Gain exclusive insight into the world of product development planning and regulatory affairs from industry experts to understand the importance of a streamlined and focused global program strategy.


Stefan Kosharevski: Good morning, or good afternoon everyone, depending on where you are joining us from, and welcome to this webinar. My name is Stefan from Business Review, and I will be your host. It is our pleasure to have Novotech with us today, who is presenting this webinar titled Achieving Regulatory Milestones and Meeting Commercial Goals. Today's guest speakers are Tracey Brown, Principal Consultant at Novotech, Dr Hiram Chipperfield, Principal Consultant at Novotech, and Robert Shepherd, PhD, Research & Development Director at Dimerix Bioscience. Before we begin, I would like you to welcome you to our webinar platform, ON24. You will notice that this webinar is browserbased, so if you disconnect for any reason, please just click on the link you received in our email to rejoin the session. In order to ask questions, you can send them in via the questions widget. Just type them into the box at the top lefthand corner of your screen and click submit. We will allocate some time at the end of today's session to address any questions or thoughts that you may have. Please use our help widget if you require any assistance, and you can move, resize and maximise any of the windows in front of you, to get a better view of the slides. But now, please allow me to welcome Hiram.

Dr Hiram Chipperfield: Thank you Stefan for that introduction. My name is Hiram Chipperfield, and as mentioned, I'm a Principal Consultant with the BioDesk team at Novotech. We will pass along to Tracey in the next section, and to finish up, we will be talking with Dr Robert Shepherd from Dimerix.

To start off with, I will start with an overview of today's webinar. We will start off with the introduction of Novotech, and then we will introduce today's topic, which is Regulatory Milestones and Commercial Goals. We are going to break that up today into two major parts. The first part is, what do you need to get into a clinical trial, and the next part is a roadmap to registration. We will follow that up with an example of one our sponsor companies, Dimerix, and then at the end of the session we will have time for some questions.

Novotech is an AsiaPacific specialist clinical research organisation, and got ontheground operations in Australia, New Zealand, and a range of AsiaPacific countries. There's a lot of information on this slide, and I won't go through it all, but suffice to say, we use bestinclass technology, and we have managed over 1,200 projects, including the APAC component for pivotal trials leading to multiple FDA, EMA, and other registered products.

As mentioned, we have a large base in Australia and also new Zealand, and then in total 1,500 people across 21 offices in 12 geographies. You can see from this slide, we have an extensive ontheground presence across the AsiaPacific region.

Novotech is a clinical research organisation. Part of the services that Novotech offers is BioDesk, and we are the inhouse regulatory affairs and product development service that is provided by Novotech. Basically, what we do is, we work closely with clients to design and implement their therapeutic product development program. We try and guide our companies through drug development process to achieve their company milestones, including regulatory milestones. The team consists of over 10 experts, with extensive experience in aspects such as CMC, toxicology, clinical and medical affairs, and also regulatory affairs.

This is just a little diagram of how this BioDesk fits in with the greater clinical research organisation services. You have clinical and medical consulting, regulatory affairs consulting, manufacturing, toxicology and medical writing. That fits in with the Phase I clinical trials, the Phase II, Phase III other clinical trials, and we can manage aspects from ethics submissions through to global regulatory submissions, all the way through to marketing authorisation applications.

That was a little bit about Novotech, and the BioDesk team within Novotech. I would now like to move onto the topic of today's webinar, which is Regulatory Milestones and Commercial Goals.

Regulatory milestones and commercial goals can very much vary by the stage of development of the company, and the commercial goals of the company. They can start up in the early stages of drug development, including target discovery, lead compound, or discovery of lead compound optimisation, the early proof of concept primary pharmacology animal studies. For a company in that stage of development, a typical regulatory milestone, which we will talk about later, or a typical even commercial goal to get to the next stage of funding, might be the initiation of a firstinhuman clinical trial.

Later on in development, we have the IND enabling package, or the critical nonclinical safety studies that need to be conducted prior to an initial clinical trial, and then an IND, or a clinical trial regulatory approval, is another milestone that is widely used by companies to promote their compound, and also unlock commercial funding.

The next stage, we move into clinical development. Depending on the therapeutic product, or the indication, this can vary. But typically, you might have a first Phase I where the first human is dosed, Phase I or Phase II where you have your first patient dosed. Phase II is where you would typically expect an efficacy indication, or some kind of proof of concept efficacy indication. Then you move onto your pivotal Phase III, where you need to establish safety and efficacy of your product. During this phase, there is also other milestones or goals, that are important for some companies. These include expedited development programs, such as orphan drug designation, or fast track approval for the program.

Even further on, once you have completed your clinical development, then you have your registration or marketing authorisation in your primary markets. These goals here can be the submission of, for example, the NBA or the BLA application, or the marketing authorisation application, product approval, product launch, or reimbursements. Then you are moving onto similar goals in potentially secondary markets, or second tier markets.

There is a lot of goals there, and we don't have time to go through all of them on today's webinar. What we are going to do is, we are going to focus on, I think, two key areas, or two key goals, that a lot of companies that we work with have.

The first one is the preclinical goal. Developing a preclinical package and getting that first regulatory approval for a firstinhuman clinical trial.

The second goals, or milestones, that we would like to talk about in today's webinar, is the clinical development for your therapeutic product. This is a slightly longer series, because it has different stages, but we are looking at very much the clinical development pathway leading up to the submission of the initial marketing authorisation or registration application.

Now I will pass it over to Tracey to talk about the first clinical trial. What do you need for your first clinical trial?

Tracey Brown: Thanks Hiram. I am going to discuss, as Hiram just mentioned, some details around the nonclinical safety studies, or the IND enabling package, that could be required for the firstinhuman clinical trials.

To discuss a little bit further detail about the first clinical trial, and what is required to support that, this slide takes us through a few different options that can be considered, depending on the type of material that is actually being developed and considered for that first clinical trial.

On the lefthand side, you can see that this is maybe a typical spectrum of studies that might be required to support a variety of NCEtype compounds. It should be noted that the package, this is a bit of a prescriptive list, but the actual content of this package should be very much tailored to the actual compound and the aim of the clinical trial.

You can see it follows a CTD type of structure, and it might start with a package of pharmacology studies, typically looking at the efficacy of the compound and understanding maybe a little bit about the mechanism of action, to give some reassurance that the NCE being developed is going to have a chance of being successful in the indication.

This also covers some safety pharmacology assessments, and maybe the adverse part of the compound, if there was to be any unwanted effects on the cardiovascular system, respiratory or central nervous system.

The package of studies will also cover some basic pharmacokinetics at this early phase, including some understanding of absorption of the material, assuming it is not a direct intravenous route injection. Some idea of early metabolism through in vitro studies, as well some basic pharmacokinetics, such as Cmax and AUC information.

Further on, and maybe the pivotal part of the study, or the package should I say, is the repeat dose toxicology studies, often performed in two species for an NCE. The duration of these can vary, and should be decided based on the initial clinical trial that wants to be supported, or at least looking just slightly into that program. Because often as you go through the program, the increment of duration of these studies will be progressed as the program progresses.

Another key part of this package is the genetic toxicology, and that initially starts with an in vitro set of studies, may include an in vivo study at this stage, but that could be deferred slightly, as long as the in vitro studies were negative.

Another aspect that is quite important, and often included within the repeat dose study designs, are some examination of the local tolerance effects. Particularly if that was an injectable route of administration, or maybe even being given directly to the respiratory tract.

We often get asked if there is any differences with packages that might be submitted to Australia, versus those that might go into, say, the FDA or Europe. I would say it is fairly typical that most of the jurisdictions have a very similar expectation through these, for these types of products, and there is very few differences at this stage.

Other types of products, [such as perhaps] captured on the righthand side of the slide, are really relating to biological type materials. The package of work that are used to support these, do vary very much according to the nature of the product, and do not necessarily follow the standard CTD format as you see with an NCE.

Their program is very much tailored according to the risks associated with that type of product. You might, for example, for a cell therapy or gene therapy, you are considering where it is deposited, how that material is then translated into a gene or a protein, and how that biodistribution pattern looks like in terms of the desired site of the effect, versus maybe tissues and organs where it is not desirable to have that material.

Live biotherapeutic products, similarly, are quite different and a unique challenge all on their own, because you are actually giving a live bacterial product at this point, and most of it is, I suppose it actually retains usually in the gastrointestinal tract, and has a direct effect maybe on the microbiota, or maybe even on a distant site. They have their own unique challenges, and are not as simple as they may seem.

Another type of product that we often get asked about, and we are going to talk a little bit more about it in some case studies later on, are repurposed drugs. Whether that is a change in indication, a route of administration, or maybe a reformulation. They have their own unique challenges in understanding the product that was on the market previously, compared to how it would want to be used going forward, and where those gaps may actually lie.

Moving on, I would like to talk a little bit about a gap analysis type of approach that we often consider when looking at new packages of information. As I have described on the previous slide, we are looking at a group of studies usually that have been put together to support the firstinhuman package. That is not just one piece of work, that may be a series of studies performed by the client themselves, the sponsor, or actually through a combination of data and literature. [What we are] looking for here, is to understand (13:53) the intended clinical trial design. We would be very keen to look at maybe the investigators brochure, as well as any indepth reports, and the protocol in question, so that we can understand whether the package as a whole supports the safety of that material moving forward.

We are looking to identify if there are any particular show stoppers that would prevent progression successfully. That may be in terms of a toxicity endpoint, or it might actually be that something appears to be missing and has not been evaluated. We would make a series of recommendations possibly as to what types of studies would actually be needed to fill that information gap, or if there was a toxicity, have we found a no adverse effect level for that, and does that allow for appropriate progression into the clinic, with a suitable safety margin, before any volunteer or patient might be dosed?

In terms of output for that type of material, it can often be written as quite a detailed document, making a comprehensive list of recommendations and comments, or could be a top level list of key aspects to the development program through a series of bullet points within an email. It is something that you can see BioDesk have performed a number of these types of analyses, quite formally or informally, as we write an investigators brochure, this is something that we do automatically all the time, and have quite [an] experience in the last six or so years that we have been in development.

Moving onto the first case study example of a gap analysis that we undertook some time ago, this involved a repurposed material. It was originally an active within a shampoo, and it had been on the market for very many years, and so had been developed probably back in about the 1970s. It was now going to be repurposed. The active ingredient was going to be reformulated in an ophthalmic formulation, and was going to be placed on the eyelid as an ointment treatment for marginal blepharitis.

The initial clinical trial was going to be a Phase I study in volunteers, quickly moving into patients, and was going to be conducted in Australia.

The historical information, because it was pretty much based on literature at this stage, and the client had no studies of their own performed, so we had a detailed literature review, and a look on the FDA website, to see if they actually had described any of the preclinical package within the publicly available documents. It was to our surprise that they actually had, considering the age of the original submission. They had actually provided an extensive amount of information, including 13week toxicity studies by the dermal and the oral route, and a series of irritancy inflammation terms, including ocular irritancy.

That was pretty good. We summarised that information in quite some detail, understanding where the effects of toxicity, because it was actually a (17:12) irritant, and where that lies and where the clinical formulation wanted to be. We did notice that the formulation that had been used in the past, did show some irritancy to the eye, in the concentration range that the client wanted to use the material moving forward. Although the formulation was about to change, so we did recommend that the client perform a new ocular irritancy study with the clinical formulation in question, just to check whether that was still acceptable to move forward with.

Interestingly on this package, we did not find any evidence of genotoxicity studies having been performed. Which was quite surprising, considering its extensive clinical use over many years. But to bring the package up to today's standards, we did recommend that the client perform some in vitro genetic tox, just to be sure that the material was having no concerns in that area.

The studies, as far as I am aware, were actioned, and the study, the Phase I study, was successfully approved and actually started, and I believe this client has now moved into Phase II.

Moving onto my second example, this is related to a Dimerix compound and package of information, which we will talk to Robert a bit later in the presentation. But this is to give you some background. It was originally a repurposed drug used in Japan for hepatitis, and was going to be used for a new indication for the treatment of various kidney disorders.

The aim was to have a look across the package, to see what information was available, and where the gaps might lie to support eventual Phase III and market application. The initial approach was to have a look at the literature information, which was extensively going to be used in this instance, to understand what studies might be required for the initial Phase II studies to begin with.

It was also important for this material, to understand the pharmacological interaction of the DMX200, as it was going to be used on a background of standard of care in these patients. Interestingly for this material, there was a pharmacological interaction between DMX200, and the class of angiotensin II antagonist that it would be coadministered with. It was quite interesting. In our experience, it is not often that you see something where you get a combination interaction, so from that point of view, it was an interesting project.

In terms of the gaps identified, we identified a series of studies that might be required as the program progresses, and there was an interaction with the FDA regarding that information, and whether the literature was going to be acceptable to support that IND submission. We are pleased to say, that that was a successful meeting.

Now we would like to move onto some discussion on the roadmap to registration, and I would like to handover Hiram to take that one forward.

Dr Hiram Chipperfield: Thanks Tracey. You have heard from Tracey how we can get into an initial clinical trial, and kind of see the type of analysis that is used to support the planning for that initial clinical trial. What I would like to talk about now, is beyond the initial clinical trial, through the clinical development, through to marketing authorisation.

There are many ways, or many kinds of documents, or plans that can be developed, in order to develop a strategy to move your product to its next regulatory goal, or to its next commercial goal. But what I would like to talk to you today, is about what we call a drug development plan. Basically, as it sounds, it is a plan on how to develop your drug. It describes the steps that are required to generate the evidence to support marketing authorisation and reimbursement these days. It includes CMC quality requirements, nonclinical requirements, the nonclinical animal studies that you need to conduct, and the type and scope of clinical studies that are going to be needed to support the registration of your product.

In addition to what might be the typical Phase I, II and III program, a strength of a drug development plan is, it highlights additional requirements, or additional studies that might be needed to support the application, such as [starting] clinical studies in special populations, or drugdrug interaction studies.

You can have a Drug Development Plan, which covers all these aspects, or you can have a more focussed, what we call a Clinical Development Plan, which is basically the same thing, except that it focuses only on the clinical development, and puts aside the quality manufacturing and nonclinical requirements. Just to provide an indication of our experience, we have prepared over 30 Drug Development Plans.

There are many ways of structuring a DDP. The one that we prefer, generally use, goes something like this. We start off with a scientific rationale for the development of the product, and this includes a brief summary of the target indication, and why the product is being developed. This really sets the scene for the product, and provides a place in the treatment cascade, if applicable, for the product.

We then look at predicate, or similar competitor products, that are on the market, or are currently in development. This forms not only an important part of commercial analysis, but also provides really useful information on the kinds of studies, kinds of information that will be needed to support the marketing authorisation of the product.

Then that leads directly into the regulatory and marketing authorisation strategy. In some cases, you will be targeting your product for a global registration study, so the major markets, including the US, EU, China, [another] case which you might have a more focussed approach. We have been seeing a number of companies recently which have a more AsiaPacific focus. That might be for commercial licensing reasons, or other reasons, but they are focussed on the AsiaPacific region, and will look at the US and Europe perhaps later in the development program.

You then have the manufacturing quality requirements at the different stages of development. Starting off with Phase I GMP, and then moving through to process validation for marketing authorisation.

Nonclinical studies do not end when you start your clinical studies, and so you need to consider the timing and strategy for nonclinical studies that you may need to conduct during the development program.

We talked a little bit before about your clinical trial strategy, Phase I, Phase II, Phase III, whether you need to consider other populations, or whether you can also have a compressed clinical development strategy.

Commercial importance is to include timelines and costs, or at least estimates, into your planning requirements, so that you can either know how much money to raise, or how long it is going to take.

Then finally, we like to include key decision points in the development plan. You may have heard of the saying "fail early and fail fast". You need to have decision points where you decide whether or not it is worthwhile to continue the development of that program.

Now I am going to talk about three case studies to try and illustrate the power, and why everyone should have a Drug Development Plan in some form or format. I am going to just note here that these cases are from real situations, but have been adapted to protect the confidentiality of our sponsor companies.

The first one I am going to talk about, is an RSV vaccine in preclinical development.

The second one is an immunomodulatory biological which has completed its Phase I firstinhuman clinical trial, and is heading into Phase II development for the treatment of atopic dermatitis.

The final case study that I am going to talk about today, is a kinase inhibitor for the treatment of a rare leukemia.

The first case study is with an RSV vaccine. It was a proprietary proteinbased platform, vaccine platform, designed to generate broadbased antiviral immunity, both cellular and humoral immunity. The stage of development for this particular program was they had promising proof of concept animal studies, so they could demonstrate that their platform, and with RSV in particular, produced robust immune response. But they had yet to start their initial firstinhuman clinical trial.

In the case of this RSV vaccine, the DDP, or the CDP, included a summary of the platform technology, and the results from the exciting proof of concept animal studies. There were no predicate or competitor products, so there are no approved RSV vaccines, and there is a clear medical need. That could be expanded in later iterations of the development plan, to cover some of the designs and products that are in development, but at this early stage, it was not considered necessary. Again, at this early stage, the company was using a generic, what I would call a generic global strategy, and there was no specific milestones identified. What that means is, prior to Phase I it was not worthwhile for this company to focus on a particular regulatory jurisdiction. I should mention that development plans can be targeted for a particular milestone. Their targeted milestone was a Phase I clinical trial conducted in Australia under the CTN scheme. They chose Australia because it has a rapid regulatory system, and they thought it was an attractive country to conduct the Phase I study.

The focus at this stage of development was on the nonclinical requirement. In putting together this plan, we put together projected GLP repeatdose toxicology study in rats, and we did not identify any other significant toxicology studies would be required. We suggested what is a robust Phase I study design for vaccines, which consists of single doses followed by multiple ascending doses in healthy volunteers. The timeline and costs for this program, which is important, so in this case an early phase study, an early phase program, were there, so around $300,000 AUD for the toxicology, and then about $1 million AUD, and a year in development for the firstinhuman clinical trial.

What these timelines and costs allowed them to do, is to allow the sponsor company to plan their fundraising, and go to the market with a specific development plan for their vaccine. Of course, for most products in development, a key decision point that was identified for this product, was unacceptable toxicity in the GLP rat toxicology study.

The next case study that I would like to talk about was a biological, an interleukin antagonist, for the treatment of atopic dermatitis. This company was a Korean company, had very promising proof of concept animal studies, a toxicology package to support three month dosing, and when we prepared the development plan, they had almost completed their Phase I study, which was a Single Ascending Dose/Multiple Ascending Dose in healthy volunteers. They were almost completed their Phase I study, and looking to plan their Phase II study, and their subsequent Phase III development program.

What did this development plan look like for this atopic dermatitis treatment? Again, we started off with summarising the scientific rationale for the product, in this case at the molecular basis of the development of this particular biological. In this field in the treatment, in the field of treating atopic dermatitis, there are actually a lot of competitor products that we looked at. These both set the standard for safety and efficacy that is going to be required for the product, set the expectations for the development of this product, and also set the provider relevant examples under the kind and scope of clinical trials that we required.

An assessment of the regulatory strategy identified a Breakthrough therapy designation would likely be possible if the Phase II results are promising. But other regulatory opportunities, such as orphan drug designation, or other programs intended to expedite drug development, are unlikely to be applicable for this particular product.

We developed a clinical strategy that consisted of the Phase I. We did not develop that, that was already mostly completed. But then based on the research and analysis, it indicated that a Phase II, double blind, placebo controlled dose escalation study in about 120 participants would be a reasonable approach.

Just to comment on the size of that trial, in this case it was based on comparative trials of similar products, because there was no good understanding of the potential efficacy in humans on which we could base any useful [power] calculations. That was the Phase II. Again based on predicate products and competitor products for Phase III, it was most likely that two, not one but two, pivotal Phase III placebo controlled studies, with at least 1,000 patients, or more likely 2,000 patients, would be required to support the marketing authorisation.

We identified that atopic dermatitis affects children, but the paediatric strategy would need to be confirmed based on the Phase II results, based on that safety and efficacy data that was generated from the Phase II study.

At this stage of development, it can be difficult to forecast timelines and costs all the way out through to Phase III, but we were able to provide a cost estimate of about $3 million for Phase II, which was very useful for fundraising. Then a ballpark for the Phase III, but noting that the Phase III [the size of them] will depend on the likely effect site. We can make our best estimate, but it is not possible to forecast with a great degree of certainty at that stage of development.

The key decision points for this program were, again, unacceptable toxicity in the healthy volunteer, or lack of efficacy or unacceptable safety in the Phase II study.

The final case study I would like to talk about today is a small molecule kinase inhibitor for the treatment of a rare leukemia. In this case, the company was really looking forward to solidify their pivotal Phase III, or Phase II/III program, and design that pivotal clinical trial package to support marketing authorisation. Their toxicology package was completed, the Phase I study had completed in a range of malignancies, and had identified a potential use for the agent in this rare leukaemia. They have also done their healthy volunteer food effect study, and moved onto a Phase II study, a relatively small study, but appropriate for this rare orphan indication 58 patient study. Where they found a frankly exciting result of a 47% Objective Response Rate, and a better safety profile compared to other kinase inhibitors.

What did the development plan look like for this product? Again, starting off with molecular basis for development, a review of predicate and competitor products. This particular company had already obtained orphan drug designation and fast track designation, so they had already thought about a lot of these things, and accelerated approval was a possibility.

The next step in their development plan, was to seek FDA and regulator advice on the proposed pivotal study program, a pivotal study design for their compound. Their development strategy, their clinical development strategy for this, which was appropriate for this product, was an openlabel, multicentre, single arm, Phase II/III pivotal study, with approximately 120 patients. In common with other oncology compounds or treatments, it was within cycles until disease progression, or unacceptable toxicity, up to a maximum period of 24 months, with a primary endpoint of ORR, as is appropriate for this particular rare leukaemia.

The cost and timeline for this program was $5 million to $9 million, and three to five years. They had a clear idea of what they needed to support the marketing authorisation of their compound.

Key decision points in this particular case were, so they designed their pivotal study, but would that be accepted by the regulators. Another decision point is the potential lack of efficacy. It was very promising in the Phase II, but will that be seen in the pivotal program, and also a potential unacceptable safety profile.

To mitigate these key risks, the first one was that the regulators would not accept the proposed pivotal study. What we helped them to do was to meet with a regulator and discuss the strategy, and that was accepted by the regulator. It is a mechanism of obtaining feedback and reducing the risk to the program.

Another way of reducing the risk, which came from the development plan, was a potential lack of efficacy. A futility analysis was introduced to the clinical protocol, so if it does not look like it is going to have an effect, then you can then save time and money by cancelling that program sooner rather than later. But that was a very promising program, which is an ongoing clinical study.

That's a little bit about how we would support companies through their clinical development, and a couple of case studies on different strategies for different phases of development. I would now like to handover to Dr Robert Shepherd to talk about his experience, and the experience of Dimerix.

Dr Robert Shepherd: Thanks for the introduction Hiram. Very much appreciate the opportunity to talk a little bit about Dimerix, and the program that we brought to the BioDesk team in 2019.

Just as a little background to the company, Dimerix is an ASX listed company in Australia. The company was founded in 2012 and was put on the Australian Stock Exchange in 2016. We very much embody the concept of being a small virtual biotech company, where we have a core internal team with a large amount of experience. But when we need external help to leverage any specific expertise, that is where we need to form good relationships with our vendors to help our little team internally.

In 2019, we needed an external source of nonclinical and toxicology expertise, to augment some of the questions our team were asking internally. We chose the BioDesk team after an extensive search for a high quality vendor, that could help us address some of these nonclinical questions, with a key focus on how they would be interpreted and work with the regulators. The BioDesk team have since then become an integral resource for us, to really accelerate our regulatory and commercial goals, by providing this ondemand expertise to really leverage our small team.

As Tracey mentioned way back in slide 14, it is really important to make sure that the nonclinical package you present to a regulator is tailored to a specific product. This has been key to us because we have been using an existing drug that was originally registered in Japan in the '90s. Since then we have taken that drug and looked to use it at a different dose, in a different formulation, and in very different indications. We have taken this existing drug and used it in our renal program, and we approached the BioDesk team looking at for a gap analysis, to identify which evidence is in the literature, and which evidence has been previously provided to regulators, that we could use for future filings for our firstinman, but also towards our NDA project.

This gap analysis that was performed by the BioDesk team, provided us a very clear outline of studies that were still required, and provided the evidence to support existing studies being used in the literature. This also included a full report of the genotoxicity data that was available, and this molecule that we are using has an extensive history of use, and so this took quite a bit of work to bring all of these sources together to provide a strong report, that we then provided to the FDA.

By bringing all of the data together in one place, we were able to take this nonclinical package of existing data, and proposed future studies, to the FDA, and had a very successful preIND meeting in 2019, where the FDA agreed with the studies that still needed to be done, which were only a few, and were very supportive of all of the work that had gone into building a data package that was appropriate for sourcing information from the literature.

Since then, we have gone back to the BioDesk team for a few followon questions, and have developed this ongoing relationship. Particularly looking at some of the questions of subsequent analysis of juvenile toxicology, what was available in the literature, and what work we might need to do. This information has been critical in informing our clinical development plan as to how we involve paediatric patients in our clinical plan, all driven back by what toxicological evidence has been available.

Together, this building of knowledge and working with the team repeatedly has been great, because it has meant that we have been able to take and build data with the team over time, and then keep referring back to that source of information, as we've had further regulatory interactions.

Stefan Kosharevski: Thank you very much. It is now time for our Q&A session. You can submit your questions via the Q&A widget. Just type them into the box on the righthand side and click submit. But it looks like we have some questions coming in already.

Our first question for today is, has COVID19 impacted your ability for clients to achieve their milestones?

Dr Hiram Chipperfield: Thanks Stefan, that is a great question. I talked about clinical development plans, and you try and identify some potential risks and uncertainties, but COVID19 was I think something that no one predicted or planned. But in terms of impact, it goes back to planning and risk mitigation, and when something unexpected does pop up, you need to reevaluate and try and find a better option. In the case of the companies we work with, we are lucky enough to work in the AsiaPacific region which has not been affected by COVID19 to the same extent as perhaps Europe and the US. As a fallback response to COVID19 for clinical development, we found a number of sponsor companies are coming to Australia, coming to Asia, to avoid a COVID19 impact to their program.

Stefan Kosharevski: Thank you very much for that answer. Our next question for today is, what are the key considerations for a US versus EU market entry?

Dr Hiram Chipperfield: I will take this one again. It is another good question, thank you. Some aspects of EU US market entry are going to be the same, and there's others they have slight variations. Ideally, you would want to have a package that will satisfy both regions. Broadly speaking, there is a perception that for the US, they prefer, or will accept, placebo-controlled trials, an example of the differences, where in Europe they prefer active controlled clinical trials.

It is important when you are planning, particularly your later stage clinical trials, to consider potential differences in both regulator preferences, and also in potentially the standard of care in your particular indications, and with the aim of developing a program that will satisfy both regions, if both regions is a commercial goal of the company. Some companies are quite happy just to focus on one or the other. But it's a good question.

Tracey Brown: Can I just add something from a preclinical perspective? We often get asked if there's differences between the two US, Europe, or whether Australia will accept anything that would be slightly different to the other regulators. I would say generally that the Australian expectation is they follow EU guidance, just to say that the EU guidance has been adopted by the TGA and that the HREC are perfectly aware of the EU guidance and ICH, and so there's quite often not a great deal of difference between the expectations of the different regions. Although, I think it would be fair to say that the Australian approach is perhaps fairly pragmatic and sciencedriven, so if there was a very good reason for something to perhaps not be there, or maybe in one species rather than two, and there is clear justification for that, that the scientific rationale supporting any variation should be clearly presented. But otherwise, they are fairly similar, at least in the early phases. Thank you for that.

Stefan Kosharevski: Thank you very much for that answer. Just a quick reminder to the audience, you can still ask your questions via the Q&A widget. Just type them into the box and click submit. But onto our next question. What methods, or regulatory process, are available for expediting approval?

Dr Hiram Chipperfield: There is a range of methods that companies should be aware of, a range of processes that the regulators offer in order to speed up drug approvals and drug development. To comment on a couple of them I have touched on, so there is orphan drug designation if you are developing an indication, developing a product to treat a rare indication. Then for truly exciting products that are impacting lifethreatening disease, there is a range of programs. Particularly if your target market is the US, a range of programs, such as Breakthrough designation, that can get you more support from the regulator, and increase/speed up your drug development timelines.

Stefan Kosharevski: Thank you very much for that answer. Our next question for today is, what are the most common, or biggest hurdles, in the regulatory process?

Tracey Brown: Maybe I could comment on that. I was just thinking in terms of toxicology aspects there initially. The biggest hurdles can sometimes be maybe not, are having a clear risk that maybe not be being examined appropriately in terms of whether that is being clinically monitored for, or whether there is a clear safety margin calculation. It is quite important to have a clear noeffect level and safety margin calculations, to make sure that you can appropriately and safely titrate into your initial clinical trial at least. Maybe Hiram has other experiences in terms of other more regulatory focussed processes.

Dr Hiram Chipperfield: Thanks for that Tracey. In terms of the biggest regulatory obstacles, to go back to what we talked about earlier in the webinar, it is not having a plan, or not have a sufficiently developed plan, to push the development of your treatment forward. It is fine to have an aggressive regulatory approach, and then validate that by obtaining feedback from the regulators. Robert can perhaps comment on this obtaining feedback from the FDA as a Dimerix experience, but the biggest obstacle, I would say, would be not having a plan, or not having a realistic plan to start with. Robert, did you have any comments from your experience with Dimerix and going to the FDA?

Dr Robert Shepherd: I think the gold standard here, is go to the regulator early and frequently as you possibly can. I think a lot of sponsors had traditionally shied away from the regulator, wanting to have sufficient data to go to them, but the regulators in recent times, particularly if you are operating with something like an orphan drug designation, which we are. We have orphan drug designations both with the FDA and EMA for our indication for focal segmental glomerulosclerosis. This has allowed us relatively open dialogue with the regulator to ask questions there that could be years of making data to support a problem that you perceive the regulator might have, that could be addressed much earlier and quicker and cleaner, than having to go and either do too much work, or risk getting to your next regulatory interaction and not have sufficient data.

Stefan Kosharevski: Thank you everyone for that answer. Our next question for today is, what are the biggest challenges for small companies starting in the area, and what [functions] should be critical to establish earlier. Robert, maybe you can take this one as well?

Dr Robert Shepherd: It's the story of my life, so very happy to talk about this one. The critical part for a small company is getting the right team, and right expertise in the room, to be able to understand the hugely complex task of tying together all of the aspects of drug development, right from the principal pharmacology, through to the manufacturing of how you are going to manufacture your drugs, through to the nonclinical studies you will need to do, right across the gambit of all of the studies that need to be done prior to getting up to your firstinman. But also making sure that everything that a small company is doing, because it is generally done with very limited resources, that every activity that is done is pushing the needle a little bit further and further and further towards your next regulatory interaction, and making sure there is no wasted capital in having to repeat studies, or having to do the wrong studies and do them again. It is really clear that having the right team and right review, particularly different gap analyses, is essential to make sure that you're doing the right thing at the right time. Hiram, anything to add to that?

Dr Hiram Chipperfield: No, I don't have anything to add to that. That was a great answer.

Stefan Kosharevski: Thank you very much. Just a quick reminder to the audience, you can still ask your questions via the Q&A widget, but moving onto our next question. What regulatory milestones [are there to do this]?

Dr Hiram Chipperfield: I mean, the regulatory milestones, in my view, are going to be similar, but to a treatment from common disease, except some aspects of the development program may look a little different. I think I touched on that in my case studies. A treatment for atopic dermatitis, as an example, the Phase III was the milestone for the clinical development, with a double blind randomised placebo controlled trial with 1,000 to 2,000 people. That is a bit different from the oncology compound where you have an open label study in maybe 100 or 150 patients. The design of those trials is different, but I think that the milestone, in that you are obtaining sufficient clinical data to support marketing authorisation, is similar.

Stefan Kosharevski: Thank you very much for that answer. Our next question for today is, how would you simplify product development?

Tracey Brown: I think from my perspective, I think as we have talked about, what is key here to avoid unnecessary work, or perhaps missing strategic pieces of work, is to have a very clear strategy. Have a very clear target product profile of where the program wants to go, what does the label in the future, what do you want it to look like, what is that desirable set of characteristics, and how are you going to create that plan and strategy to be able to achieve that desirable label? If you can work out the strategy and the most effective way to get that, and have regular regulatory interactions along the way, as Robert mentioned earlier, perhaps rather than just leaving it until later on, at Phase II for example, which might be a bit too late, should in theory give you a very streamlined and cost effective process.

Stefan Kosharevski: Thank you very much for that answer. I think we have time for one more question, which is, what is the process for starting a clinical trial?

Tracey Brown: Maybe I could talk about that one for maybe in Australia, which might be a little bit, people often ask the question, what do they need for an Australian submission, which might vary a little bit from people's experience with an IND submission for example. In Australia, the key documents for this process is a summary of all the information with CMC preclinical toxicology, and any clinical if that is available, needs to be summarised in the investigator brochure. That, along with the clinical study protocol, are the two key documents that are submitted to HREC for submission and review of that package, and approval of that clinical trial. That differs from an IND which would have a much more comprehensive, particularly CMC summary, detailed in that IND, which is not to the same level of information that would be required for an Australian submission. I don't know if there is anything on that process, Hiram, you wanted to comment on?

Dr Hiram Chipperfield: I could be here all day talking about what you need to get into a clinical trial, but that might be all we have time for today.

Stefan Kosharevski: Thank you very much for that answer. (58:40) I will mention that is all the time we have for questions for today. Keep in mind if you did not get your question answered today, they can be answered at a later date offline.

That just leaves me to thank Robert, Tracey and Hiram for what was a great presentation, and to Novotech for sponsoring this session. To attendees, you will receive an email shortly telling you how to access the ondemand version of this webinar, or you can do this through our website, which is Thank you once again, I hope you have a great day.

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