Welcome to Farmer Talk Radio. This podcast is focused on enhand strategic FDA collaboration working with Cedar and Sieber from the twenty twenty five Chief Medical Officer Summit three sixty. For more information on the CMO Summit, editorials, podcasts, or webcasts, please visit CMO three sixty dot org. Thank you and enjoy the podcast. We have.
A group of panelists with a very diverse experience of regulatory interactions and essentially get their advice on the best ways of working with Cedar and Seber. Inevitably, with all of the changes that are happening in the FDA, we may have to address some of those potential changes. But the focus here is really on people's experience of how best to interact with the FDA that we know and love. So with that, I'm going to ask for introductions.
I'll start off.
I'm Peter Francis. I'm the Chief Medical Officer in chief antipic Officer at Rath Therapeutics, which is an aav gene therapy company principally working in the ophthalmic space. I have a considerable amount of experience of translating into early phase development. Number of indication number of products for principally rare diseases in the ophthalmology and other areas.
Richard Granton, chief medical Officer Lyndrith Therapeutics were an oral drug delivery technology out of MIT, but prior to that, I worked in the pain space in well and carometabolic.
Cart preaching.
Our preaching Chief medical officer at Precision for Medicine. We're a global cro focused on oncology and rare disease. Prior to my role at Precision, I joined in May of last year. I was at the FDA for nearly ten years. In the latter half I served as a division director of one of the solid tumor oncology divisions within THEEDAR.
I'm Norman Sussman. I'm chief medical Officer at Direct. My training is in liver disease and the company is focused on an acute form of alcohol liver disease called alcohol associated hipatitis.
That's great, thanks for the introductions.
We thought the first area that we might focus on from a sort of best practice is how best to structure your interactions with the FDA. Examples being how to prepare who to send and so on. So maybe for this first question, I'll hand it to Harpreet first, she's had the most hands on experience at the FDA, and then we'll get the other panelists to comment to Thanks.
Peter, Well, we were talking earlier about how much to go into the recent events at FDA, and I think this panel would be remiss to not, you know, focus particularly on Cedar and Seber. So I'm just gonna I am going to answer your question, but I just want to spend a few moments talking about what has happened to my former colleagues at the FDA in the last several weeks and months. And we have seen and this is two prongs. We'll start with Segur and then moved
to Sieber. C Derr has seen substantial departures from Peter Stein, who headed the Office of New Drugs, so that crosses all therapeutic areas. In the oncology group, You've seen the departures of key leaders in the Oncology Center of Excellence with Mark there, Paul Klutz, the head CEDAR head, Patricia Cavezoni now CMO at Pfizer. So that predated some of this of what we saw in the last couple of weeks. And I think as far as interacting with FDA. What you will see there is as far as Sea dur.
Goes, I think things will be.
Somewhat routine and normal in terms of I and D reviews, meetings.
They're continuing to have them.
What I do think we need to pay special attention to is who's showing up at those meetings, who's doing the talking, who's noticeably absent, because more departures will come, so those noticeably absent leaders may be actually recused because they're looking elsewhere. But I think these also present opportunities for emerging leaders to come through and take acting positions
as acting associate directors, deputy directors, and so forth. With Oncology, who makes up about forty percent of sedar's work, I do think they do have good leadership remaining, and so we'll get later into the panel about what I think those strategic interactions should look like.
See Burr.
On the other hand, I think I saw a very substantial loss with Peter Marx, who was really presiding not only over all the vaccine work, but this very robust cell engene development area, really setting up those regulatory frameworks for the first Crisper approval with CASHJEV, the first celling gene approval for pediatric form of leukemia and so not having him at the HELM I think should cause some concern and wanting to understand in the months moving forward,
who's going to fill that gap and will those policies and frameworks that he had been developing to really streamline
and expedite. You know, there's over two thousand cell e gene products in the pipeline, there's over thirty registrational phase three trials and cell e gene so Sibur, I think is where you're going to see a substantial deficit in leadership, and you know, we need to look to see in the coming months who's going to step up and fill those roles all with the other And I'll talk a little more and then we'll come into how I think these can be opportunities to enhance our interactions.
But I think you hit on something it's really critical to the discussion this afternoon. I just want to go back to, which is I think a lot of us have realized along the way that the FDA holds the collective knowledge, if they can't talk about it specifically, are there any concerns that you have that that collective knowledge may be may be affected.
By this, absolutely, yes, and I think that going to the opportunities, I think there are several opportunities for those of us in this room, and as we're thinking about building our teams and who we send to the FDA meetings. You want to as cmos, especially of biotech, you are the lateral to the division director.
The division directors are mds.
They want to talk to the mds who are developing the asset, and you as cmos, if you have a robust track record in interacting with the FDA, the newer FDA leadership may actually need to hear what the precedent has been, or you may need to beef up your.
Team with some of these FDA folks.
That are being impacted by the reductions and force to kind of turn back around that knowledge to support you. So, yes, it's a concern, and also their opportunities to enhance our collaborations to bring back some of that knowledge.
Yeah, I was going to say, we had a discussion before and that resonated really well with me. I've worked primarily in small biotech and so I don't have the big farmer experience, but oftentimes we see those mistakes made you see them as regulators and so regular you know, maybe your regulatory affairs wants to run the show. I have found that basically it's down to it's about patient safety and efficacy, and that's a physician the physician discussion oftentimes,
and you need to present it that way. If there's going to be a discussion about pharmakinetics, you should have that individual there. You should really plan those meetings that you bring your best and brightest and pair them up with the agency.
And I agree.
I think there's an opportunity now for us to come in and basically restate the historical perspective for them because we're on the same page about delivering a drug that's going to improve the lives of patients, and that's what they want to hear from us. And that's oftentimes we make it too much about following the guidelines in a regulatory procedure, and I think we should. My experience is that does not help very much of getting your agenda across now.
And I was very encouraged by what Tuprey said because it happens that I'm in a section where a lot of my colleagues work. Even though I try not to have any x party discussions with them. But I think it's a mistake. Companies frequently view FDA as the opponent, and it's much better, especially at the medical level, to think of them as a collaborator. They first of all, they frequently get some of the top people in my specialty are on those panels. And number two, they get
access to data that you will never see. They're reviewing protocols and drugs that you're not going to know about. And so when they say something, don't get upset about it. Think what did they say and how does this apply to us, and try to be try to be responsive to that. The other thing I would say that I see sort of peripherally is people are always trying to skirt the rules, pull the wool over their eyes, try
to get away with something. And I think being honest and saying here's what I know, here's what I don't know, will really pay dividends. And that's what I would encourage any CMO to do.
I think there's a wise words.
My interactions have largely been at with siber and I entirely concur that there may be a tendency to think of the as an adversarial relationship like you've got to get this through. Come and get this through the best ways to engage positively and very much to read very very carefully what the agency is telling you in that feedback, and for that reason you need to be transparent too, because they will tell you the answer. They want to see the drug approved, they want to see the drug progress.
They're not trying to kill it. But they also have all that information, and so engaging as positively as you can and working with them. I've got to say that in recent past, by experience with siber is that they've been very much more interactive than I remember them being
several years ago. So bear in mind that, particularly at the earlier stage, even if you don't have like an RMAT or something else, the agency seems very willing at the moment to engage semi informally if you have some questions. The responses seem to come back. No longer have I been experiencing responses which like we'll get to this in the I and D process, It's usually you get a lot of insight at an early stage.
I don't know whether others can add to.
That that approach to navigating the agency.
So I thought when they were not having live meetings. That was a major major step back for us because we got a series of letters. I think what Peter said is very important. Have other people read the letter to you. Don't just take your interpretation. Have an expert, have your colleagues, some other people. But the letter we got was so concerning, and I knew who the people were, and I thought, how did they come with this? You know, this was such a such a departure from standard of
standard of care. But when we had a live meeting, literally in five minutes, the whole thing was resolved. And so if you have the if you're able to have a live meeting, it is so much better. It just really smooth everything out and everyone left saying I know exactly.
What after and FDA is very open for business.
I mean, part of what will has substantially changed for these, you know, for the physicians, for the FDA staff, is that they are now required to go in Monday through Friday to the campus in Silver Spring, Maryland, and that will cause some attrition. At the same time, it will open up the door for more in person meetings, and I highly recommend going in person.
There's way more.
That you can pick up where people are sitting who's doing the talking, and you can get way more out of those interactions, particularly if you're taking a subject matter expert with you. For example, if you're CMO, perhaps you know you just need that bolstering of how does this struggle look in the clinic, what are investigators saying about it? Having that peer to peer interaction in person is substantially more valuable than online.
Yeah, I agree.
I mean one of the key meetings I remember asking for a in person meeting was critical for reading the room, understanding what they're nodding, what they're agreeing to. But the other interesting part was, are you know you have to do your briefing document way in advance? And things evolved between that time and between the meeting, and there was a feeling in my company is, well, you can't share
any information that wasn't in your briefing document. And I was going to, like, of course i will in the in the in the discussion, if they ask for it, I'm going to have the piece of paper with me with the additional data, because again in that case, it's more of a collaboration. It's going to help them understand more. Sure, I'm not going to come to the meeting and say I blind signed to them, but we're going to have
a discussion. And as soon as they asked for it, I was able to give an additional data that just changed.
You know.
Again, alaid some of their concerns which we didn't have the time of the briefing book. So again my point is not going off script, but being prepared, anticipating where your gaps are and trying to fill those. And then also I think is really important, particularly if you bring in I made this one mistake. I brought an academic from Cleveland Clinic and that person kind of went rogue on me with and arguing. So that's that's a be careful with that.
Sometimes cavet who you two take it.
And we all know each other, right, So like the division director of the lung cancer division, which was me, I know all the lung kol, so I may have certain relationships and the division may. So it helps to have an insider that you can actually vet which kol you know may be better received. I wanted to ask you about and so Peter, you talked about c Burr. Have you a lot of That's the influence of Peter Marx taking a playbook from Rick Pasitor with the Oncology group.
Have you guys done the interact meetings and are okay? Can you talk about that.
A little bit?
I can? I can.
I'll just follow up just with just what you were talked about before, which I think is very very important. And I've kind of moved to this in my own practice, as it were, which is never turned down a face to face interaction with the FDA. This is sort of a tendency or will go for written responses only and it'll it'll be easier, but there's nothing like seeing the
whites of the eyes. There really isn't. And you actually build a bit of rapport and that can go a huge way, because you never know when you'll need to be interacting again. And if you had a positive you've built a bit of a relationship, then you can have perhaps more of a difficult yet constructive conversation across the table.
And so I'm.
Really glad we all I guess we all lived through the COVID era where it was all not but but now now we're we're all back.
I would thoroughly recommend recommend that.
In terms of the the the interact, which in my mind largely.
Replaced the so called pre pre I n D meeting.
I think it's a I've actually found I've any I've only done one directly. I have done a three Type D meetings which are similar sort of set up. I think the interact my works pretty well as as a as a way to move move your program forward. You the pre pre I n D was never minuted formal responses, and so.
You never quite knew what you were taking away.
Whereas I think the interact adds that level of minuted responses, you have a much clearer idea of what's going to be going forwards. I would add that the Type D mechanism, I know that's been around for a short period. I don't know how many people in this room have availed themselves of it, but I think it's a really, really
excellent idea. It's essentially a single topic, but that means that you get in the room not just a general cast, but you get all of the key people who are reviewing, say the clinical section in the case of this particular conference, and you can really get some excellent feedback. There's a little bit more of an onus on the preparing company because you have to submit the questions with the full package ahead of time. You don't get to send the pre i D. You get to send it in early
and then the package later. But I've found that the interactions have been extremely good and very welcome.
From the agency. They'd rather have that kind of an interaction with you, at least at the SEBA. Does it address your question a little bit?
Yes, I mean I think that we're talking about how to how to interact. I think the interact meetings I've heard have been successful in that kind of we're going to file an ID, but we're trying to figure out what may be gating how the FDA may react to this somewhat novel trial design or endpoint. And I the most commonly used topics for Type D in my experience
have been around optimus and dose selection. You want that dose selection, you want that you want that in writing that FDA agrees with your dose is somewhat of a risk, in fact, if you're taking somewhat premature data. But and on the briefing documents, I think some advice that I would give is that you especially now right with a constrained volume of staff, these one hundred plus page briefing documents are just such a nightmare, and you know it's
the job of the individual contributor. So I'm telling you, as cmos that the division directors your lateral at the FDA, but there's two lines of reporting up to them. So there's the individual contributor who's as we call medical officers, who's getting this briefing document and consolidating it into basically an executive summary, which you see in the form of
the FDA meeting background. They write that, and they have to condense those hundred plus pages of this briefing document and put the salient parts, and then cascade that up to their middle leader, which we call the cross disciplinary team leader, who then vets this document and then it gets pushed up to the division director. So the division director is not seeing your one hundred page plus briefing document.
So what I think would be wise, especially at this critical time, is to basically build that executive.
Summary at the top of.
The briefing document so that if it is going to be essentially lifted, you've created the salient points, You've put it in nice bullet point formats, You've delineated out your key topics, you've backed up each of your questions with the rationale for what the response you think should be is you're basically framing it up because it's going.
To have to go up two levels to get to your lateral.
Rich Now, well, I think it gets back to trying to sit in their seats from where they are and they're trying to do their job. And I believe always I need to make their job as easy as possible so they can go home at night and sleep well and not worry about is this somehow two years down they missed something. It's my job to make certain that all that's in there. And I can give an example where sometimes you don't also push the envelope because we're
all trying to achieve the same goal. We were trying to do get a pediatric indication for a pain injection drug, and you know, the complicated way to do it was do your dose. You know, we didn't know where to start with a dose, and we couldn't really do it with kids going in the surgery because be on ethical not to treat pain. How we're going to find this out, Well, what we propose was let's look at real world data
is being used off label. Let's go to a leading institution where they're using it there and mind their data and provide all this information to the FDA use claims database TOS, saying hey, we're not seeing any toxicity at this dose. Let's model that exposure in humans and what we think it would be and that's our starting dose. And the FDA said, okay, that's reasonable. Second thing, we said, look, we can't do it in a setting. We're going to
have to make certainly these kids are safe. We're going to do it in kids that are going to be in the ICU for three days because I can't do blood draws on these kids all the time. But they're already got pickline. I can do this very easily, and this is the highest first patient population, so I will know if they're in trouble. And I said, that's not a good idea. That led to a study that was doable in a year's time, led to approval for kids down to the age of six years of age, and
then led to a European acceptance as well. Just because we dared to say, what is the best thing to do to solve this problem? And the FDA said, let's go with that.
No, I'm going to change the subject. I have nothing to add. The one thing I wanted to be aware of is that people on the panel read everything. They are very familiar with the literature. And we were turned down once by a paper that I happened to know the first author, and it was just bogus, but it was very hard to argue because it was the opposite viewpoint. So where you can so we recently had a situation where we had a difference on what an end point was.
So I got some people together and we wrote a paper that's accepted because that says it's peer reviewed, and this is accepted by a high quality journal, So I think that's a CMO. You're in a good position to contribute to the literature, even if in the broadest sense, is a little bit self serving, but you know, it
was peer reviewed. The other thing I would say, and this was an interesting case, they also read the company literature, and I know of a case where they turned down an application for orphan status because the company had claimed in their commercial literature that this drug would work in a whole lot of other things, and then they wanted this They wanted approval for this particular indication, and so their own hype actually hurt their application, So be aware
that they read everything, and you should know what your company literature says.
I think some great some great points there as well.
I love you, I love your example.
I think, aside from dosetting as well, you know, we in my field, we have a lot of unresolved issues about approvable endpoints and effect size, and I think the mechanisms we've discussed, but also informal discussions with the agency embracing that I found, particularly with Receiver, that they want to engage, They recognize that we don't know everything, and
that they're open to open to suggestions. I think normal hit on the fact that you need to be comprehensive in your review, don't be selective, but once if you are comprehensive and you're open to that and you're open to their suggestions as well, it can be a very constructive relationship.
And I think we.
Found we had a very clear example where that didn't happen in ophthalmology, and we ended up with an endpoint where the bar was Olympic level, and it just meant that probably at least one, if not two approvals were not granted because that endpoint couldn't be level, couldn't be reached.
We've now in that era.
After that, there've been a lot more positive engagements and the agency has shown flexibility. And there was a period after that where they said, well, the agency is not flexible, they'll only allow this. But actually, with constructive engagement and comprehensive data reviews and data mining, suddenly the agency is much more open into changing that endpoint and making it approvable. So that sort of concurs with what you're saying, Hotpread.
Yeah, I say a lot about endpoint development and validation. I mean, no endpoint really has met the Prentice criteria and so kind of moving back, which is which is basically you know, delineated in the REGs, and so FDA has to be at the table when thinking about developing new endpoints, and the way to do that is a little bit constrained right now because they really should be at at the ground level, having meetings, you know, involved with the KOLs, with industry on what endpoints are.
You thinking about.
I'm sure they're already thinking about them, because certainly other sponsors have come to them. MRD is a very classic and wonderful example in hematologic milndencies minimal residual disease. And you know what the FDA did was work with academic collaborators who worked with sponsors, had an Oncologic Drugs Advisory
Committee and O or an ODAK or an AC. This also will be constrained now since that entire department was let go, as my understanding, so probably less ad comms unless they're reinstated.
But having FDA kind of walk you.
There's a playbook to developing novel endpoints and it starts with having FDA at the table approving on a novel endpoint. It is a monumental task and ask of a regulatory agency, and it's all about risk, and so it's in the FDA's hands to determine what level of risk may or may not be acceptable, and we wanted to do it in a collaborative way. So I think today my advice
would be the moment that we're aware. And by the way, FDA is able to join meetings that are local where they don't have to be paid to travel, they don't have to have travel so if they're in the DMV area, they can attend things online right now that aren't necessarily politically focused, So one of my colleagues is attending a meeting on Saturday about novel endpoints in Saracoma currently at the FDA, So being able, so they're not totally closed
right now, and so bringing them in, giving them some grace as you are interacting with them, I think is important, especially today, but also you know, involving them in these discussions.
So if you want to open up.
For questions or Sidney County's we've we've only got three and a half minutes.
We're going to wrap it up.
But we thought this, this topic in particular, would would benefit from questions from the audience.
Yes, please, Jeff Oxnard, lung cancer doc, Blossom Health Therapeutics. I came to know hartpre at you know, national meetings, and I think from your answer, I'm guessing you don't expect the directors to be at the national meetings where we are used to seeing them, and so access for these kind of getting to know your director requires more time spent in DC. You're saying.
Yes, and I mean I do think they'll be to join things. But we know, for example that FDA this year will not be attending AACR huge loss. FDA will likely not be attending ASCO and all your other therapeutic conferences for the force, you know, for the next several months. We don't know. Marty McCree was at the FDA last week. He was there on Wednesday in person. He gave an opening speech.
It didn't really.
Address many of the hot topics. So we'll just have to see how things play out. But Jeff, I don't have a great answer for that. I mean, go to the meetings, go to Silver Spring, have meetings with them, and meet them in person.
Yeah, I would add that working in the red disease space just turn just that question.
We've had quite a lot of success.
Engaging the agency through patient advocacy groups and patient advocacy interactions. As you're as you're a small bi tech working in the space and you're beginning to build those patient advocacy relationships, they can be extremely helpful and being able to engage the agency, particularly with regard to end points. Any anybody else have any other questions?
Shorter than must be?
I guess lunch was excellent and so we're all relaxing. I think with that, I mean we're pretty much wrapped it up. Any last words, normal, no pearls of wisdom.
When it comes.
I think I've shared everything I should say.
Get somebody on your team or that you can tap into who has FDA experience and can help you strategize ahead of those meetings.
I spend a lot of my time looking at briefing books.
Helping make sure the questions are the right questions and helping make sure we can lead the FDA at least closer to the answer that you're seeking. Get an expert on your team, yeah.
And if you can't within your group. I've often used a lot many consultants in different eras, particularly if I'm working in multiple disease errors where I'm not engaged with that division before myself. I think it's said to have someone in there so you get a little bit understanding. And if you're working with Europe. The one thing I noticed differently from there when I was at my raperture at Latvia, I went in with the same as the first time I had that interaction, and I felt like
the same perhaps would be tensioned. At the end of the meeting, they said we want to stay for cookies and coffee, and I was like, are you kidding me? Yeah, okay, sure, so don't treat that we regulated the same particular cross the pond sometime too.
That's a great way to end. Thanks so much, thanks to penelists, We.
Hope you enjoyed the podcast. For more information about the CMOS seven three sixty editorials, podcasts, or webcasts, please visit CMO three sixty dot org. Thanks for listening.