Webinar: Managing IND Submissions Using Lean Principles

In this webinar, Kivo CEO Toban Zolman and Director of Regulatory Theresa Pinnell discuss how to apply Lean methodologies to the regulatory submission process, focusing on an IND submission to the FDA. The webinar outlines:

• What is the Lean methodology?

• What are the  5 tenets of the Lean methodology?

• How do those tenets translate to the regulatory submission process?

• What does a typical IND timeline look like?

• How do you continue applying Lean processes throughout the IND process for success?

Watch the full video , or read the transcript below. 

Should you be working on your first IND, these resources may also be of help:

• Whitepaper: Building IND Regulatory Systems
• Article: A complete guide to the IND application 
• Or contact us for tailored support

Full Session Transcript

Theresa Pinnell: Good morning or good afternoon depending on where and what time you're logging in from! Thank you for joining Kivo's educational webinar, "Managing IND Submissions Using Lean Principles." I'm Theresa Pinnell, Director of Regulatory Solutions, and I'm joined here today with Toban Zolman, CEO of Kivo. 

We're going to get started with a little bit of background about me. My name again is Theresa Pinnell, Director of Regulatory Solutions here at Kivo. I've worked with multiple small to mid-sized organizations over many years at multiple organizations supporting IND or first marketing applications. I've also had roles with QA manufacturing companies as well as supporting with medical writing projects.

Toban Zolman: I'll introduce myself; my name is Toban Zolman, I'm CEO at Kivo. I've worked with a bunch of large pharmaceutical companies helping define global regulatory submission process and coordinating electronic submissions including literally writing a book about eCTD guidance in the early 2000s.  I spent the last decade or so, actually, outside of regulatory in software development, implementing Lean software practices and processes at five different companies and in manufacturing and service companies as well. So today we're going to be  combining Theresa and my experience across a variety of organizational sizes and types of companies to talk about adapting Lean principles into submission management.

I wanted to take a second and orient you to who Kivo is. Kivo provides regulatory information management software focused specifically on emerging drug development companies. That includes a Part-11 Compliant electronic document management system, content authoring templates that are built into that authoring and collaboration tools, as well as capacity to do simultaneous editing. We support submission, archival and eCTD viewing, eTMF and quality document management solutions as well.

Kivo is a new name; we rebranded and spun out into a new entity at the beginning of the year. But we've been at this a while. We've got eight years of development in our product line, have worked with over 40 sponsors to do 5 NDAs and 50+ INDs. What we'll be presenting today is a collection of what we've learned in the industry over 20+ years, as well as really what we've seen focusing specifically on emerging companies that are pursuing their first or one of their first INDs, and how to do that in a Lean way.

To dive into this, I'm going to take a little bit of time to orient everyone in attendance to the Lean framework, how we've applied lessons of that framework into submission management. Then Theresa is going to talk through putting all of that into action around a fictitious IND timeline to understand how you chip away at this and progress through an actual IND submission using Lean principles.

I want to start by going through the Lean framework and specifically put out some assumptions and disclaimers.The first is a lot of the concepts that we're going to present today, I would classify as advanced common sense. In other words, I'm not saying we're doing anything or articulating anything that's truly novel, but I think what we're attempting to communicate is really what we've seen and what works and hopefully give you some insights that you can apply to your organization.

I would also say that we are not Lean evangelists at all. However, we've seen Lean principles be successfully applied in a bunch of other industries that are facing significant constraints, namely around time and resources. And time and resource are really the primary constraints that we see emerging companies facing when they're going through drug development and trying to get an IND through the FDA. My personal bias is that a framework like this is really most helpful when you use it to frame decisions and priorities versus going all in on some sort of really strict dogma or rule that, "oh, if you're doing Lean, there's only one way to do Lean, and this is the right way." Really, I just want to use this to give us a lens to analyze how you make trade offs when you go through this process and see what insights we can gain from that. So that's kind of my assumptions and my disclaimer before I get into it.

First though, let's talk about what is Lean. This may be a term or a concept that's new to a lot of you. From a very high level, Lean is a way of thinking about creating needed value. Needed value is somewhat a loaded term, but effectively, what are you producing? Is it cars? Is it software? Is it drugs? A medical device? What Lean attempts to do is look at a way of how you produce that end result with fewer resources and less waste. That's really the goal of Lean, to reduce the amount of resources it takes to produce something and create less waste along the way.

Lean was formalized by Toyota. They started implementing a lot of these practices after World War II and really crystallized those in the 1980s until there was ultimately a book written in 1990 that coined the term "Lean" based on how they ran their business. Lean has been applied in countless industries since. As I said, I've used it heavily in software development and manufacturing.

The best way that I like to describe Lean to someone who's looking at it for the first time is to orient the worldview, if you will, of Lean into something we're all familiar with. That is, Ford created assembly lines, Toyota created supply chains. That's really where Lean comes in.

Let me explain what I mean by that. If you look at the history of what Ford did with manufacturing, they created assembly lines and they owned every single part of building a car all the way down to opening rubber plantations in Brazil so that they could even take over manufacturing the rubber for the tires. Toyota took a very different view. Toyota basically said, what is our ultimate value? They looked at the end result, which was a car, and tried to break all of that down into its component parts and figure out where they actually added value.

What they determined is they added value in things like the design, the efficiency of the engine, things that differentiate a Toyota from other vehicles. What doesn't differentiate it was headlights, the seats, things of that sort. So what Toyota did is they basically doubled down on things that provided strategic value for the company and they outsourced everything else. This is where Toyota creating supply chains comes in. They would tee up partners to produce seats, bring those seats literally across the street from the seat manufacturer to the Toyota assembly plant, and just in time get the seats installed for cars that had already been ordered by dealers and purchased by consumers.

So some of the core tenants that we see in Lean are terms that a lot of us have probably heard potentially out of context, like "just in time". Just in time manufacturing refers to manufacturing a product just in time for it to be delivered to a consumer so that you don't build and maintain inventory, which can create waste limiting work in progress. The term for this that you'll hear a lot is Kanban, or literally "working on one thing at a time", and then finally standardizing processes so that someone can come into a process. Everything is well documented and understood, and people can essentially teach themselves how to do a particular job. That's kind of what Lean is from a high level and how it was developed.

What I want to do is spend a couple of minutes talking about the Lean framework, and then we're going to apply that to the regulatory process.

Traditionally, the Lean framework is viewed as five core tenets. The first is defining value, clearly defining the actual need or value. We're not going to spend a ton of time on this in this presentation, but we are going to spend a little bit of time looking at what's the end result or the actual need that is derived from the regulatory process as part of building an IND.

The second piece is mapping the value stream. This is really talking about removing everything that doesn't directly add value. The other way of thinking about that is eliminating waste. There are a bunch of types of waste that can be eliminated. You can eliminate wasting time, inventory defects, resources...all of those things that can be removed from the process to ultimately make it more efficient. We'll talk about how you do that in the context of regulatory.

The third piece is creating flow. This is purely looking at process. Once you have removed waste from step two, how do you ensure that the remaining process remains functional? After doing that, it's possible to remove so many things or try and simplify so much that you no longer have a process that has a flow to it.

The fourth item is using a pull system. This ties in directly to just in time, and that is having the end result "pull" the work that's happening. The part of this that we're going to focus on today is really limiting the amount of work in progress to ensure that the end result is what's driving delivery. It's possible to load a whole bunch of people up with a whole bunch of work and they're all working on it at the same time. You end up without a ton of visibility and without individuals understanding what is driving that work and how you are getting that to an end goal.

The fifth piece of this is pursuing perfection. This really is looking at [this process] as a cycle or an iteration where you're going to do continuous improvement to try and make all of this work.

Okay, that's the Lean framework you can see from this high-level abstract.So how do we take these concepts and apply them not to making cars as Toyota did, but to the regulatory process? 

With regulatory, we're not talking about headlights or seats. We're talking about three core ingredients that go into any drug development process. Three levers that you have to pull to try and optimize what's happening in your organization. And that's really people, process and tools.

10 years ago, when I spent a lot of time helping large pharmaceutical companies implement electronic submission processes, the mantra that I always had was, you have base your process off of the people you have, get that process ideal and optimized, and then pick tools to meet that. Well, what I have learned now, working in depth with emerging / small companies, typically with fewer than 100 employees...this doesn't work. In fact, you need to flip flop these.

You need to take tools that you have access to that you can realistically implement in a time frame that makes sense and map your process into them. Emerging companies just don't have the time or the resources to find tools that map perfectly to a theoretical process that you could come up with. Instead you're going to try and make quick decisions, get tools in that solve the bulk of your needs and then build simplified processes that align to that that you're going to improve and iterate on over time.

Let's break each of these down. On the people side, the first thing that we talk about is to be practical and realistic about staffing levels. Theresa and I are on a lot of meetings with customers who have just made their first regulatory hire, or maybe their second, and they're hiring folks that have come from much larger companies who are now going to lead regulatory in a 25-person organization. What they lay out on the phone to us is a very aggressive hiring plan to pull a lot of the tasks in-house to be able to implement software and do validation and have regulatory operations. The reality is, if you have a submission time frame in the next six quarters, in the current hiring environment and with the budget constraints that are present for most small companies, it's just not realistic. Instead you've got to identify what strategic roles you can bring in-house and then use partners for any piece of that that's not directly tied to the value stream. We'll unpack that a little bit more with specific examples. But people is the first place where the orientation has to change from a larger organization to a small organization to make all of that work effectively.

The second piece is Tools. I would say, solve for what you need for this IND, don't optimize now for future problems. A great example of this...I had a conversation recently with a 3-person company. All of them worked together in the same room and they were talking about the needs they had from a tool standpoint with workflow and routing for reviews and approvals and having multiple sign offs and stages and it was like, timeout! All of you are literally in the same room. You can turn and talk to each other. You're not routing something to a VP who works in a different state or different country. You're over-optimizing for problems that you don't have now and likely won't have for 36 months. So pick tools that solve your needs now and also pick tools that require little to no IT support.

The reason for that is you likely have little to no IT in a small organization. Picking tools that require installation, validation, support...all of that layers in labor and effort that you likely don't have resources to handle. The third thing here is to pick tools that take the least amount of effort to implement. This may mean either they actually take little effort or the vendor that you work with has the support structure to do a lot of that work for you. Either way, the goal here, the theme, if you can't tell, is to remove as many of the burdens off of your organization as you possibly can.

The final piece is to focus on compliance. Compliance is one of the key things that you have to meet. So anything you can do to pull complexity out of the tool while maintaining compliance is the key thing that you need to do.

Final note on process. It's really difficult to stitch together a perfect, well-documented work instruction based process for every step that's going to happen to do an IND in a small company. What we talk about is identifying the areas of key friction. Those are typically viewed not just by Lean, but anyone who looks at business process as any place. You have handoffs, either cross-functional handoffs like between clinical and regulatory, or partner handoffs, let's say, from the sponsor to a publishing group. Optimize and really formalize how those handoffs happen, cross-functionally and between partners and make sure that that is airtight.

Align all of your processes to tools you've already picked. Focus on processes that affect compliance. Again, compliance is a very strong thread through all of this. Then the final thing, which will be a mantra we talk about a lot today, is simplify everything.

Whatever your first draft is, I guarantee you it's too complicated. Simplify it and then likely simplify it again. These are how we look at applying those Lean principles to an overall regulatory process and specifically the areas of people, tools and process.

Let's look at submission management as it applies to this, and then Theresa is going to dig into how you actually navigate an IND timeline based on that.

First part of this is defining value. Lean cares deeply about needs. What needs are the people, the tools and the process solving? One thing that I find really valuable is orienting your thinking on an IND to, what are the three key needs? What are the three key values that this IND effectively or the IND process effectively provides?

The first is meeting submission deadlines. You have to meet submission deadlines that are defined and based on feedback with the agency. So that's number one. You have to meet the deadline. The second is you have to maintain compliance while doing so. And the third is throughout all of this you need to take a step back and ensure that you're demonstrating the safety and efficacy of your drug. So if you're not effectively telling the story of how your drug is safe and effective, then you're ultimately not going to reach the milestones and get the approvals that you're looking for. These are three things that I feel like really effectively tighten conversations. If you're talking about optimizations or future states, if they aren't driving these three things, you likely don't have the time, and you don't have the people to execute on them.

The second piece of this is mapping the value stream. Lean asks lots of hard questions like "which people's skills add direct strategic value"? Go back to Toyota. They were like, "our strategic value is the design of the automobile, the quality of the automobile, the service organization that we can create". If a skill doesn't add strategic value, then consider it labor. And labor is easy to outsource.

So in the context of drug development and regulatory specifically, you want to bring people into the organization that support the defined values. Again, these three defined values - meeting deadlines, maintaining compliance, demonstrating safety and efficacy - you're going to outsource to partners for anything that's just labor that doesn't reinforce that strategic value. At some point it makes sense to bring labor resources in-house once you've reached scale. Then you can control all of that and start to eliminate steps in the process.

I think a great example of this is regulatory operations or publishing tasks. If you have scaled to the point where you're doing multiple submissions a month, maintaining multiple products, there are some efficiencies to be gained by having some of that in-house. If you're pursuing your first IND or one of your first and have very limited products, there's not enough repetition in that process to have those staff as part of the organization.

We would also say question the tools or even features within the tools and processes that complicate any part of the process beyond what is needed to meet your deadline, maintain compliance and demonstrate safety and efficacy. There are a lot of elaborate RIM features that really only pay for themselves or make sense if you have a large portfolio of products. If you're not at that stage, you don't need them.

Fnal piece here is front-loading your core tool selection. Part of Lean is assuming that you are working in a cycle. So the earlier you can have some of these core tools, especially on the compliance side in-house...it does a couple of things for you. It reduces the amount of waste or the amount of migration and other work you have to do later. And it gives you more cycles, more iterations to optimize that process as you go. These are the activities that add value.

Third thing is creating flow. Flow represents the optimum level of efficiency where you can't practically remove additional waste. You're not going to get here on an IND. You're going too fast, you don't have enough resources. But what is important to pay attention to are two key areas. The first is, do you have enough expertise in-house, both skills and people, to complete the IND? One of the stumbling blocks that we've seen working with customers is they simply have not, either by choice or by how challenging the hiring market is, been able to get expertise in-house to fulfill submission timeframes that have been set by executives, investors, et cetera. We feel like it's really important to ask early, do you have the expertise to actually complete it? If not, identify early on what needs to shift - either escalating bringing those skills and people in-house or pushing timelines out in order to proactively align resources and time to create an efficient process.

The final piece here is process and tools. Document management and collaboration tools will need to support a much more complicated set of folks than it would be if you had a big company, controlled every single part of it, and everyone was just in a different department. You'll be working with medical writers, with CROs, with CMOs, RegOps and publishing groups that are outsourced. All of those disparate companies and groups in and out of your organization are going to need a common place to exchange content, information, planning, et cetera.

One of the things that we've seen as a repeated theme is underestimating the complexity of handing things off when not everyone is in the same company. As much as it is a reality of how you have to run and manage an IND when you're an emerging company. I would also say that your partners are your partners, but their interests may not always be exactly aligned to yours. They have other partners, other customers, and competing timelines. So anything you can do as part of the process to insulate yourself from competing priorities from partners, as well as to formalize the handoff of content and information between those partners overall really helps streamline things.

Fourth, using a pull system. This really is all about just limiting work in progress. It is possible, because of electronic submission standards, to outline your entire table of contents right from the beginning, blast all of that work out to all of the people and let it go. The challenge with that is you have so many people doing so many things and each individual has so many discrete documents tasks in progress, it's really difficult to discern if things are running on time, if they're behind, et cetera. We talk about aligning people in process around rolling milestones to shorten the horizon of everything that's happening and limiting what individuals can be working on at a given time. That gives you a much more accurate view of what's happening.

A great example of this outside of regulatory is how Lean has been applied to software development. In the old days, you followed what was called a "waterfall approach" where you would write all the requirements for a release and then everyone would go heads down for six months, create the whole thing, and then produce software at the end. What has been discovered - again, advanced common sense - over the past decade, is that the shorter you can make those horizons, the more accurate your planning becomes. So most software development firms run very small iterations of say, two weeks, where each developer is really only responsible for completing one or two or three tickets. Then you push the smallest possible shippable unit, the smallest increment in the feature, and then you can test iterate and improve that from iteration to iteration. The result is you ultimately move faster, you have higher quality, and all of that happens because you have less waste. The same thing can be done in the regulatory process, although you will be artificially inserting some of those milestones to keep horizons short and limit the amount of work in progress.

Part of this is implementing tools based on that and based on your current resource model. Then iterating that process and iterating on expanding functionality over time to keep everything as tight and in control as you possibly can. Which really leads us to our final piece, which is how you look at continuous improvement.

The mantra that we have stated over and over is, solve the needs you have today, not the ones you expect in the future. This is incredibly critical. You can't boil the ocean and you frankly don't need to. Your horizon for your company is really to submit to the IND. It's not necessary to have all of the infrastructure in place that you need to support an ultimate NDA. Small, quick, incremental improvements impact your team in a positive way. Focus on that. You don't have to make big gains. Lean talks a lot about two second improvements, spending time every day to cut 2 seconds out of a process. And over the course of a year, that adds up to a monumental shift.

The same thing can be viewed here from a submission process. Everything you can do to extract tiny gains compound over time. A great example of that is buying authoring templates that you need for the region and type of submission. You're doing what's right in front of you, for example, an IND to the FDA and then worrying about other regions, other template types, et cetera, once you get through that. That doesn't mean you should be myopic or short sighted in what you do, but just understand you don't need to solve all of the future problems in one shot. That's what Lean is and how we talk about it in the context of regulatory. I'm going to turn things over to Theresa and have her put all of that into action.

Theresa Pinnell: Thank you, Tobin. And thanks for the explanation of the Lean framework and how we can apply that to regulatory submission management.

My example schedule is a generalized and rolled up view. I'm going to disclaim that and say it's not exactly specific. The timeline is generous.It's over about a year and a half for an IND. I think everyone on the call could probably argue with me, and we could all make jokes about how that timeline could be a lot shorter. I've certainly seen over my years working with emerging biotech and pharma that I've seen an IND written in probably four months and executed and submitted in that time frame as well. But seeing as how we are going to try to use some of the best practices I've seen over the years, we're going to take the first bullet item and we're going to plan early to save that time in the end and apply some of the Lean methodology that Toban has explained to us by thinking through the value propositions, working through the value streams, applying some of this methodology, plan early and work through it to really help us get through some of what may be called the stressful time at the end of the process of submitting your IND.

A lot of the companies I've worked with have really held the belief that the FDA is a strategic partner. They are not your enemy. They are a powerful resource. You can use your project manager, communicate with them often and early.

Clearly, the Pre-IND meeting is a vehicle for this way to communicate with them. They are a way for you to get your ideas bounced off of. For example, the protocol - getting early feedback on that so that you can support one of the most important goals, which is understanding how your protocol is put together so that you can really get started with your phase one trial and get into your first-in-human trial. You want to do everything that is working towards that goal, and you want to arrange everything that you plan early around all of those types of goals.

To continue upon that, we're going to keep the idea of rolling documentation that you're going to see me repeat over and over again in the timeline, and Toban brought it up as well. It's a really nice way to kind of think about how to schedule within the timeline, align your resources and milestones around the entire authoring, which is creation of the content that supports your safety and efficacy and your CMC documentation, the chemistry manufacturing controls around that all. The way through to the publishing aspect so that you are working through pieces of the IND at certain periods of the time and then moving on to the next piece of the IND. So at the end of the time period, you're not working on the entire bolus of documentation at the end. You're limiting not only the pieces, but you're limiting what's happening to your internal team as well as with your partners. This even goes all the way down to spending money with your budget; you're able to spread your budget over a longer period of time and use it more effectively.

We're going to dive right into the [IND] timeline and focus on one of the most important stages - which actually takes the longest time - which is planning. This first six to seven months is the time period to design the car, as we've talked about in the Toyota example, right? We're going to really try to use some of the first tenets and themes from the Lean methodology and apply them during this planning phase.

As you talked about with defining value, our three components that we've established with this IND is we want to meet a timeline for our submission, we want to be in compliance and we want to support the safety and efficacy.  I'll even add another one, which is we want to show that we have our dosing under control with our chemistry and manufacturing module three section. Everything that we think about in this January, February, March, these early time frames...everything that we do in the work streams that you see represented under the people, tools and process, everything is going to align with those values.

As we get into mapping the value stream, this is the part where we are aligning the skills and we're taking a look internally as well as outside of our organization. What do we need to have internal? What do we need to look at outsourcing internally? What are the strategic roles that we need to have in house that are going to support our values? One of those strategic roles is the regulatory affairs role. This person is going to quarterback the entire project. They're going to have the relationship with the FDA. They're going to internally liaise with your subject matter experts, your scientists, your quality folks. This is a key person that should be hired in-house that is also going to help you make decisions about all of the rest of mapping the value stream, including the partners that you need to fill in for the other types of roles. These types of roles are going to write, publish, create the data for the other sections of the IND where you might need a little bit of support that you aren't necessarily going to hire full time in-house.

For example, you may not hire three or four medical writers to write the non clinical section and QC those sections for the duration of the entire IND project. But you are going to need them for certain key periods where the writing is going to be intense. You're going to need those people there for a three month period or a four month period. Fetting that budget put together, finding those resources, getting the contract signed...all those things are happening during this first six month period. Then as you're thinking about, well, now I need compliance, now I need all these people to interact and work in the most efficient manner. I need to create flow, right? I need to make sure that all these folks can create the content, they can review the content. I can do it in a compliant manner and I want to do it in an efficient way because we don't have a ton of time and I don't have a ton of resources. So what are the tools that I can look at to bring in house that are going to meet these goals and needs that are going to be fast, quick, get me where I need to be in the fastest, best, most efficient way possible?

This is where we talk about electronic document management and authoring templates and even simple tools like an Excel spreadsheet for eCTD tabled contents or a Microsoft Project. How you blend these tools together and search for the right partner for a tool helps you bring efficiency and get all these partners together and build a simple process. You don't want to over engineer it, you just want to make a simple process to get the partners to work together with your internal teams. You can plan out that process using the eCTD table of contents and plan out who is going to author those documents, where those documents are going to be (which is your electronic document management system), and how they're going to do it. They're going to use a document management system to collaborate. You're going to start to build out those handoffs and you're going to start to build out your timelines, which is the whole point of a planning phase, right? It's going to set the stage for building out those improvement cycles. We're not getting into pursuing excellence at this point, but we're setting the stage for understanding how can we see into or get visibility into how are we doing in this process? How are we setting up to be successful for the next few months? Because as we get closer and closer to getting to that submission timeline and we have a lot of work to do, how are we going to get better and how are we going to learn from this? So setting a stage, planning and putting all the pieces together, that's what's happening at this point.

When we move into the next four to five months, it's sort of two major sections here. There's the writing of  key documents and then there's the execution of the Lean methodology.

The writing sections are happening with two key sections, I believe, and I think anybody else that you would ask would agree as well - the Module Three, which is your CMC section, and the Module Four, your nonclinical section. These are the key components of your IND which are going to support your argument for being able to start your phase one trial. These documents are critical for making sure the content is correct, the science is correct. You're supporting that you have control over your manufacturing process, and you're showing through your nonclinical studies and through your data that your drug is safe and=  it might be efficacious against this disease indication. So how do you support that using Lean methodology?

You take all the planning that you put together and you execute through your value stream. You're executing with your partners. You're using your tools, your authoring templates and your electronic document management and using the creating flow idea of providing efficiency with those types of tools. You're applying the pull system with your tracking spreadsheet and you're going to break up those sections into certain time periods. You're going to start to apply it, pursuing perfection within the process.

I'm going to go through one example and then at the end I'm going to talk about one of the last work streams that's here in the "people, process, tools". Typically the Module Three section is one of the first sections to be written in that July/August time frame. Typically your internal team, your regulatory affairs person or project manager is going to assign, let's say, a description of drug product to a writer that is within your contract manufacturing organization partner. One of the ways you can use this within your Lean organization, with all the planning and execution that you've already applied, you simply give them access to your electronic document management tool. The authoring templates are there, they can start writing in the authoring templates.The sections are built there, the tables are already applied. You gain efficiency by giving them access, giving them a start to writing in the template.

The partner starts doing that heavy lifting of writing the document. The reviewing and the sign off happens internally with your team within the document management system. As that process is going through and you have that document going through a first draft review, a second draft review, going through a QA/QC review...all of that is happening as a collaboration within your document management system. During that, you're capturing the gateways and what's happening. During the project team meetings, you're looking at what's working, what's not working, and you're making small improvements to the process. These are all Lean things, using the systems that you've put in place and the teams and the skill sets. So you're going to take all the learnings that you've had maybe with that one document and you're going to apply it to the next document in module three, and the next document.

Then it comes to apply to your next group of vendors and the next group of writers in your Module four documents.You're simply going to apply the same process to a different group. Typically the Module four comes later, so it comes in that September/October time frame. You're going to apply the same type of process. You're going to have already worked on module three, you already have learnings. You can put those documents aside for now. Now you're continuing with a pull system. You're doing a different type of work in progress. You've moved on to the next type of document. You can apply some learnings that you've had and you're going to go through the same process of giving that person access to the system using a template, going through a review process with your internal team.

Now you've gone through two rounds with two different vendors. You've given them access to an electronic document management system. You've gone through a review process. You've learned some things. You've executed on the Lean methodology and you're working through and executing and getting to be pretty darn good at this whole system. You're almost expert level I would consider. So when you add another vendor to the mix, because at this point it's time to bring in the regulatory operations publishing vendor, you're now adding another vendor to the mix. At this point it should be pretty easy because you've already gone through the process with your CMO and maybe your CRO that's working on the Module Four documents. It should be relatively simple. The idea here is that you are continuing and you're reusing a process, but you're learning and improving as you go. So by the time you add regulatory operations, it's a simple switch on.

You pick a vendor, you test with them that they can log into the electronic document management system. It's a key piece of time where you're getting work done, but you're also improving your process as you move forward. All of this work becomes really critical as you move into the next phase where things start happening a lot quicker.

I call out December and I call out the publishing section as its own timeline because there's a lot of work streams that are outside of publishing described in this month. But I do like to focus on publishing here because there is quite a bit of publishing work. I want to take a step back before I get into the details of that and say that as you get into this December time frame, that four month before the submission date, three months before the submission date...The themes that we're seeing here, applied from the Lean methodology, creating flow, pursuing perfection, limiting work streams, things like that, these should start to be just flowing in the background. These things should start just kind of operating on their own.

The tool should  start to just be something in the background. It's not something you have to think about, it's just something that you use on a daily or a weekly basis. Your process should be something that's just simply incorporated into your everyday work life. This is when all the hard work starts to pay off from the previous eight to nine months. The work streams that are happening now get more critical again about directly affecting the IND and things that are critical to making that happen.

Requesting the IND meeting happens during this time period. Sending a background package to the FDA. This is when the communication with the FDA becomes really important. Your regulatory affairs internal team member gets really critical at this point in being able to communicate effectively internally with your subject matter experts, your CSO, the CMO, being able to put that package together and utilize whatever resources you need to pull in, whether you need to pull in another outside resource to help with that background package or not. But it doesn't matter at this point because everything else is just sort of singing along. Then the processes your publishing team are starting to actually publish the Module Three and Module four documents. That's drug substance, nonclinical drug product - all those documents that were finalized the months before are now getting published and that cycle is all being done behind the scenes. It's so much easier now. The other work stream that's happening right now is the Module Two summary documents are being written.

But again, the process and the tool at this point shouldn't even really be a thought. It should just be singing in the background because it's already been incorporated into your normal everyday life. Then we get into final content review and submission, otherwise known as crunch time. These are the last three months before the submission deadline, and it's sort of the same idea around the mapping of the value stream. This is when you're really finally working towards meeting that submission timeline, being in compliance and making sure your content is in the right place and you are representing your product in the best place possible.

All the hard work comes to fruition here. The work streams are just being able to flow from a process and a tool perspective. This is an extremely busy time period for your content, though. Extremely busy. You have the Pre-IND meeting with the FDA and fun things can happen during the pre-IND meeting.

At the same time you're also doing some review and finalizing some key content pieces. So the module two summary documents were written previously, but now you're doing some final content review of those. You're working on those final module 5 clinical documents; the IB, the Protocol, the Module One and the forms are finally being put together. You're fast and furious doing some final publishing with your regulatory operations partner. There's a lot of back and forth happening between your vendors. You're using your tools on a daily basis. There are a lot of changes that may happen, especially in that last few weeks. Maybe days, hopefully not days, but maybe. Having your tools, your flow and all the learnings that you've had really becomes important now to be able to execute quickly, efficiently, and precisely.

If you've done the hard work and you've applied your learnings, this phase doesn't become as scary as it can be. And you're not working until midnight as I have supported some of my friends before. You want to come out of the IND meeting, and there might be some changes, but you don't want to be finalizing that content on midnight on March 30. If you are, you want to be able to support that in a way that you can get it done and get everything out the door. But it is a busy time, so you want to be able to work efficiently and get all the pieces aligned and into this submission correctly. Getting that final piece of content to the regulatory publisher, approve it, get the final package off and out to the FDA is the goal. Once it's finalized, then you can celebrate.

Now you can move to the next one. Post-submission, after you've had a week of vacation, it's an opportunity to come back to defining value. Again, you reassess time with your contracts, with your tool and your vendors. This is an opportunity to say, are we going to just keep doing ongoing submissions to the IND we've already submitted? Or are we going ex-US? Are we doing a CTA? Are we going to reuse content? Is this a time period where we're going to change our goals and do different goals? And what are the skills, what are the people? How do we need to change what we currently have to meet those upcoming goals and timelines the tools that you have? You're going to import the finalized submission into your document management system for archiving and viewing. You're going to continue to use your authoring templates to create ongoing submissions. And if you need to add those other templates for ex-US, you're going to do that.

If you didn't have time during those last busy three months to do any process improvements, now is the time to take a step back, analyze the whole process from start to finish, and apply those lessons learned. Adapt and change as needed for either the next submission set specifically to this IND, or apply it to other types of submissions.

I know that's a lot to go over and we could always get more detailed. I could probably spend hours and hours talking about submission timelines and all the requirements there, but I'm going to turn it back over to Toban so that he can try to apply some final thoughts to the timelines and Lean mythology. 

Toban Zolman: Thanks, Theresa. To wrap all of this up, key thoughts from our side.

Focus on keeping the most critical aspects of what you're doing in-house on the strategic side (things like regulatory affairs, bringing in core systems, et cetera). Outsource and manage tasks that are either commoditized or not repeated. Things like RegOps and publishing audits, quality contractors, CROs. When it comes to the tools, simplify and streamline those by taking on as little implementation, validation, and support responsibility as possible. And finally, as Theresa said, really think about FDA reviewers as you go through this process, both in terms of thinking of them as strategic partners and also just trying to understand what their perspective will be when they are viewing the submission, and craft that narrative around safety and efficacy as effectively as possible.

We want to thank you for your time today and for joining us for this webinar. If you have questions, you can follow up with Theresa or myself directly using the emails on the screen. We will share out a recording of this webinar over email, and if you would like the slides as well, please reach out and we can get you copies of those. We want to thank everyone for your time, and we hope you have a great rest of your day.

Theresa Pinnell: Thanks a lot.