMC section is supposed to demonstrate a state of control. When you think about CMC and CMC sections, the body of an entire submission, I found over the years that CMC is often a bit of an afterthought. You're filling out Module 3, you put the summary together, and that's it. The real glamour is the clinical data. I think it's often overlooked at the completeness of your document's supportive filing and the understanding of the technical in that state of control. What do you usually tell clients if they ask you, “Hey, here's where we are in our program. Do you think we're ready to go forward and start to draft this submission?” What do you tell them in terms of the state of control and what you think they should have?

“We find that the clients are also looking for a submission to be a learning opportunity for their own people.”

Ed Narke 

Well, that's an interesting question. And it depends- that's a regulatory answer- it depends. I look at it as a superhero, essentially. The best, greatest superhero out there is Batman. He's not the smartest, he's not the strongest, he's not the fastest, but he has intellect. That's a noun- the capacity for understanding, thinking, and reasoning. So when you just asked that question, I thought of the analogy- if a tree falls in the woods and no one is there, does anyone hear it? And in the regulatory world, what do I tell somebody? If I'm explaining something to you about what has to happen strategically or what goes in submission and you do not understand it, do you really get it? That question is kind of an interesting one for the audience. The technical information you mentioned, submitted in Module 2 and 3, is clearly spelled out in guidelines, but it's also grey.

The CTD, the common technical document, it's a format, essentially, that has summaries, reports, and data; it's fairly well laid out. The question is, how do you populate that? Again, back to how much information is in those things. How much do you put in? Why do you put so much, and why did you not put certain information in? Any information there has to conform to the requirements – recommendations found in the regulations and CFR- Europe and the US. So the content is well defined. There are various documents out there, and there's considerable latitude for assimilating, discussing, comparing, and contrasting these compliance pieces or any of the data. There's no real answer. So every program is different. You start with your framework, and you sort of fill in the blanks. You start to build this, and it's modular. We talked about this before, many times, several layers; some have greater detail because there's more information. If you have 25 batches versus 3, you're going to tell a different story. You're going to present different types of information. If there are holes in certain areas, it's an art form. You have to basically pull 27 sections together to tell a story. This modular format integrates different studies and disciplines, analytical versus the process versus disability. Presenting that information is a kind of art.

Brian Lihou 

Yeah, over the years, I have represented the technical side. I didn't truly appreciate the regulatory experience and the benefit of that experience on a project until I started working with DSI more and doing more submissions because the technical folks work in a technical bubble. The regulatory folks understand the trends, the story that's trying to be conveyed, and the potential pitfalls from a reviewer standpoint. I think helping to guide those technical people what may seem common sense to me, if it doesn't read that way, you're set up for questions. That's why I think the experience level of that regulatory point person during the submission is critical.

Ed Narke 

Yeah. And like Batman and the intellect thing, just pulling all those things together includes common sense. So the focus of this Module 3 is really to demonstrate the quality of the product, the candidate, the intermediate that goes into it or that's part of it, including the substance, anything that comes before the substance, raw materials, etc., and then the drug product to the satisfactory of a reviewer. Everyone's held to the same standards, and no one gets a break, based on whether you're a small company or a large company, if you have an efficacious, really novel drug versus something comparable to what's out there. So getting this module right saves valuable time, starting early during the review. The Quality Module is a vital piece of an NDA, just as vital, and maybe even more so than the clinical. The thing that you mentioned- starting this a bit late is never a good idea. I know it's done for resource reasons, maybe you don't have a person to put it together, but there are things to consider. We talked about this in earlier podcasts. When you start to submit an IND, start to put stuff together there, build a strategy document, layout a plan, put placeholders in there, work with your vendors, talk to them about their capabilities, maybe bring a consultant in to outline that, speak with the FDA, put questions out there that you know are going to come up at some point that you're going to not know the answer for; you may not until you get in front of the FDA. Still, there are always reasons to have something like that in the strategy.

“When you're preparing to undertake this preparation to write this, the first and probably most critical step is to engage across the disciplinary team.”

Brian Lihou 

Yeah, I think that's my point. I'm not sure if I'm falling into the category of Alfred or not in terms of being the technical person that works on the project to Batman, Alfred.

Ed Narke 

We may start calling you Alfred then.

Brian Lihou 

I've been called worse, it's fine.

Ed Narke 

We already have a queue. So let's just keep going.

Brian Lihou 

That's right. I think the other thing that I've found is that, in working with other clients in the past, they either lean heavily towards technical with not a lot of regulatory experience, or they're heavily regulatory with essentially no technical experience. It's the balance in the marriage of the two. When we talk to clients, we talk about that wholesale approach. We have the technical person involved in the content offering, but you've got that regulatory oversight that guides the story throughout the submission. We always tell our clients that those two components are critical. It's not done to just tag on all of the resources and things to a project- it's done because it's checks and balances. If you don't have that, it shows. It shows in the sections, and you've chosen the questions that come back.

Ed Narke 

Absolutely. We went through a couple of things that we'll touch on today, but I think a lot of these blend together. My second point for this part one was about the resources. I learned my trade here, what I like and do here, and what I used to do here- I learned that at a large company, a manufacturer, writing drug master files was a different intention. Putting all that information wasn't to get approval; it was to have information available for inspections, references, and those things like that. It was maintained. There was not a lot of pressure to talk to the agency about what was in there. So, when I moved over to Big Pharma, obviously a very different environment, the information was pulled together. These marketing applications were dispersed to maybe hundreds of countries around the world, especially in large pharma. So the level of information and how it was put together had to translate to managing it eventually. Doing it for the last 15 years with smaller emerging biotech, we could touch on the limitations and what we're dealing with there. Anyone listening to this at a small biotech knows the resource constraints and knows what the priorities are. You mentioned that before- not putting a lot of emphasis on CMC. These marketing applications are held when they're submitted to the same standard as a large company. Merck or J&J are vertically integrated companies that have a lot of resources. So the expectations are the same.

To transition to the next topic here: resources required for compiling the CMC dossier, not just for the marketing, but making a good submission and managing it throughout development and post-marketing. So, Brian, you've dealt with this- dealing with the resources. You mentioned, a few times now, starting things too late, and then how many people are on it, who is on it. Can you talk to me about some of that stuff, maybe share some of your recent experience?

“One of the things that's often a recipe for anxiety and stress is not understanding roles and responsibilities.”

Brian Lihou 

Absolutely. So we've evolved over the years in doing this. And we've evolved as a result of lessons learned with many clients and many submissions. Often, we find the clients are also looking for a submission to be a learning opportunity for their people. They'll say right off the bat, “there are these sections that are going to be written by us; you can write these sections.” We can work with that. Absolutely. I think they're right to a degree; it is an opportunity for people to learn because it's a new company, they're gaining momentum, they expect many more submissions, and often, they don't want to rely on a consultant to do that. They want to grow that skill in-house.

There are a couple of key components that we require going forward. You have to have effective project management. You have to have true traceability of each of the sections as they progress through the different stages of authoring. Often those sections are completely tied into other sections, and they're gated. You can start one section after one's developed. Having that understanding at the PM level is essential. Whether it's the PM with the client or the PM is assisting it on our side, you have to have that first and foremost. You also have to have the critical dates established. Once you have that, you can manage to it. Now beyond that, we have an author, a regulatory author. So we will get out and say, “here are the required documents to get started to author.” We will provide a pre-determined list based on the CTD, and we get those documents in. The author then begins to craft it. The other piece, which we feel is important when we author, is a technical review. The author is the author; they take the content, they build the sections. The technical review makes sure that the source information content jives with what's being written. Then you have the regulatory review- this cannot be overlooked. On our side of the fence, we ensure that our regulatory lead reviews every section that goes over to a client. The regulatory lead, in our opinion, understands the correspondence, understands the direction that the filing has to go in, and ensures that all of these authors for the various components are following one cohesive story.

Then we bring in a formatter. Everybody can work in Word, but a formatting person is essential when it comes to some of these tables and the intricacies of formatting. They know the templates that we're working within, they'll know the publisher that it's going to, and they can turn around sections to be review-ready in a fraction of the time that a technical or regulatory person would take to do. Then, just as important as identifying the client review- often, we'll have clients that want to continue to review until the wee hours of the morning when a section is considered final, and then you have to open it up and do it again. So understanding the client's workflow is important and understanding our expectations for a client, which is to have cohesive comments back from your review- then we remediate the comments, and then we go on to publishing. So really, it's an author, a regulatory lead, an SME, a subject matter expert for that particular discipline, whether it's analytical, drug substance, drug product, and our formatting person. And that constitutes the DSI Team, all run by the project manager. And that's our approach typically.

Ed Narke 

That highlighted a question that I had, and I think he answered it already. So to summarize, when you're preparing to undertake this preparation to write this, the first and probably the most critical step is to engage across the disciplinary team. The members have to possess technical knowledge and the ability to collaborate effectively, as well. So establishing this team early is very important, right?

“One of the areas that's essential when you're putting together your authoring team is to have somebody at the client that truly understands where the skeletons are.”

Brian Lihou 

Well, there's an important piece. Everybody comes with different backgrounds and experiences, so you're bound to have different opinions. Who has the final say? I think that's important to get into.

Ed Narke 

Yeah, that's great. We've been on some of these teams, and I've been on teams in bigger companies, where everyone wants a piece of something, too. To accomplish its goals, everyone needs to understand and agree on what the goals are. That includes if you're working with a sponsor, helping them, assisting them, and some of that involves risk assessment. So what are the weakest aspects of working in that environment? What are some of these things to consider?

Brian Lihou 

That's a great question. So I think one of the things that's often a recipe for anxiety and stress is not understanding roles and responsibilities. I mentioned all of these different components that make up the authoring team. But make no mistake about it, this is a regulatory exercise. And what we find is- we see it with clients, we see it even internally amongst consultants- everyone has their own experiences and background. As you mentioned earlier, the guidances are written somewhat vague. They're left to interpretation. It's a good and a bad thing. At the onset of the project, it's really important to know that the regulatory lead on the project has an ultimate say in the content and the direction of the filing. They have to be in lockstep with the expectations and the strategy of the client. If you have that established early on, then when you get into these ‘professional disagreements,' the regulatory lead comes in, they have the background, the expertise, and they will guide the project. So I think it's really important to set those roles and responsibilities because it helps as you get closer to the deadline. A lot of emotion, a lot of pressure builds, and discussions happen- it's good to have those, nip them in the bud, and have targeted, focused discussions led by your regulatory lead.

Ed Narke 

When we're talking about the adequate resources for putting this together, the people, the process, those types of things like the goals, and cohesion here. I'm going to touch on it here, but I think we might come back to it, maybe the part two of this podcast, but it's probably something you could speak to very well- doing this a long time. I like to hear you, and sometimes I remember the good old days. In an ideal situation, the Quality Modules would be written once all the requisite data is available. But, unfortunately, the realities of modern drug development- you have CMOs here and there, you're bringing these guys on later- there are gaps in development, stuff you can't find. Rarely, if ever, are we afforded this luxury. So can you talk about maybe that plan? There are different scenarios. Some folks have Phase II, early Phase II, and they get some breakthrough designation or some fast track, and then suddenly it becomes very important, their submission date. Other folks come, especially maybe to us, and they have efficacy already. They want to file marketing applications at the end of the year. So different things are going on. So the reality is that the data is never just there, right? And if you wait till it's all there, then you're going to delay something. So can you give us just your feelings? Over the years, have you developed some thoughts on this one? Or is this what it is?

“Over the years, we've worked to build efficiencies that take a lot of the guesswork out of compiling the submission.”

Brian Lihou 

No, I think you framed it up perfectly. So each client is different, each company is different, each company's understanding of their submission readiness is different. We don't understand the drivers that have them file when they do- we don't really care. We care if it is ready and if we're putting forward a solid submission. So I think one of the areas that's essential when you're putting together your authoring team is to have somebody at the client that truly understands where the skeletons are, that truly understands and is forthright and saying, “listen, in development, we don't have the following items. They are planned, but we don't have them.” Okay, we will look at that; we will rate that risk. If the risk is great, then we may advise you to wait until that data comes in. However, if it may not be. As long as you demonstrate the plan you have in place, and you can speak to it, whether it's referencing the protocol or content of a protocol, you may be able to work around that with the understanding you may get questions. But for us, it is someone who understands their document library. We’ll often get access to a document library, and the file names don't match the content. There may be a numbering system that we don't know.

So one of the workarounds we developed over the years was that we would have to open every document in the past, and we would label that document because we know what it is now, and we put it in the appropriate section content. But now, what we've done is we provide a pre-determined checklist. And that checklist has the types of documents we're looking for and the CTD reference for why we're asking for it. That person can say, “well, that's report XYZ, I know it is. I'll put it in this bucket.” If you can keep that integrity in the way you request documents, the way you transfer documents, and then the way you file them ultimately to be used in authoring- if you can keep that CTD continuity, it heads off a lot of stress and anxiety. Often, we have clients that are just under-resourced, and they'll say, “Okay, I don't have time for this.” Rather than having five different people look all over the room, you have one person who's the gatekeeper, and you control that information. That, over the years, has helped streamline our approach. I haven't met a client yet or worked at a company where their filing system was par excellence to your point where everything you can imagine is available when you need it, so you have to be creative. I think you don't want to lose time trying to understand what you have- it should be done quickly, and then you should start focusing on the true gaps or the true potential risks, not spending your time opening files and looking for what the content is. So that's important. I also think in terms of efficiency and preparedness, what we typically do is we ask for Word versions of documents, especially some of these larger development reports. To sit and retype the entire report probably isn't in anyone's best interest. But if you can lift relevant sections out that are applicable and drop them into CTD, it gets that thing moving faster; it gets those draft sections back to the client for review quicker. Over the years, we've worked to build efficiencies that take a lot of the guesswork out of compiling the submission.

Ed Narke 

Okay, so in resources, I think I'll hit this here. I want to be fair to the management teams out there- they're under pretty much constant pressure raising funds. We mentioned this in an earlier broadcast with Judy Magruder- early-stage companies looking for money, building an effective team, keeping ahead of the competition, not being second or third, ensuring viability for the clinical development strategy. I know I always say CMCs should be the first most important thing, but, clinically that's as important for the patient. So drug candidates out there, pretty much everywhere now, to develop many sponsors and management teams, most of these places have varying degrees of familiarity or experiences with manufacturing requirements. We're lucky- we worked in manufacturing, so it's kind of second nature, like riding a bike. But can you talk to maybe some of that, as far as different companies, different management teams have that different experience? Sometimes they lack experience, and they're also charged with making decisions and signing off on the budget. Can you talk to me and Meranda, who has these questions for us often? Tell us about some of that variability- are there good reasons for that? Is it better for management teams to be hands-off in delegating, or does it present some problems? That's a dynamic that we deal with out there. It's not just the writing of submissions and submitting it- there are people involved, experiences, and previous experiences where someone had an issue, so they've become more conscious or risk-averse.

“I think respecting the people's experience that brought the project to this point is critical.”

Brian Lihou 

Yeah, I think that's a really good point. We've talked quite a bit now, but I think respecting the people's experience that brought the project to this point is critical. If you come into this situation where you are just saying, “What do you mean you haven't done X, Y, and Z?” You don't know the reasons why particular studies weren't started, you don't know what got them to this point, and you have to respect the people that brought the product to this point, whether it's executive management- everyone has a role, and often, we're brought in to represent a specific function, which is the details- get the details, get me the submission, and there we go. We are very careful not to dismiss what anyone brings to the table. You may have a particular scientist responsible for the molecule or the drug delivery system themselves, and they've seen this thing from bench to where it is now. Well, they are critical, and they have to have and feel as though they have a really important role in the whole process because that's the cherry on top, getting that application done. They've taken this thing, and they've nurtured it, it's grown, it's done well in clinic, it benefits patients. Understanding there is a lot of passion on the client's side and respecting that passion and experience that got to that point is critical. If you don't do that, whether you work with us or not, if your author doesn't have that basic understanding, it will create not necessarily an adversarial relationship. Still, it will affect how information exchanges and flows. Because if that person who has fostered that process and grown that process trusts the people representing it in a filing, they're going to tell you, “Listen, here's an area we did not develop as much. I'm not sure what this means, but we plan to do it down the road”. We can work with that; we can work with it. This is where I go back to that the regulatory strategist is critical. Because we can tell that story, we are in a state of control- however, these things are planned for this date. By acknowledging that- and it doesn't appear as an omission- you get out in front of it. I think it also puts the reviewer's mind at ease that at least it's acknowledged and in a state of control.

Ed Narke 

It does. We can go on and on about resources and tell good stories as well. But the third piece of this that I was morphing into before we get into this was the Module 3 and some of the specifics. What do we tell sponsors? What sponsors should know about CMC regulatory, for example, to prepare for a marketing application. We put data together, have an FDA meeting, and submit something, but a lot more goes into it. We can ask each other questions or share some of the stories. There's initially an IND- we talked about this previously in a podcast. You want to open a clinical study, and there are a couple of things you checkbox and some data. The true art comes transitioning in Phase II/III. The expectations are raised, more information is generated, or some discussions have to happen if not generated. Some fast-track programs are going fast, and there's not much time between Phase II and marketing application. Planning is probably a better option than chance, right? Meranda, maybe you can come in here. You've been listening to clients and some of that- tell us what we need to know, tell us what's important now?

Brian Lihou 

Publishing templates, some of those things have to be pre-determined, that's in your wheelhouse. Having the importance of templates and educating all involved on the templates and relationships with the publisher. We get in situations, honestly Meranda, where we say ‘template,' and there's a blank stare on their faces in meetings. And they say, “well, we'll use yours.” What's clinical using? Maybe something along those lines?

Meranda Parascandola 

“Planning is probably a better option than chance.”

Yeah. I think it would be important to discuss a little bit more about where to start- you don't just open a Word document and start typing up your submission. I think it's important for sponsors to get ahead of the game, figure out the templates they'll be using at least.

Ed Narke 

When should this happen? Or should this happen in Phase III, two months before they're going to have a submission? Or would you suggest, when you initiate an IND, not to have your final templates but provide something in a format where you're building towards something? So I have some thoughts on that.

Meranda Parascandola 

Yeah. So typically, what I would do if I was moving on from an IND and starting to develop an NDA or BLA, would start from ground zero, making sure that I at least have an outline chart with all of the eCTD sections outlined in that manner. So you start your thought process in CTD. From there, if you want to know what goes into those sections, it's important to start thinking about your submission templates. With those submission templates, you could have- just depending on the publisher, or depending on where you get your templates from- it could have instructions for you that are very insightful. It says, “this is what goes in this section.” I think a lot of sponsors are confused about what goes where and why it's important. Understanding that ahead of time might be able to give them a better idea to tell a story about that submission, rather than looking at it later and saying, “wait, this might go in this section.” They think about it, and they're like, “well, I wish I would have known this before” so that they could tell the story a little bit better that way.

Ed Narke 

Right? I just had a fond memory. Do you remember DoDocs?

Meranda Parascandola 

Oh, yes.

Ed Narke 

Brian, this is a side story. A long time ago, I wanted to create some sort of thing called CMC blueprint, where you open up a piece of software, it asks you a question, you put information in, and it just builds a submission for you. So we tried to promote that and sell that to small biotechs/emerging companies that didn't want to write anything. It didn't go over well, let's just say. But when you mentioned that, maybe a couple of years ago, we found this group called DoDocs, and they had some sort of advanced Google Docs, where you can write in questions. So we tried it again, but it didn't work. So ten years later-the point here is there's no real one way to do it- you have a blank Word document. There's plenty of granular information in guidances. It doesn't apply to every product. Use common sense, as I mentioned before. So what I would say is, no matter when you do this, you should probably do it from the beginning. The aim here is to design a quality product, and that's pretty clear, right?

“Typically, what I would do if I was moving on from an IND and starting to develop an NDA or BLA, would be to start from ground zero, making sure that I at least have an outline chart with all of the eCTD sections outlined in that manner.”

Make sure that the manufacturing process is consistent and delivers the intended performance each time. It's like baking a cake- you're creating a recipe, the cake should taste the same all the time, that's the one spec for that. So any information that you get from the very beginning, any knowledge gained from the stakes- you do certain things early in development, they don't work. Anything gained in these studies; you put together developer reports; we talked about that in a previous podcast, why that's important, why these build towards your submission. This all happens over time- your manufacturing experiences, providing scientific understanding as you go along, to support your establishment of your specifications, your process, the controls, and those things like that.

It's interesting if you think about this- where do you want to be? What do you want this to look like? You don't have to have your final templates, but if you're using something. You’re maintaining them. You're putting the right conformance information, information that's not going to change, that inherent knowledge, putting that in the correct sections, and then start filling in some of the compliance pieces and setting certain data, such as justifying a spec or why a process should start here for GMP. Those are all things that are supported by that. I think that's one of the things when you're talking to a potential sponsor out there, someone that may not have thought about an NDA until they get to the point- it's really important to just kind of pay attention, put an emphasis on the information and the story because if you get to the last stage, and you have good clinical data and your story's incomplete, you don't know where this came in, what that character was, there's a hole here, there's no ending- this is where reviewers come and find some issues. So it's really about building a story. One of the things- the investment- is when we should start writing this. The investment should be made wisely. If you're limited on cash and resources, and it's going to be a long trial, you may want to think about that, versus if it's a get up and go, we just got a partnership with Pfizer, and they're going to pay for everything. Understanding that science does not come cheap. Tight financial environments- most of these products aren't going to make it all the way; maybe 50% make it to Phase III, a lot less make it to the final destination.

Brian Lihou 

I think it's important to note that the cost of doing an incomplete filing is monumental. A lot of these companies are based on milestones, and there are certain expectations. And the expectation is when you come to the time of filing, that your submission, your application will be accepted. We've seen this where we've advised, and decisions were made, and suddenly, all of the questions start coming back and having a plan to manage that if indeed, it does come back. But more importantly, understanding where it could come back and be ready. The cost of it is expensive, the process of authoring the submissions is expensive, but if you consider the cost of not having it accepted, to me, it just seems as though you commit to the project when you can afford to do it, but understand that it is expensive. You can manage costs, the burn rate of hours, and all of those things and understand them. It is an expensive endeavor, but the cost of doing it incorrectly is also just as great and often not understood.

Ed Narke 

“I think it's important to note that the cost of doing an incomplete filing is monumental.”

Exactly. That's a good point. So really, the goal sounds like it should be increasing your level of understanding your process knowledge and everything like that, not just generating volumes of data- that costs money. We talked about this before, too- some folks have different thoughts on it. Regulatory authorities are part of the team, right? They're your friends- seek advice, ask for their advice, and also educate them- they're not there to help develop the product. It's not that easy necessarily to get in the other audience. Sometimes, if you don't have data, it's going back to how you tell the story. So seek advice, have those requisite meetings when you can, and ask good questions versus just three general, canned questions. So you had your checkboxes. Ask questions that you can get something out of, maybe based on making decisions on when to do things or something that you might want to document and have an agreement on that's binding that you can come back to. Often, you can do this, especially more recently, and have post-marketing commitments, especially if you're a fast-track program. I mean, ultimately, the authorities control your product's fate. It's only an advantage for a company to seek out that reviewer's thoughts and then make sure they clearly understand the science behind your process by putting that data or agreeing on what type of data is there.

Brian Lihou 

That's the benefit of having that experienced regulatory lead because they will guide you in those decisions. They will guide the technical people in the story that's got to be told and what they need to be prepared to tell. So I can't stress that enough, whether internal to a client or they hire that consultant, I would kick the tires and ensure their experience is current.

Ed Narke 

“Regulatory authorities are part of the team, right? They're your friends- seek advice, ask for their advice, and also educate them.”

Right. I mentioned this somewhere, or I think I had a blog on our website about it- one of the most important meetings in my mind, I know there are a lot of different meetings that are important for reasons, but end of Phase II meeting- that should be something you planned for years before you get there. What you want to talk about and build an adequate strategy to talk about there. This way, you have adequate time to respond to any concerns, and there will always be some concerns, especially for fast-track programs. Authorities are not expecting a company to agree with everything they tell them to do in every instance. Still, they do expect thoughtful considerations and scientifically justified responses and strategies. So as you're going into that, think about some of those things. I can kind of bring up a list, just some things that we've dealt with: CMC regulatory compliance concerns for small molecules and biologics. I have a list of 17 different things anywhere from qualifying impurities; how many times have we seen that in different ways. Specifications, setting them, based on what. Impurity profiles, there are 10 or 15 things that could happen there. These are all things to think about as you're going into that.

Where do regulatory starting materials start? Genotoxicity…but there are other things, the inherent things, changes that occurred over the process with time, site changes, any anticipated changes that will happen. You want to get ahead of that because you often may not have a supply chain that could support a launch. So things happen after that, that you have to consider, and they will change prior to your submission or with a comparability protocol, for example. I think that's just the overarching last thing I'll leave here with- identifying any CMC issues throughout the program, throughout development, site changes, any novelness to your program. Not every program is the same- every program, like a snowflake, is different. They look alike, sometimes the same color, but there's not one that's the same.

So, Brian, Meranda, anything else to wrap it up? We'll be moving into sort of the details on our next podcasts. Hopefully, this was somewhat helpful. So, check us out for the next time in the next podcast, part two, where we'll get into really some of the gory details of Module 3, some of the things that we've seen over the years. Then we'll talk a little more about the quality overall summary, which is near and dear to Brian's heart and mine. We can talk about and discuss why we didn't follow guidances or some of the reasons that we did certain things for a reviewer to be able to get a preview of what the story is all about.

FDA CMC regulations and guidance simplified through examination, real life experiences and risk-based advice. This podcast hopes to educate sponsors and individuals on agency related regulatory CMC matters. We will focus on the critical CMC issues and build programs that enhance drug development. CMC topics will include Regulatory Starting Materials, API and Drug Product Process, Formulation Development, Supply Chains, Analytical Controls. Advocating and interpreting CMC Strategy, directing CMC Operations and Quality Assurance oversight in conjunction with developing CMC submission content that represents the best interests of emerging biotech. NOT INTENDED TO BE PRESCRIPTIVE ADVICE BUT RATHER INTERPRETATION THAT IS RIGHT FOR YOU. Since 2007 we have provided our partners with innovative strategies and exceptional advice intended to enhance program development, product approval, and marketing presence.