July 19, 2024
Host: Oliver Ball, Director of Business Development, Dark Horse
Presenters:
Opening Remarks
Oliver Ball: Alright! Welcome everybody. We are just going to wait a second for people to join in congratulations, those who joined on time.
So for those who have not joined one of the Dark Horse Webinars before. Welcome to the Unbridled Excellence Webinar Series. I'm your series host, Oliver Ball, Director of business development for Dark Horse.
We really set this initiative up to share some of the experience that we've generated now over 10 years of operating in the cell and gene space. Over that period we've had over 400 clients, all in cell and gene across all the different product modalities that you get in industry and development phases as well. But today's webinar I'm very excited about because it's really one that has been quite popular, and for those who have suggested topics when registering for previous webinars.
And it's one that we spend a lot of time thinking about and working on at Dark Horse. So today is hopefully going to be very interesting and useful for you guys.
You know, writing an IND is a really substantial undertaking that requires a lot of work and a lot of focus. And actually, it's something that many people choose to outsource as well. So Dark Horse now we've had the privilege of working on, I think now, over 40 different IND submissions over the last few years.
Whether that's reviewing draft content, the clients have provided us and actually writing the whole IND, which we do quite a lot of too or some combination of the two.
We've developed our own suite of tools internally, that we call Centuri to actually write INDs and Wendy and Sarah will touch on this briefly, which really allows us to do that in a very efficient way.
And we use technical writers overseen by our ex-FDA reviewers to make sure that we're producing very good quality content.
But we're not going to spend too much time giving you a sales pitch on that today, today is going to be more full of useful value, added tips and tricks to help you with your own IND authorship processes.
That is, if you choose to do that rather than just asking us to do it for you. So with that I'll just remind you quickly that you can submit questions through the chat box on the Zoom interface. If you have any thoughts or questions that come up during the presentation. Please just feel free to put those in, and Wendy and Sarah will be able to answer them at the end of the session.
As all our other webinars, the content today will be available to view on demand as well. So in the days following, you can go onto our websites and you can find the on demand content share if you want to.
So without further ado, I will hand over to Wendy and Sarah to introduce himself and get into the presentation.
Presenter Introductions
Wendy Liang: Thanks everyone for joining us today. Our goal is to provide some tips and tricks for efficient cell and gene therapy IND authorship with a slight emphasis on an initial submission for an FIH IND.
And we're your presenters today, Sarah. Would you like to introduce yourself?
Sara Mills: Yeah. Hi, everybody. My name is Sarah Mills. I'm Senior principal and head of the cell therapy CMC Department here at Dark Horse. I've been with the practice almost 8 years and have been working in CMC activities for cellular gene therapies for over 14 years. It's nice to be with each of you today.
Wendy Liang: And Hi, everyone. My name is Wendy. I'm a senior consultant at DHC. I joined the practice in 2021, and since joining I've had the privilege to work on many regulatory filings for our clients, including multiple INDs.
One thing before we get started today was that we just wanted to make sure you know that we made it clear that this is a tip of the iceberg when it comes to IND authorship, and we will not have time to do a step-by-step walkthrough of how to write a cell and gene therapy IND.
It is our hope, though, that by the end of this webinar, you'll walk away with better understanding of the elements of a successful cell and gene therapy IND.
Dark Horse Experience Overview
Sara Mills: Yeah, so for a moment. What I want to do is I want to talk a little bit about the breadth and depth of the experience that we have at Dark Horse. That really has led to our ability to put together a webinar like this. As Oliver mentioned, we've helped author over 40 INDs. These numbers keep changing and, as you can see on the screen, we have a figure that kind of is over the course of the past 3 years, the what kind of regulatory authorship and collaboration we've performed at the practice.
You know, this is informed by over a decade of experience working with global clients across all stages of development, services and services delivered through what now we have titled Centuri really allow us to optimize and maximize efficiencies of cost, timelines and resources while we still get to deliver this high value and quality of the expertise that we have here at Dark Horse.
So if you do choose to talk to us more about our IND authorship, it would be likely under this header of Centauri if you would like to engage in those activities. And when we do that it leverages our custom templates as well, which allows us to keep the cost down, and authorship, while also incorporating all of this kind of wealth of experience that we have over the past 10 years within the organization.
So just a little notes there on Centuri, and how we've really use all of this expertise that we are going to get a little bit of a taste of today to build a system and some tools to support our clients. Thanks, Wendy.
Today's Agenda
Wendy Liang: Yeah, thanks, Sarah. Alrighty. So, moving on for today's agenda, we'll first discuss what an IND is followed by some key concepts for an IND application.
Then we'll discuss recommended pre work to be done before drafting an IND, and then we'll also discuss module specific and general authorship recommendations.
Then we'll discuss the submission process, information requests and IND clearance.
And then we'll end with expected activities after clearance of your IND.
We will have time at the end of this presentation for questions and answers. So just leave them in the chat as they come to you.
What is an IND?
Wendy Liang: Okay. So from a legal standpoint, an approved IND allows you to transport your investigational drug across state lines which you'll generally need to do to take your drug from your manufacturing facility to your patients from a practical standpoint, the IND indicates your intent to collect or to conduct clinical trials with your unapproved drug.
Key Concepts for IND Authorship
Wendy Liang: A key concept for IND authorship is the common technical document or CTD format. CTD format is an internationally agreed upon format for preparing applications for new drugs and global jurisdictions that have adopted this format include the US, EU, Japan, Canada, and Switzerland.
CTD format consists of 5 modules for US INDs module. One contains administrative and prescribing information, such as forms cover letters, letters of authorization, pre-IND documents, designation requests, and your investigators brochure.
Module 2 is dedicated to summaries of your non-clinical quality and clinical data.
Module 3 is focused on quality information for your drug. So this includes information on the manufacturer and testing of your drug.
Module 4 is the location of your non-clinical study reports and data sets.
And module 5 contains clinical information like your clinical protocol, your informed consent form, and any investigator information, if available.
Electronic Submissions
Wendy Liang: So once upon a time INDs were filed by paper and CD-ROM, former Dark Horse team members from both the sponsor and FDA Reviewer side often tell us about their experience with Geron's IND for OPC one, which was submitted to FDA in 2008.
Something like 7 paper copies of the IND were delivered to FDA in multiple trucks.
Starting in 2017, though CBER mandated submissions to be filed in electronic common technical document format or eCTD.
The platform for submitting this electronic documentation to FDA is called the Electronic Submissions Gateway or ESG.
The thing to note is that you'll need to request an IND number from CBER before submitting your cell and gene therapy IND.
Your pre-IND number is not your IND number for CBER submissions while this is the case for CDER submissions.
Publishing Process
Wendy Liang: Okay, a final key concept for IND authorship is the premise of publishing. It's common to work with a publisher to prepare your IND for submission through the electronic submission gateway.
Publishers perform backend activities that ensure a successful submission such as validation checks to ensure that your submission will not be automatically rejected by FDA's electronic submission gateway.
Some publishers also provide formatting toolbars and IND templates that can expedite IND authorship.
At DHC we work with Omnisha for filings we submit on behalf of our clients. However, if our clients have a preferred or established publisher they already work with, we can work with their publisher as well.
On the right is an example of how publishers will prepare and organize the contents of your IND in eCTD format. Typically, your publisher will provide this output to you for you to approve before it is submitted to FDA.
Pre-work Recommendations
Wendy Liang: On the following slides we have a few recommendations for pre-work that IND authors can do prior to starting to draft your IND.
Documentation Gathering
Wendy Liang: The first pre-work activity we'd like to discuss today is documentation gathering. While this is not an exhaustive list of documents that you'll need to write your IND, it is a good sampling.
Things like manufacturing SOPs will aid in drafting your process description if you don't already have one.
Certificates of analysis and origin batch data and stability testing plans will also be required to be provided in the IND.
While method, qualification, verification, and validation reports do not necessarily have to be attached to your IND, this information does have to be adequately described in the corresponding IND sections.
Information on facilities such as materials, personnel product workflows, cleaning procedures, and segregation procedures will also be important for inclusion in your IND.
Non-clinical study reports will need to be submitted in module 4 of your IND and summarized in module 2 of your IND. For a lot of clients, some non-clinical studies may still be in process when you're first starting to write your IND, and so it's important to know your strategy and timeline for completion of the studies, so that you can schedule your submission accordingly.
Finally, if a clinical protocol is not yet available, a clinical protocol synopsis would still be helpful to start drafting sections, such as the clinical overview and general investigational plan.
Language and Formatting Alignment
Wendy Liang: The second pre-work activity that we recommend to align on is language and formatting. Typically multiple people are involved in writing an IND, so you want to make sure that you put in work to make to have your submission have a unified voice.
We recommend that the authorship team meets before putting pen to paper to align on topics like terminology, product descriptions, and even formatting.
This alignment helps minimize the amount of revisions required once everyone starts drafting, and it also helps ease the reviewing process for FDA.
In the bottom right box, we have an example of boilerplate language that we would recommend to consider using throughout your submission to orient the reviewer on your product.
Drug Substance vs. Drug Product Definition
Wendy Liang: The final pre-work activity recommendation we have for you and your team is to align on the definition of drug substance and drug product for the purposes of your IND.
The drug substance is typically the active ingredient of your product, while the drug product is the finished dosage form which generally contains the drug substance and any excipients.
The reason this distinction matters is because the manufacturing, testing and controls for drug substance and drug product are described in separate sections of Module 3 in the IND.
Traditional definitions of drug substance and drug product have not translated well to cell therapy manufacturing. A lot of times the line between drug substance and drug product can be largely artificial.
For example, for the process described on the left, the line between drug substance and drug products can be drawn either before the harvest step or before the formulation step, as shown.
We wouldn't consider either one to be wrong. You just need to align as a team and be consistent throughout the IND.
So this slide includes our pre-work recommendations for IND authorship, and we'll now be moving on to module specific recommendations.
Module-Specific Recommendations
Module 1 Recommendations
Wendy Liang: The module one is the location of administrative and prescribing information, and for this module we have one recommendation, which is to consider submitting a fast track designation request with your initial IND submission.
Receiving fast track designation comes with perks, such as more frequent meetings and communications with FDA, eligibility for accelerated approval and priority review and rolling review for your future BLA.
While you can submit a fast track designation request anytime during clinical development, our general recommendation is to submit your request with your initial IND if possible.
Our colleague, Kristen Baird, who's an ex-NIH clinician and former FDA clinical reviewer, frequently reminds our clients that fast track designation requests are best performed early in development.
Clinical data is not required for a fast track designation request and clinical data can also be a double-edged sword. So the more data that is collected the higher the chance that some data could come back and undermine your overall package.
Module 2 Recommendations
Wendy Liang: Module 2 contains summaries of CMC, non-clinical and clinical data for Module 2. We wanted to discuss which summaries are recommended, and which ones are not required for initial submission.
Since not all summaries that make up module 2 of an IND are required to be included in an initial IND submission, the question is, should you include them? It's a common topic of debate, especially for the quality overall summary.
At DHC our preference is to include a quality overall summary with the initial submission as it provides a high-level summary for non-CMC reviewers to reference when reviewing other sections.
That being said, it would not be an issue if you decide not to include one with your initial submission.
For a first in human IND submission, there won't be any clinical data to submit. And thus you don't need to include section 2.7.
However, if you do have clinical data associated with your investigational drug, such as from a different IND, you could include this information in section 2.7.
This slide concludes our recommendations for Module 2. Again, if you have any questions, drop them in the chat, and we'll be moving on to Module 3.
Module 3 Recommendations
Wendy Liang: Our first module 3 recommendation is to avoid providing excessive details when describing your manufacturing process and analytical methods in the IND.
On this slide we have some examples for the level of detail we'd recommend and examples of what we think is too much.
There's definitely a balance to strike, providing too few details could be inappropriate and could trigger an information request from FDA.
In general, things like incubation times, vector MOI and seeding densities are important to include, while things like the percent CO2 of your incubator are generally not that important.
With that being said, if you are using a non-standard parameter for percent CO2, and this is important to the manufacturer of your product, then you might want to consider including this information.
Again, this is all on a case-by-case basis. But your overall goal is to reduce unnecessary revisions to the file.
Here's another example of the level of detailed we'd recommend for an analytical method description.
In this example we recommend not focusing on listing manufacturers and catalog numbers for materials used for analytical testing.
These materials may change throughout development without impacting the method.
The only exception to this recommendation would be for flow cytometry reagents. FDA typically does want the catalog numbers for these.
Process Flow Diagrams
Wendy Liang: Our next recommendation for Module 3 is to ensure that your process descriptions are paired with process flow diagrams, process flow diagrams are helpful tools for reviewers to orient themselves on your manufacturing process, as they contain information on the unit operations that make up your process, the duration of the process, key materials and equipment, and the analytical testing performed at each step.
We recommend trying your best to keep your process flow diagrams within one to 2 pages.
On the right of the slide is an example of how DHC codifies processes using a simulated process and fictional drug.
As an example, we've submitted many process flow diagrams in this format on behalf of clients. And we know that global health authorities, including FDA, find this format helpful.
Control of Materials Section
Wendy Liang: The control of material section of an IND is generally a very hefty section for a cell and gene therapy IND. This is the section where you describe all the materials used in your manufacturing process.
For materials of human or animal origin, FDA will be looking for information and documentation to support that your raw materials were appropriately procured and tested.
Additionally, FDA is increasingly expecting sponsors to evaluate their materials for human and animal-derived components up to the secondary and tertiary levels.
If there are any gaps in the sourcing and testing of human or animal-derived materials, the sponsor is expected to explain how they will close these gaps.
Typically, this means that additional testing will be performed by the sponsor because the manufacturer's testing alone is not sufficient.
FDA published their most recent thinking on human and animal-derived materials for cell and gene therapy manufacture in April of this year.
Blake, a consultant at DHC and Sarah, who is co-hosting this webinar have authored a review and commentary on this draft guidance which you can find on DHC's website.
Depending on the components of your drug, the control of materials section will have different content. On this slide we have examples of how the makeup of your drug will change the headers of your control of material section. For example, if your drug is a lentiviral vector or adeno-associated vector or if your drug uses LV or AAV, you'll want to include information on the derivation, manufacture and testing of the producer cell line, the plasmids and the viral vector manufacturing raw materials.
If your drug product is derived from iPSCs, you'll need to describe the donor eligibility, determination package for the donor material, and you'll also need to describe the derivation, manufacturing and testing for the various cell banks you manufactured from the donor material.
Once the providence of the starting material is appropriately described, then you will move on to describe the raw materials used to manufacture your drug substance.
For an autologous leukapheresis-derived therapy, you'll want to describe things like the collection testing and shipping of the leukapheresis before describing the raw materials used to manufacture the drug product.
Device Components
Wendy Liang: If your product has a device component, this information will typically go into section 3.2.R of the IND. Some example devices are custom surgical tools such as pocket formers and drug product introducers.
On the right of this slide is an example table of contents for a delivery device that would be described in section 3.2.R of the IND.
You have any further questions on Module 3 and what was presented today. Please leave a comment in the chat because we will now discuss Module 4.
Module 4 Recommendations
Wendy Liang: For Module 4, we'll have one recommendation to share today again as a reminder. This is the location of the IND where you will include all of your non-clinical study reports supporting your drug.
For certain types of non-clinical reports, you will need to include the study results in SEND format.
SEND stands for standard for exchange of non-clinical data. It is a standardized format for organizing non-clinical data for review by FDA.
Single dose toxicity, repeat dose toxicity and carcinogenicity non-clinical reports require SEND data sets to be submitted alongside your final report.
The exception is, if your study started before March 16th, 2023, then SEND data sets are optional.
SEND data sets can be retroactively generated from completed non-clinical studies. But our advice to sponsors is to communicate with your CRO early on ideally, before you start the study that you will need the results in SEND format so that they can plan accordingly.
The reason we're bringing up the requirement for SEND data sets today is because if your study requires SEND data sets, and you don't include them in your submission, your submission will be automatically rejected by the electronic submissions gateway.
If you're working with a publisher, your submission will also fail their validation checks. So you will have a heads up before you submit.
General Authorship Recommendations
Wendy Liang: In the following slides we will present a couple general recommendations for IND authorship before we move on to what to expect for IND submission, information requests, and post-IND clearance.
Risk Register
Wendy Liang: One of our recommended best practices for IND authorship is to maintain a risk register, that is, keep a log of gaps that could potentially trigger a clinical hold of your application.
An example gap that we would rate as high risk for a clinical hold would be a missing certificate of origin for a bovine derived raw material.
An example of a gap that we'd rate as medium risk for a clinical hold would be changing a dose determining analytical method between the IND enabling runs and the clinical manufacturing runs, for example, a flow cytometry assay assessing CAR positivity.
And finally, an example of a gap that we would rate as low risk for triggering a clinical hold would be the lack of a biological potency assay described in your IND for a vector release.
Do's and Don'ts
Wendy Liang: We'll end our recommendations with a general list of Do's and don'ts for do's we recommend:
We recommend ensuring information is consistent between sections. We discuss this as part of pre-work, but this is something that again should be checked before the submission.
For don'ts, as discussed, don't provide excessive details. Work on striking the balance between providing sufficient information without providing so many details that you're constantly updating the IND for small changes.
As discussed at the beginning of this Webinar DHC has built IND templates under Centauri, that incorporate all of these best practices, especially ensuring consistency in organizing content in a row tested manner which FDA has seen many times before, and we have used successfully.
This slide concludes our IND authorship recommendations, and thus we will now move on to discussing, submitting your IND information requests, and what to do post-IND clearance.
IND Submission Process
Submission Timing
Wendy Liang: We recommend that when you are ready to submit your IND that you consider submitting your application on a Monday, Tuesday or Wednesday.
This is because FDA has exactly 30 days to review a new IND submission without exception.
If you submit your IND on a Thursday or Friday, the deadline for FDA to complete their review will fall on a Saturday or Sunday.
When FDA's action date falls on a weekend, FDA has to complete their review on the closest business day before the deadline. This shortens their overall window, and thus submitting on a Monday, Tuesday, or Wednesday, is a courtesy for the agency, but it is definitely not required.
Information Requests
Wendy Liang: During FDA's thirty-day review window, they may reach out to you with information requests. These requests will typically come through email to your company's regulatory contact, and they will come from your IND's regulatory project manager or RPM.
Generally you will be given 48 hours to respond.
Some requests will be labeled as hold items, meaning that the IND will not be cleared to proceed until the comments or questions are adequately addressed.
Some requests may be labeled as non-hold items. These items can be addressed after IND clearance, typically before licensure.
You will respond to IND information requests either by email or through submitting your responses through the electronic submissions gateway.
If your RPM does not specify what method they prefer to receive your responses when they first reach out to you, we do recommend following up with them to confirm. Typically, it is easier to submit responses through email. So we recommend going that route if it is acceptable for your RPM.
Common Information Requests
Wendy Liang: On this slide we have examples of common information requests that can be received by sponsors throughout the IND Review period.
For CMC FDA often focuses on human or animal-derived materials and ensuring that there is sufficient information or documentation supporting their safety.
Another common information request we see is the agency asking for further clarification or justification of a drug product release specification.
For clinical information requests, it's not uncommon for FDA to request revisions to your dose escalation plan and inclusion or exclusion criteria.
And for non-clinical information requests, it is common for FDA to request additional information on the representativeness of the drug product that went into your non-clinical studies and what you plan to manufacture after IND clearance.
This typically happens when it is not sufficiently clear in the IND that the drug product that went into non-clinical studies was the same or representative of what you plan to manufacture for the trial.
Responding to Information Requests
Wendy Liang: On this slide we have some recommendations and example format for responding to FDA information requests.
You should address each of FDA's comments or requests in a single document.
Something to note is that you're not necessarily obligated to accept all of FDA's recommendations.
The risk of not accepting their recommendation is higher if it is a hold item but if you do plan to reject any recommendations you should justify why in your response.
And we talked about this a little earlier. But if you're responding or excuse me, if you're submitting your information request responses through email, you should plan to submit the responses to your IND after IND clearance, which we'll talk about in the next slide.
Post-IND Clearance Activities
Wendy Liang: Okay? So 30 days after your IND submission, you should hopefully hear back from your regulatory project manager that your IND is clear to proceed.
This is always a very exciting day, and we do recommend that you celebrate all of your hard work.
And something to keep in mind is that you don't have to do it on the day your IND is cleared. But within the next few weeks we do recommend that you file an IND amendment with all of your information request responses as well as any sections updated to address FDA's information requests.
We also recommend that you include a Reviewer's Guide, which includes a summary of changes.
Finally, we recommend submitting red line and clean versions of all updated sections to make it easier for reviewers to see what changes were made to the file.
About a year after your initial submission you will need to file an annual report. FDA is accepting the Development Safety Update Report, which is an international format for annual reports and something to keep in mind is that you want to make sure that you are submitting it within the timeframe that they specify. So 60 days after the data lock point.
Okay, that concludes our slides for today's webinar, and I believe now we will move on to questions and comments.
Q&A Session
Sara Mills: Yeah, and I can help Wendy. I'll look at the Q&As now and then I'm going to read some out, and then I'll toss it to you for some of them, and I'll answer some of them. Does that make sense?
Wendy Liang: Yeah.
Sara Mills: Okay, cool? So thank you all for your time. We have gotten some questions through the Q&A little widget, which is wonderful. And I'm going to just start at the top. This is a little bit of a longer question, and likely will require a little bit longer of an answer as well. But I'll do my best is the first part of the question is, when creating a specification and acceptance criteria, how does the level of detail required of an IND differ from that of a BLA?
Can you touch on setting acceptance criteria as report result on an IND for certain quality attributes on DP for LVV and then setting values for BLA. Is that an acceptable strategy?
Yeah. So your spec is definitely and the acceptance criteria on your spec is definitely an attribute of your IND that will evolve and mature over time. It is pretty common to have a specification and early development that has many more report results. However, there is going to be an expectation that there are some of the attributes will require a value driven acceptance criteria as well. It's very common to have potency as one of those values which is initially report result or just, very low, so very low bar or very high bar if you want to stay underneath it. So that will evolve and oftentimes the justification of specification section that mates with the spec itself, will be a lot looser and lighter in its content in an early phase IND over time, as you gain clinical manufacturing experience. That is where you will see it evolve.
And likely what you will start to get is, if you do not evolve that spec, you will start to get feedback from health authorities, FDA included. As you approach a registrational study in which you will be politely reminded that you must reevaluate your spec based on your clinical manufacturing experience prior to that.
The last thing I'll mention about that is a few areas that we've seen multiple clients kind of forget about are the potency assays that are associated with your gene modifying material. So lentiviral vector will also require a biological potency assay ahead of registrational study. And in the middle of your development stream, and that we will be expected for other types of material as well. Not just Lentiviral vector.
It is very rare to see report results through your registrational study for a lot of attributes. Typically, you're going to want to evolve that specification, at least step it in the right direction ahead of that registrational study, and not wait all the way till BLA but you know, that's very loose advice, and also would be a little bit product dependent.
And then I just want to make sure I cover all of that. Is it better to list these as characterization attributes, and then leave then and move them to the spec.
Yeah, so just the last thing I'll say on spec in general is that we, our typical best practice is to put all of the tests even if they are just report results and so for characterization only on the same table like it, on the piece of paper in the same table, we typically do not separate them. And we include a column that lists if it is part of release or part of characterization only.
Wendy, I'm going to pivot to you. There's a question here about fast track. It says, can you please describe the procedure for requesting fast track at IND submission? I know this is something you've done quite a bit of recently. So maybe you'd be willing to take that one on.
Wendy Liang: Yeah, thanks. So the process for requesting fast track designation at your IND submission is that you will file the application under section 1.7.1 of your IND. So you know, you would submit your IND as normal. But you would have an extra application in section 1.7.1, and in the application itself you would be describing the condition that you are targeting, and you need to give some background on why, it's a life-threatening, serious condition. You need to provide some information on what the current therapies are, and it obviously helps if there are, you know, if you can show that for patients where the current tool or for patients who receive current therapies and that don't work, they don't have other options. So something you want to emphasize is the seriousness, life threateningness of the indication, the lack of alternative options if the current standard of care does not help, and then you want to also discuss your clinical data and how it shows promise or excuse me, your non-clinical and your clinical data that supports the promise of your therapy. And again, clinical data is optional for a fast track designation request. So you won't be dinged for not having it. But of course you will need compelling non-clinical data if you don't have any clinical data.
I hope that answers your question, and please like add a separate question, if that's it, if you need more. You want to make sure in your cover letter you make it really clear that you have a fast track designation request in your submission, because FDA has to respond in 60 days.
Sara Mills: Thanks, Wendy. There's another question here, says, should RNP be considered a drug substance or a critical raw material?
Yeah. So I think what gets a little bit confusing about all the gene modifying materials, be them viral vector or non viral gene modification and that would include RNP is we kind of use language that can make it can confound the way in which we think about it. So I think FDA has been pretty clear that this is that our gene, our non viral gene modification materials, at least from the guidance, is considered a critical raw material. However, the expectation will be as you go through development, that if it is not at initial submission in its own, like 3.2.S leaf described that that amount of detail will be expected as you mature your file and move through development. So our typical recommendation is just to start at the beginning with the materials for which your RNP contains, so the nucleic acid material, and in its own 3.2.S and just start that way. You're going to have to mature the file in that way, anyways, and the expectation for the amount of detail that you will need to provide will be easier to do. Instead of what we used to do kind of the old school way, which would be nest all of the information on your gene modification material into 3.2.S.2.3 control of materials, which made 3.2.S.2.3, a gigantic section of the IND. So that's our typical best practice is to give it its own 3.2.S leaf and module. I hope that helps.
Okay. So the next one I will take as well. For the analytical procedures in IND submissions, does FDA need qualification or validated procedures?
Yeah. So the consulting answer is, it depends. The long form answer is that every test method that you are using especially for release of drug product will be expected to be fit for purpose. Okay, and fit for purpose is a test method to test method specific evaluation, which likely then can overlap with what we would consider qualification, which is a step below, and not a formalized definition of full validation. It is best practice to have those all qualified at the time of IND submission. But I would be remiss if I didn't mention that I have seen files in the past accepted without formal qualification data within the analytical method section of the IND. But that would be best practice.
If you do not have that qualification completed and if, additionally, there is any intent to use data from your early stage clinical trials for any kind of licensure enabling, like other than safety reasons, if you want to maintain that ability, then our suggestion and you'll hear this from many of my colleagues and other talks across the globe is we highly, highly recommend you have a very robust retain program. Okay, retains a drug product from your non-clinical and your early phase clinical trials are incredibly valuable. You'll be surprised how many reasons and different ways in which they can be used as you wrap up and you move towards submitting a BLA. It's very, very important.
Okay? So a few other questions. Wendy. Oh, here's one. What software do you use for process flow diagrams?
Wendy Liang: Yes, the process flow diagrams presented in today's slides were made in ConceptDraw diagram.
Sara Mills: Okay what I'll just mention as well that we Dark Horse works a lot on Mac, not solely on Mac, but mostly on Mac. So ConceptDraw is the program which we have access to. It does have a way to convert to Visio, and so many of our friends that are working on PC, you may have access to Visio as well, and that works very well as well.
Okay. Is LV infectivity assay accepted as a potency assay for IND filing of lenti-derived cell therapy products?
No, not typically, it needs to be a biological potency assay. So that can be you know, depending on what type of drug product you're developing, it needs to sometimes it can be as easy as using a similar or the same potency assay as to is used on drug product and doing it on a cell line, and setting up an acceptance criteria based on that. There was another part of that question as well. Does that help?
Wendy Liang: Does FDA need the potency assay to the mode of action to reflect clinical efficacy?
Sara Mills: Yeah, to step back before we step into that question. I think you know the baseline recommendation that we always make and when we're performing our early stage gap analysis and risk assessments, what we evaluate is not only the can a single candidate for potency, but what we would like to see is multiple candidate potency assays in development to provide an orthogonal approach to get to MOA. Many of these therapies are very complex, and therefore, you know, save what now has become gold standard test methods for something like a CAR-T with a cytokine killing assay, or maybe alternatively interferon gamma what we would like to see is multiple candidate assays that can allow you to kind of take multiple lines and get to the point at which you can describe MOA more clearly. This is something that has come up in multiple BLAs and MAs outside of the US as far as really critical, and something that needs to be thought about early. That being said, potency is not required.
There is not a requirement for potency assays in your initial IND file. But I would personally say that that's a very big mistake to not have that in development and not be taking samples and testing at least on a test method, as we mentioned earlier, that would be report results only potentially. And that's because if you lose, and if you lose that opportunity, if you do not take that opportunity to take samples and test those early phase that early phase material, you may not be able to leverage the CMC data and those clinical production runs the same way in later stages.
Oli, how are we doing on time?
Oliver Ball: You've got a couple of minutes, Sarah. So probably time for maybe one, maybe 2 more questions.
Sara Mills: Yeah. Oh, here's one Wendy. Do you need to wait 30 days after submitting an IND amendment before initiating the changes or the clinical trial?
Wendy Liang: Yeah. So in general, there is not a hard requirement. But in one of FDA's recent guidances they did say, if you're making multiple and significant CMC changes, they do recommend giving them about 30 days to review before you start manufacturing using the changed process from a clinical amendment perspective.
Again, there is no hard requirement that you wait 30 days. The general recommendation is that you submit the changes to FDA before you implement.
That being said, you know if you don't hear back in 30 days, it does not mean you won't ever hear back. So that's just something to keep in mind. If you don't hear back in 30 days, it's not agreement per se.
So just something to keep in mind. If you're making sweeping changes and you don't hear back in 30 days you still might hear back later. So just be careful. Try not to make changes that you haven't discussed with FDA already, or have properly risk assessed.
Sara Mills: Yeah, what I would say in addition to that, Wendy is if you do, if you are like we have done for some of our clients done what ends up being you know, kind of shifting an early phase file like we've been talking a lot about here into kind of in preparation for registrational study or something like that, what we have personal experience with this is, we've put that together. We have that nice reviewers guide that you were talking about earlier and then the RPM gets back to us pretty quickly and says, this is a major amendment we are going to need at least 60 days. Do not proceed. So I think that also demonstrates the power of the reviewers guide is that the cover letter and the reviewers guide working together to really prep FDA for what we are providing.
So I think that's the other kind of important part of the IND amendment strategy.
Closing Remarks
Sara Mills: Okay, well, I you know, Oli, I'm sure you have a few words to say as well, but I just wanted to say thank you to everybody for joining I hope that you found some value, and the tips and tricks that Wendy has shared, and you know just me on color commentary. But if there's any other questions that come up, or if anyone would like to talk more about Centuri and the way in which we've really streamlined authorship of these early phase INDs and later stage INDs, as well as we've talked a little bit about. Please let us know you can reach out to any of us individually at any time, and we're happy to schedule a phone call.
Oliver Ball: Yeah, thank you all for joining just as another reminder that the contents they will be available to view on demand after today. So keep an eye out on the website for that. You can also see all of our other webinars. You have 8 other on demand webinars available to look at as well, which will super interesting and valuable as well.
And just one other thing as well as if anyone has any kind of big requests for topics that you're interested in us covering, we're always looking for feedback on that to make sure that what we're putting out there is as of interest and relevance to you guys. So do reach out with those ideas as well. Otherwise, thank you again for joining. And thank you, Wendy and Sarah, for the fantastic webinar. Today we'll see you at the next one.
Sara Mills: Thank you.
Wendy Liang: Thank you everyone for joining.