Project Optimus Series | The Regulatory Implications of Project Optimus

In this episode, Dr. Wael Harb, Vice President of Medical Management at Syneos Health, continues the exploration of FDA's groundbreaking Project Optimus and its profound implications for oncology drug development. He is joined by Zohra Lomri, Executive Director, Regulatory Affairs at Syneos Health, to discuss how this initiative is transforming dose optimization strategies and reshaping the clinical trial landscape.

The conversation delves into the FDA’s emphasis on balancing efficacy and tolerability, the shift away from maximum tolerated doses, and the integration of patient-reported outcomes. Zohra provides valuable insights on the regulatory expectations for dose-ranging studies, the importance of leveraging non-clinical data, and the role of pharmacokinetics (PK) and pharmacodynamics (PD) modeling in optimizing trial designs.

Whether you’re in oncology drug development or interested in regulatory innovation, this episode offers actionable advice and a glimpse into the future of patient-focused drug development.

The views expressed in this podcast belong solely to the speakers and do not represent those of their organization.

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Transcript

SPEAKER_01 0:00

Welcome to another episode of our podcast series on FDA's Project Optimus, where we explore the transformative changes this initiative is bringing to oncology drug development. I'm your host, Dr. Y. Hart, Vice President of Medical Management at CineS Health. In our previous discussion, Dr. Nick Kenny and I discussed the foundation and the origins of Project Optimus and its broader implications for clinical trial design and patient outcome. Today we'll build on that foundation by focusing on the regulatory perspective. And I'm thrilled to be joined by Zora Lomri, a seasoned regulatory expert who brings invaluable insight into how Project Optimus is reshaping regulatory strategies for oncollege drug development. The regulatory implication of Project Optimus. Next on CineS Health Podcast. Zora, thank you for being here. You're welcome. Thank you. Zora, let's start with a high-level overview of Project Optimus. What is it and why is it such a significant step forward for oncology drug development?

SPEAKER_02 1:10

Well, Project Optimus was initiated from the FTA to address the fact that once a drug was approved, you may get into situations where a patient cannot tolerate staying on the treatment because the dose worked, but the associated side effects were not manageable long term, or sometimes just specifically for some patients. And looking into the filing information in clinical trial, the trend was to usually focus on the select the dose that we make sure gave the most efficacy. And starting from there, you know, it was determined that it might not be the strongest efficacious dose, may not be the ideal dose to ensure continual treatment. That in a nutshell summarizes FTE's position.

SPEAKER_01 2:06

Why is now, why there's a big focus on project optimist and a push for it now compared to a few years ago?

SPEAKER_02 2:14

I think partly it's because the science has advanced fairly fast. So the science has progressed in a way that we can slice and dice better the data and we have better means to understand the dose exposure response relationship. Also, because we look more at the patient-reported outcomes. So now we're taking into consideration more, and the feedback is treatments are sometimes too harsh. I mean, that's really the main reason.

SPEAKER_01 2:43

And how is the change in the type of drugs we develop for oncology today, shifting from chemotherapy to biological therapy, have an impact on moving toward Project Optimus?

SPEAKER_02 2:57

So the FDA to support, because now we have a lot of biologics and sometimes even cell and gene therapy products. The FDE is actually showing a lot of guidelines in terms of determining the efficacious or the optimal dose. And there's a strong push into looking into non-clinical data in addition to clinical data.

SPEAKER_01 3:20

So for biological drug, we don't have to get to the MTD like with traditional chemotherapy and a lower dose than the MTD might be the optimal dose?

SPEAKER_02 3:32

Well, the FDA wants the research to be planned in a way that we look for the MTD, but there are situations when you can't get to it. So that information that we were not able to reach the MTD needs to be documented. You need to have data to support it. And then alternative options are considered.

SPEAKER_01 3:52

Let's dive, Zora, into the regulatory perspective. What are the key expectations the FDA has outlined for companies developing drug under Project Optimists?

SPEAKER_02 4:03

So the requirements, you know, for Project Optimists in terms of clinical study is definitely to have cohorts that are large enough to be fair, to be confident in terms of the dosing recommendation we make for the next study, to ensure also that the dose selected aligns with the non-clinical findings, and that the non-clinical studies are also designed based on what is known whenever possible about the drug class or its biological effect.

SPEAKER_01 4:38

You mentioned about selecting a dose range as we go through the dose escalation. During dose escalation, the FDA has been asking to select a dose range and selecting doses for further expansion in a randomized fashion. Can you elaborate on why this is important?

SPEAKER_02 5:02

Well, the dose ranging is really to ensure that there's no bias introduced. Typically, the cohorts are not extremely large. We're talking about six to up to 40 patients sometimes per cohort. So to avoid a bias, to expedite finding efficacious dose and the ability to preserve the safety of subjects, but also provide the most efficacious treatment. As we know in oncology, typically subjects are in the terminal stages of their disease.

SPEAKER_01 5:37

So we are looking at more than one dose level. So we're not only looking at safety, we're looking also, as you mentioned, at the efficacy. Is it also important to look at PK and PD and modeling when we're selecting the optimal dose?

SPEAKER_02 5:52

Yes, as much as possible, DFT recommends that it is dosed based on PK modeling. There are actually situations where model-informed or model-based approaches are absolutely acceptable. You can also do a backfield cohorts, and you can think of having a study design that would allow you to add or eliminate cohorts or doses as you move along. The major requirement from DFT is that all these study design and modifications while the trial is ongoing is to have that prospectively defined.

SPEAKER_01 6:34

That's helpful. We find that many biotech companies, as they are doing their early phase oncology trials, they are trying to avoid those optimizations because of the number of patients required and the expense and timeline associated with it. What's your experience in skipping dose optimization in early phase oncology trials? Is that possible, or do you think the FDA is recommending that we do that in the early phase one, phase two studies?

SPEAKER_02 7:07

So what we see is that the FDA recommends doing the dose optimization, having dose ranges at the early stages. They really push as hard as possible. It is recognized that there are situations where it's either not practical because there's a rare occurrence of that specific condition, or like it's an orphan type of cancer. So that's why they will allow a model-informed, for example, type of study design. They may allow like going in for just a single dose. However, what I can see coming from interactions we have with the FDA is these model-informed or these, I don't want to use the word shortcuts, but the alternatives to dose ranging are not typically accepted on the basis of a single ascending dose. The FDA wants to see some multiple dosing in the same subjects.

SPEAKER_01 8:07

Is a backfill an alternative strategy for dose optimization that allows us to skip randomization? Have you seen that strategy in the design used successfully with the FDA?

SPEAKER_02 8:21

I personally have not seen it, but I don't see why it wouldn't be accepted as long as there's the proper justification. I think the way we need to look at trial design and dose-ranging studies is we know what the consider like a baseline design, which would be the optimal dose-ranging or dose-finding studies. And then any modification to reduce the number of subjects or reduce the number of doses needs to be justified. I know that the more toxic a drug is, the more steep the toxicity appears, the more conservative the FDA will be. So I wouldn't say, like, in general, for oncology, this is what you need to do. You really need to look at the safety profile of your drug and also like the efficacy input before approaching the FDA with alternative or more condensed phase one programs.

SPEAKER_01 9:25

So the FDA might have a different take based on the drug profile that might mandate or not mandate dose optimization. Have you seen a different response from the FDA and recommendation for dose optimization based on the acid class? As an example, small molecule TKI versus ADC or cell and gene therapy. Is there a different recommendation that we're receiving from the FDA?

SPEAKER_02 9:53

I would say the FDA is fairly consistent, whether you use ADC, cell engine, biologics, or small molecules. The non-clinical data is very informative. So if you have a new, let's say new molecule for a very well-known drug class and your non-clinical data supports a very similar approach and outcome in terms of efficacy and safety, you're more likely to not have to do too much in your phase one program. If, on the other hand, there's any signal of unique safety concerns, I'm not saying worse, but just different safety concerns of the molecule studied compared to the class, then the FDA will become more conservative. I want to add like with the cell and gene therapies and biologics, the FDA really is very open to accepting alternatives or considering alternatives. I see a lot of back and forth between, let's say, I and D or pre-IND meeting. They allow more back and forth because they want to understand as much as possible. And I can see they're striving to minimize because I know it hurts financially your company and time-wise, but also the longer you take to complete a program, the longer a patient is without that specific treatment.

SPEAKER_01 11:17

Indeed, this can be quite challenging for companies trying to meet this regulatory expectation. How can companies overcome these challenges?

SPEAKER_02 11:26

The reality is really invest in what you do from the non-clinical perspective. The better these programs, we know they take longer, maybe more expensive, but it's not as expensive as doing additional clinical studies because some elements were not well defined at the non-clinical level. Make sure that when you look into the dose selected for your clinical trials, that you have looked into all the doses in your non-clinical studies. Best example I can provide is an oncology treatment at the non-clinical stage. There were like three doses that appeared to provide some biologic response, some efficacy. The lowest dose was clearly not going to be something of value in terms of the clinical studies. However, the second and third doses showed some adequate efficacy response. The third dose was the highest showed a better response. The client elected after completing their phase one program, which was very limited and could not really show like there was a difference between the second and third dose, you know, dose two and dose three. When we went into the phase two trial, which the client wanted to be pivotal, FDA recanted and asked them to re-include the dose two, which had worked to some extent. So based just on the strength of the non-clinical data, the FDA requested an additional dose to be evaluated, and that trial, instead of becoming eligible for approval, became a kind of a phase two trial.

SPEAKER_01 13:10

That's great advice. Invest more in the non-clinical studies to avoid the expenses and a long timeline in the clinical study. Yes. How does Project Optimus align with the global regulatory frameworks? What should companies keep in mind as they are developing the drug outside of the US and interacting with other regulatory agencies?

SPEAKER_02 13:34

So when I look at the trials and the sponsor that we support, my challenge is in fact we tend to start with the feedback from the FTA because it's recognized as being the most conservative, especially for those optimization discussions, and then we go to Europe. So I do not have a clear vision of what European or other regulatory authority bodies would say. Would they be more conservative or less conservative than the US? But I do see in general that they do not discuss further what the FDA input is. They are though situations where I see the European regulatory authorities accepting those justifications, dose selection based on clinical data and not so much on non-clinical. So, for example, for the case that I had explained, where just because of there was a dose working in the non-clinical setting, it had to be reintroduced at the clinical stage, we see the European authorities putting a lot more weight on the clinical information rather than the non-clinical.

SPEAKER_01 14:51

This is helpful. What have you seen, Zora, when a company has done their dose finding study outside of the US and they determined the dose for the phase two study and they bring that to the US? Does the US FDA accept the dose or is the FDA requiring to do those optimizations in these settings?

SPEAKER_02 15:13

I would say by large, they do accept the data as long as those phase one studies were designed with the spirit of what the program optimist is thinking. I would say even for foreign companies like non-US studies, the sponsor should really take into consideration the dose optimization. What we see is that the FDA can say, well, you can proceed with your study in the US, but your study is not going to be considered pivotal because we do not have enough evidence of the optimum dose.

SPEAKER_01 15:50

So are you seeing that if the dose optimization was not performed, the FDA is asking these companies to do more than one dose level and randomization before they move to their pivotal study?

SPEAKER_02 16:06

Yes. And when possible, we can try to include a PK arm population PK in the study to not delay too much the completion of the overall phase three program. But yes, you always pay a penalty with the FDA when you have not developed enough your earlier stage clinical program.

SPEAKER_01 16:29

Finally, Zora, what do you see as the long-term impact of Project Optimus on oncology drug development?

SPEAKER_02 16:36

Really, the impact I think is going to be global. I see already the impact of Project Optimus on non-oncology indication. We see it also in the orphan drug setting. To think that you can be modified because there are less toxicities or because it's an orphan disease is not the way to advance your program. The best way, really, is to see what's the best information you can get, justify all or any missing information if you want, supported maybe by class information or by additional non-clinical or sometimes CMCs, especially for biologics. You can look at all these aspects before moving to the next. But overall, I think it's better for drug development, even though it means right now what we see, it's an added burden from a finance and timeline perspective. But I think it's here to stay. It's here to stay.

SPEAKER_01 17:35

Yes, absolutely. It's better for patient students that will be receiving a dose that's less toxic and better efficacy. Well, thank you, Zora, for your valuable insight. It's clear that Project Optimus is not just a regulatory initiative, but a transformative approach to drug development. Thank you to our listeners. Thank you for joining us. Stay tuned for our next episode. We will explore the operational challenges and opportunities associated with the dose optimization. See you next time.

SPEAKER_00 18:05

That's all for today's episode of the Senios Health Podcast. I'm your host, Nick Kenny. If you have other topical issues you'd like to hear on this podcast, please do send us a message at podcast at Senioshealth.com. And for access to more future-focused, actionable life science insights, please visit the Senios Health Insights Hub at insightshub.health. Shortening the distance from lab to life.