In a recent exclusive interview, Fierce Biotech’s Chris Hayden sat down with Alex MacDonald, Vice President of Model-Informed Drug Development at Allucent, to explore the impact of Project Optimus, an FDA initiative aimed at transforming dose optimization in oncology drug development.
Historically, oncology dose selection relied on determining the highest tolerable dose in small, non-representative patient populations, often leading to post-marketing dose adjustments due to toxicity issues. Project Optimus seeks to rectify this by promoting more rigorous dose-finding strategies early in development.
Alex highlighted how sponsors can align with FDA expectations by adopting advanced statistical methods, engaging early with regulators, and incorporating larger, more diverse trial populations. He emphasized that integrating multidisciplinary expertise—including statisticians and pharmacologists—will be key to navigating these changes effectively.
As oncology trials evolve toward precision-based strategies, sponsors must prepare for a future where dose optimization is not only expected but essential for long-term success.
To learn more about how Allucent is guiding sponsors through these changes, watch the full interview or visit Allucent’s website.
Chris Hayden:
Welcome everyone, and thank you for tuning in today. My name is Chris Hayden. I’m a producer here at Fierce Biotech. Today I’m joined by Alex MacDonald, vice President of Model Informed Drug Development at Allucent. Alex, let’s take a moment and let you introduce yourself to our audience.
Alex MacDonald:
Thank you, Chris. Yes, my name is Alex. I’m a clinical pharmacologist by training. I’ve been working at Allucent for two years and I head up basically what is the quantitative clinical pharmacology functions at Allucent. So that’s basically PK pharmacokinetics modeling the specialist data programming. I have about 25 years experience, mainly in big Pharma, sponsor side, and I joined Allucent in the consultancy sector about two years ago.
Chris Hayden:
Well, welcome Alex. Thank you so much for joining us. So we only have five questions today, so let’s just jump right in. Okay? Can you briefly explain to us and our audience what Project Optimus is and why it represents a shift in dose optimization for oncology drug development?
Alex MacDonald:
Project Optimus is initiative that’s been set up by the FDA within their Oncology Center of Excellence. The purpose is really to reform dose optimization and dose selection in oncology drug development. There was a recognition recently that the historical practices, which kind of go back almost to the inception of cytotoxic chemotherapies, that the dose ranging and the dose selection of these drugs was not fit for purpose anymore.
Basically historically, what would happen is that you would test, would test the dose finding of these drugs at the beginning of drug development in a very small non-representative population of sick patients. Then you would empirically determine the highest toxic or the highest feasible dose. Then you would take that forward into subsequent development. So this is in stark contrast to almost every other disease area where actually you establish quite formal dose finding in relatively large numbers of patients relatively late on in development. So it’s a completely different approach historically in oncology.
They’ve been finding that obviously a lot of the doses that have actually come forward into practice have either been too toxic, or that there’s been too many dose reductions, or that there’s been too many dose interruptions, or leading to discontinuation of the drug. Ultimately, often that means that there’s a post-marketing change in the dose for an approved product. So yeah, it’s very much tackling a problem that’s been going on for a long time and has quite considerable considerations for sponsors who are developing drugs now in oncology.
Chris Hayden:
Well, that’s interesting. It sounds like a much needed change for oncology trials. Talk to us a little bit about how does Project Optimus impact the traditional approach to dose selection and early phase clinical trials? What are some of the key considerations for sponsors here?
Alex MacDonald:
Well, as I said before, the oncology drug development is quite different to other disease areas. That still continues to be the case. The majority of trials starting patients, and they are typically patients who have very few treatment options. So they’re kind of end-of-life stage, stage four, advanced metastatic. So they have an opportunity at least to be involved in an investigative drug trial.
So that continues, but these days starting to look more quantitative and more precise ways of determining both the safety of the drug, but also looking at the activity of the drug, and also the pharmacology of the drug in the early phase setting. So in dose escalation, typically now we will employ more advanced statistical techniques that make an estimation of the tolerability of the drug and the dose response for tolerability much more precise than would’ve been done historically.
Also, there’s starting to look at different regimens and alternative doses once we go into what’s typically called an expansion, which is generally in a population more consistent with what you’re intending to treat the drug with. In larger numbers, they’re now starting to look at more than one dose or more than one regimen. So that’s quite different to what has been done historically. This is what’s emerging now as a strategy for trying to adjust for Project Optimus.
Chris Hayden:
Well, that’s a great point, Alex. It sounds like these changes will allow for much more precision in the early phase trials, which could ultimately lead to better outcomes for patients. I’m curious, what practical steps can sponsors take to align their dose finding strategies with FDA expectations under Project Optimus?
Alex MacDonald:
Well, I think the first step is, it sounds like an obvious one, is actually to understand that there’s probably an expectation that they need to do more sophisticated dose finding that has been done historically. So that starts from the planning of the phase one trial. That also starts with understanding what the likely doses that make sense based on their non-clinical data, based on their expectations of the pharmacology of the drug, and also other drugs in the same class that have been moving forward. So everything starts with the planning.
Then there’s also the implementation, which as I said before, there’s been quite a sea change now to move to more sophisticated statistical methods in the beginning trials. So thinking that the old paradigm for developing chemotherapeutics is not typically enough anymore and won’t give you the precision that you need to have those conversations with regulators.
Then also to think about the size of the trial will probably need to be large and it would’ve been historic. So in terms of the costs and things. But that will pay in the long term because actually the alternative is to wait to the end of development where you probably will be asked to do dose ranging in potentially large pivotal trials, which has an associated cost with the subject numbers and some other costs with regards to development.
So these are the things that a sponsor can think about. Then also about early engagement with the regulators with the data that you collect in those earlier trials to demonstrate that you have, in fact, done the dose optimization that they think is necessary to allow you then to go into larger randomized trials.
Chris Hayden:
So early engagement with regulators on dose optimization plan is crucial to ensure they align with the expectations set by project Optimus. That brings up another interesting question, Alex. What challenges do sponsors commonly face when implementing these dose optimization strategies? How can they navigate them effectively?
Alex MacDonald:
Well, I think the first one is sort of understanding the designs of the trials. Probably the only benefit of the historic way of running these trials is that they are very empiric and they are very simple to understand. But the flip side is that they are not very good. So seeking advice, having statisticians and clinicians who understand this way of working is extremely helpful so that you understand what the added benefits of these types of trials and that they’re not a hindrance to you progressing, but actually they will help you almost universally in the long run.
Having pharmacologists to help you understand the starting position for the drug, what the starting doses are, where your likely dose range for therapeutic benefit is likely to be. Again, historically, you haven’t needed that information to enter into trials, but it’s extremely valuable for you to know where you think you’re going to be.
Understanding that the, measuring antitumor effects in a phase one setting is limited, probably irrespective of how you design that trial. There are, in the early phases of the trial, typically you might have a mixed population of cancer patients where it’s very, very difficult to demonstrate that you have consistent efficacy across patients. Even when you go into slightly larger groups of patients, to be able to discriminate between doses is often difficult. So I think you have to rely on other data in addition to that activity data that you’ve got to demonstrate that you have at least attempted to do dose optimization.
So I think it’s understand that you need an integrative picture of the data, of your safety, of your activity that you have, whatever pharmacological biomarkers, pharmacokinetic information that you have, it’s all viewed as sort of weight of evidence. Then when presented to the regulators, then you obviously have a good holistic picture of where you believe that right dose is.
Chris Hayden:
It seems that having multidisciplinary experts like statisticians and pharmacologists on board is key to navigating these challenges. Now, let’s look forward a little bit, and I’d be curious to hear how do you see Project Optimus shaping the future of oncology drug development, and what should sponsors be doing now to prepare for the future?
Alex MacDonald:
Well, I think the first one is to accept that irrespective of what you believe your drug is doing and what the optimistic outcome might be, that you would be anticipated to have to do some dose ranging in oncology development. Now, there may be a strategy of when and where you decide to do that. But I think you need to build that into your development plan and your strategy that there will be a point where you need to demonstrate that this dose, at least that you’ve got comparable data versus other doses, that it’s either as safe, or more effective, or that it’s more effective, or to look at what the risk benefit is. So you need to plan that from the beginning, I think, into your development.
There are cases where if in extreme unmet needed areas or whether your drug is transformational, that you may get the ability to get conditional approval without dose finding. That does happen on occasions. But typically you will then have to then follow up to demonstrate not only does your drug work in a more concrete fashion, but actually we then have to do the dose ranging as well. So that’s not a get out of jail card, but you may be able to do that in lieu. But to prepare, to go into a development program thinking that is what’s going to happen is probably a bit naive and you’ll set you up for probably failure down the line. So that’s the first thing I would say around the future.
I think that this will become the norm. That actually, the early development in oncology is moving away from the traditional and moving slightly more towards other indications where there is an expectation of maybe even more than testing two doses, that maybe you do a full dose ranging depending on the type of indication. Because obviously as patients live longer and the treatments improve, the expectation that these patients can put up with extended toxicity is no longer the case. So that paradigm needs to change as well, that patients can suffer, and they can take dose reductions or they can take a drug holiday, and then they come back. That’s not effective treatment for the patient. Actually, it’s probably not good business for the drug manufacturer either because their drugs are not as effective as they probably could be.
Chris Hayden:
It sounds like rather than simply reducing doses or taking drug holidays to manage toxicity in patients, improved dose optimization will be the expected approach moving forward. Well, Alex, it’s a fascinating conversation, super interesting in what’s going on in this oncology drug development, and I think it’s fascinating and important as well. I just want to thank you for taking the time today.
Alex MacDonald:
You’re welcome, Chris. Thank you.
Chris Hayden:
Once again. My name is Chris Hayden and I’d like to thank Alex for joining us today all the way from the UK for his expertise and his time. I’d also like to thank Allucent for sponsoring today’s discussion, and thank you very much.
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