Certara Talks – Pivotal Trial Mandate

Suzanne Minton 0:03
Oh, and I think everybody has to re now that’s recording. Sorry guys, this is annoying. I think you have to re-share your camera, please.
Please.
Thank you, everybody. OK.
Hello and welcome to another episode of Certara Talks. I’m Doctor Suzanne Minton and I’m a Director of Content Strategy at Certara. And today I’m talking to my colleagues, Jeff Fatzinger, who’s currently a Vice President of Regulatory Strategy, Doctor Fran Brown, who’s a Senior Vice President of Drug Development Science, and Doctor Ananth Kadimbi.
Who is a Vice President of Real World Evidence? Welcome to Tara Talks.
So I thought we could talk about a article that came out in the New England Journal of Medicine recently entitled 1 Pivotal Trial, The New Default Option for FDA, FDA Approval Ending the Two Trial Dogma. And this was an article by doctors Prasad and Macri out of the FDA. And so I was hoping that.
You could tell us, Jeff, what the gist of this article was about.

Geoff Fatzinger 1:09
Yeah, first the article. It’s not new. It’s not a new statute. The FDA already have the authority to allow A1 adequate and well controlled study plus confirmatory evidence since 1997. It was just not the standard default.
What they have raised is, is that they’re arguing that the FDA should make fuller use of that authority to approve novel products based on the one high quality, adequate and well controlled trial plus confirmatory evidence, which is very important rather than.
Assuming it’s always two, so they wanted to shift the perspective of the agency to look at the single approach if appropriate, rather than two. It has not lowered the bar. It has just changed the default evidentiary, the architecture from potentially 2 trials by habit to one adequate well controlled.
rolled study plus very, very precise fit for purpose confirmatory evidence that drug developers should look at as an opportunity to redesign programs around the one study approval option.
Where appropriate, which is very key, so they can strengthen the pivotal study, build a confirmatory evidence package very early in the process, engage with agencies sooner, use things like MIDD, regulatory strategy, RWE.
To make the package approval ready rather than as an afterthought throughout the process. So it’s it is following up with their regulatory mind shift about the totality of evidence.
Being more important than simply checking the box and running a trial that might be duplicative of previous information.

Suzanne Minton 2:58
Thanks, Jeff. And so I’m, I’m hearing what you’re saying that this isn’t a new change, but still this seems like it’s going to be something that drug developers are certainly going to need to know. So Fran, can you tell us why you think, you know, what you think is important for drug developers to take out of this change?

Fran Brown 3:18
So, you know, as Geoff says it, it isn’t new, but I think what is new is the breadth at which it could be applied. But as far as advice to drug developers, I mean, I think people shouldn’t take away the message that this means they can just halve.
What they were expecting to do and think it it it is sufficient and satisfactory. What they need to think on on doing is how they meet the expectations of evidence, but in more innovative and creative ways.
Building around the central tenant of a of a single pivotal study, and that can mean that they can meet some of that confirmatory evidence in different ways. There’s the potential to.
Actually align and move some of that potential evidence into a post marketing setting. But these conversations will be bespoke in at least initially and until some of the precedent gets established and they will need to be discussed early.
And I think there are caveats really for especially for companies that are developing on a global basis that although this might meet the expectations for the US, they’ve also got to design a program that meets expectations for for the EMA and for for other key.
The geographies they want to commercialize in. So how are all of these pieces fit together into their registration package I think is is far more complex than just sort of crossing out one study on their project plan.

Suzanne Minton 5:02
That makes a lot of sense. Thanks, Fran Ananth. Fran mentioned that as drug developers are moving from the two pivotal trial paradigm to the one, she mentioned that they need to make use of some innovative and creative approaches. Can you tell us what some of those approaches might look like?

Ananth Kadambi 5:19
Yeah, absolutely. And I think both Jeff and Fran have touched on this a little bit, but I’ll elaborate a little. So you know, the consequence of this editorial is going to be that that sponsors will need to plan earlier, probably in early phase two.
For the the to maximize the likelihood of success of their of their registration package. So to ensure the maximal likelihood of success, the sponsors still need to meet an evidentiary bar and you know, as the FDA have implied in their editorial.
That bar is is still pretty high, right? The the requirement for one fewer clinical trial doesn’t necessarily mean that the they’re going to require less depth in the data in order to make decisions for approval or not so.
Sponsors will need to consider where these potentially evidentiary gaps from a single pivotal study could be supported by model-informed drug development approaches, for example, to optimize dose selection and other characteristics of the pivotal trial.
But as Jeff mentioned, it also allows for proactive use of real-world data. And this is something that’s already gaining traction within the FDA who’ve rolled out an advancing RWE initiative in in 2025 and have laid out a framework for sponsors to engage with them.
To help plan and design real world data studies to support evidentiary submission.
The one comment that I would add to this is that this whole new paradigm has the additional benefit of enabling earlier bridging of the evidentiary gap that currently exists between regulators and and payers, and the payers who reimburse the drugs once they’re improved are are more.
Grounded in real world effectiveness than they are in clinical efficacy and safety. And so bringing RWE more to the forefront in the development pathway also has the added benefit, if you will, of those crossing, helping cross those downstream barriers earlier on, which is something we’re slowly.
At least starting to see a shift in the industry towards anyway in terms of earlier planning for post market and peri approval activities.

Suzanne Minton 7:33
Thanks, Ananth. Well, I really appreciate the opportunity to talk with you all on this, this hot topic for our audience. It’s been great talking to Jeff, Fran and Ananth. And if you want to learn more about some of their work, you can visit us on our website, sirtara.com.
I’m Suzanne Minton and you’ve been watching Certara Talks. Take care and we’ll see you next time.