Clinical Development Plans

Clinical Development Plans

Alexander: [00:00:00] Welcome to another episode of the Effective Statistician and today we’ll talk about a topic that I myself very, very little insight into because I’ve worked only very shortly in this area and so my perception about This whole thing we will talk about today is very limited because we will talk about clinical development plans and how they get established very early on in the life cycle of a, of a compound.

And for that, I’m super happy to have Carrie here on the, on the show. Hi Kerry, how are you doing?

Carrie: Good. Thanks, Alexander. Thanks for inviting me and having me on, on this podcast.

Alexander: It is super, super nice. Carrie is part of RCONIS, which [00:01:00] is still small and still pretty new company. And it’s based on just four people at the moment.

So it is Gennad Vazma, Friedrich Parker, who both worked on the, R packed R package said many of many probably know if you’re working in early phase and then Daniel Sabanese, I think is the correct pronunciation. And that’s actually Carrie’s husband. And so Carrie is the force.

On the team and I would say from all these four people, she’s the most applied one. And so I’m very, very happy to talk today about something that’s pretty applied, but before we go into the topic Carrie, maybe you can shortly introduce yourself.

Carrie: Yeah so I am a statistician and I have a degree in stats.

I’ve been working in the pharma industry for about [00:02:00] 13 years in big companies, started in big company in Boeing, going Ohio, and then I switched to Roche. And after Roche, I briefly worked Working a small company in Eidosha, and then in Vecchio Bio, and later on became Ironwood. Yeah, so that’s kind of my my work experience.

Alexander: Yeah, and I’ve been working pretty interesting to have worked in both kind of these big companies like Roche and Beringa and also small, more kind of startup companies. That’s super interesting. And we’ll actually dive a little bit into this. And the episode today. So in terms of your area, you have mostly worked in the very early clinical development area, haven’t you?

Carrie: I’ve been working in late stage. I started mostly in, in, in late stage. I, I was trial level statistician and then. Become a project lead, but [00:03:00] mostly we’re seeing in in late stage, like phase three onwards for, for the filing. But in between I work in early development as well. And so it’s kind of jumping back and forth and depending on, depending on the timing, depending on the status of the company, the strategy.

So I’ve been involved in both early and late stage.

Alexander: Cool. Very, very good. So the topic of today are clinical development plans and how they come about. So whenever I have been on on on any kind of product, yeah, there was always a clinical development plan already in place. So Kerry, how is that kind of, when actually is the first clinical development plan for any kind of compound put in place usually?

Carrie: Yeah. So usually, ideally you [00:04:00] want to have, the team wants to, to have a high level clinical development plan before the molecule, before the compound entering human, entering phase one and in non, in In non oncology, that means healthy volunteer. So you want to have that high level plant already planned.

Yeah. And there are also cases where depending on the strategy of a company, Sometimes if they license in and compound from the other company, then probably the other smaller company, they already run, they already finished phase one or phase two sometimes. So then they may or may not have a clinical development plan.

So one thing, very important, as soon as you have access. to a potential molecule that you want to very quickly grab a key [00:05:00] stakeholders, key team members into the discussion of clinical development plan. You want to start early as soon as possible.

Alexander: So when I think of a clinical development plan, How does that actually look like?

So what should a clinical development plan that is kind of, that you set up before your first phase one study starts? How does, what kind of things should

Carrie: Right. So it’s a good question. So I mean, before we talk about clinical development, maybe I briefly talk about the, the so called the target product profile.

Alexander: Ah, yes, the TPP, yeah.

Carrie: Yes, the TPP, yes, yes, because the CDP is highly tied. With the TPP.

mm-Hmm, .

So you want to have a TPP. You set up your minimum threshold, basically a minimum treatment effect you want, you want to hit, and then you know that [00:06:00] that treatment effect is considered clinically meaningful, consider considered as commercially viable.

So that’s very important. You have that minimum bar there. And then the commercial colleague or discussion with, with clinical people they will have a target to go, like they want to hit, right. And then the optimistic, like, you know, because we, because at that stage, you probably don’t know how much trim a factor you will hit.

So you want to have a. a bit more optimistic, confident

Alexander: scenarios, you actually need to hit some kind of average and some kind of, well, that would be really awesome. Yes. Yes. Yes. Yes. Right. Target

Carrie: patient profile. You

Alexander: of course, not only have the treatment effect, you have also the population, the Yes. Yeah, you have some very

Carrie: high level, the target [00:07:00] population, the very high level safety profile, you have the Primary endpoint and a little bit on the key secondary secondary endpoints listed there.

And then once you have that, then you can, you can, you can build that into your clinical development plan, your CDP, right? So then in the CDP, we all know you go, it goes from phase 1, phase 2, and then the phase 2. A very critical question is the, is the dose finding, right? Dose finding, finding the regimen, finding the right dose, find the the right regimen.

And then from there, then you start to look at the relation between the PK, PD. So you have a, after the proof concept, after the dose finding, then you roughly know what’s the, Yeah, you would have a guess, right? You would know what would be your dose, what would be your regimen. And then you plan your phase three, right?

And then the phase three, you want to power, you want to take into account of that targeted [00:08:00] or minimum trimming factor. You, you want to, you want to hit you power for that. Then you have your sample size, right? So, Phase one, phase two, phase three.

Alexander: That is very important. Yeah, that’s exactly. It’s kind of the shortest, shortest, shortest path to getting it to regulatory approval.

Yes. And when you think about regulatory approval, do you think about FDA approval there or do you think about email approval or do you just think very generic kind of thing?

Carrie: Yeah, so usually you will also you, you, you need to bring your regulatory colleague in this discussion. Depending on the disease area, depending on the landscape You know, you will take into account EMA, FDA, or sometimes the MFPA as well, PMDA as well.

Right. So then, so because what do you don’t want is that you focusing on the [00:09:00] FDA and then, and then later you, you plan to engage EMA scientific advice pretty late. And then they give you very different opinion. Then what do you do?

Alexander: Right.

Carrie: Yeah,

Alexander: different endpoint, different doses, different treatment durations, different population whatsoever.

And then you, oh, we need a complete new phase three study. Okay, that’s pretty expensive and pretty time consuming.

Carrie: Exactly. So you don’t you want to avoid that situation, right? So you, you will, you will, you will. You will take into account both if your targeted market is both U. S. and the EMA, you know, the European area you know, rest of the world.

If, if, if China population has a huge potential market, then you also want to have that engaged as well.

Alexander: When you create such a clinical development, I guess you’re not starting from a blank page. Yeah. [00:10:00] What would be your first documents or things you would look into to create a clinical development plan?

Carrie: Yeah. So usually phase one is pretty standard, right? Phase one, healthy volunteer, you do the dose escalation. That’s pretty standard. And for phase two, I will say you will, also looking to what, what data is currently available from the preclinical study, right? Because from preclinical study, you have a sense of the safety profile from the animal studies, right?

The, the dose the dose range exposure from the animal study. So you, you want to discuss with your clinical oncologist colleagues to see, you know, what kind of, Those is, is potentially you want to test it in the face to you will look into that as well. But that’s within the molecule within within the program.

And then if there are other competitors or other other [00:11:00] molecule that is same mode of action. same class. And then if they are ahead of you in the game, then you are looking to, if they have publication, then you also looking to, you know, in that molecule, in their study, how they do the study, you want to take that as kind of a reference kind of.

And then you can help you to design your, your phase two studies, for example, or even phase three. So you can, so depending on the disease, right? So similar action, existing data from the preclinical, you will, you will, you will take into that available data into account.

Alexander: Yeah.

Carrie: Yeah.

Alexander: So if you already have run dozens of studies and let’s say lung cancers and you know, you don’t have a completely new thing.

Yeah. Then you probably can build on lots of development plans that are already out there and kind of tweak it. [00:12:00] See kind of, are there any different assumptions? Would you, would you also look for kind of different? Risks around clinical development plan, because One exposure I had was to Alzheimer’s.

Yeah. And it was in Alzheimer’s. There was lots of broad discussions. Okay. Do we go really fast or do we go slow? Do we even have a phase two study? Because well, the phase two study actually needs to be so big that you can directly run a phase three study. So would you, would you consider kind of different alternative routes, kind of, you know, the super fast, medium and slow route.

Carrie: Yeah, yeah, that’s a, that’s an interesting question. You’re, you’re, you’re, you’re, you’re thinking. So usually, excuse me. So usually the CDP, you will not just have one option

you

want to the team, you should discuss with the team, different scenarios, different options. [00:13:00] And then you will list. The pros and cons of each option, for example, this is the most conservative option, right, then you can imagine probably the most conservative is very low risk, low risk in the sense that the the failure rate might be a little bit lower.

Because you, you, you spend more time, you spend more money in the early part, phase two part, you have a way of understanding of the data before you go on large scale phase three. And then it could be the approval date may be later because you have some white space. Then you want to build in the engagement with health authorities, right?

You want to take this, you can have another more aggressive option, which commercially always very open, very open. They like that kind of option, right? Very, very aggressive, but then it’s also a team’s job or, you know, to, to list what is the risk here, right? How, and then [00:14:00] once you identify the risk. And then you discuss with the team, you discuss with senior management, they may say, okay, there’s a risk, but sounds like you know, the risk is not that big.

How does it, the risk is manageable. You know, how do you want to mitigate the risk? Right. If you go with this route, if the FDA come back, or if later on something happened, like you choose the wrong dose or something, or. Yeah. Then how do you, how do you want to, how to say, rescue that that happened.

Right. So you, so you, I think it’s a very important thinking process because while you are shaping different options, that means you think different design options for phase two, phase three, or sometimes you even consider adaptive phase two, three, right. And then also like the timeline You also will force you to kind of gather what is the competitors data out there, [00:15:00] like the how to call this CI

Alexander: Competitive intelligence.

Carrie: Yes. Competitive intelligence. Right. So you also gather that information and they help you to shape different options. Yeah. So

Alexander: yeah. Yeah. Yeah. So in terms of then coming up with these kind of different design options, what kind of.

Capabilities or skills do you need to actually, you know, to be a good designer of a clinical development plan?

Carrie: I think one thing I learned over time is that I think This day is there are many interesting design, my creative design and complex design and then there are some interesting examples out there.

Some regulatory guidance there some channel, allow you to discuss with the FDA or or or scientific advice earlier. If you want [00:16:00] to have innovative design I think the FDA has some kind of complex design program pilots, something, something along like that. Right. I don’t remember the exact name. So,

Alexander: It’s called something like innovative pathways or something.

Carrie: Yeah. Yeah, exactly. Yeah. So, and that’s where I was mentioning earlier that, you know, if you’re Seeking a non conventional route in non conventional option of your CTP, then engaging a regulatory colleague is, is very important. And sometimes even through talking with FDA, they can, they may give you feedback because I, tend to think that the FDA, they see a lot of sponsors propose,

they have a larger database in terms of interesting design options. So they, they may, they may give you some hints, some direction to, to to, to, to help you [00:17:00] to, to design in, in, you know, your CDP, your, your trial in a more efficient way. Right. So, yeah.

Alexander: Yeah. Yeah. Sometimes they may I ask questions like I’ve seen that whereas this question asked about, how do you manage a specific side effect, and you think like this side effect, we never ever even talked about where this is coming from.

Only a couple of months later to find out that, Oh yeah, there was a competitor that had that side effect with a similar method of action.

And then, yeah, from these kind of hints, you can you can understand, okay. Okay. Maybe we should take care of these things. Yeah. So, so you can get some kind of indirect competence. Yes, yes, yes,

Carrie: yes, yes. That’s quite interesting, right? Yeah.

Alexander: That is very, very good. So you definitely need to have very good interactions with your regulatory people.

I [00:18:00] think another aspect. that I think is fascinating is also the money side of it, isn’t it? Because risk is one thing, speed is another thing, and the third element is usually money, yeah? So how costly these kind of clinical development plans are. How, how do you kind of estimate these costs?