FDA Direct Ep. 7: This Week at the FDA!

I'm Marty Makary.  Vinay Prasad, Sanjula Jain-Nagpal. Great to see you guys. So, busy week at the FDA. 
Yeah. We're going to talk about the three big panels we heard from selling gene therapy experts, patients, advocates. We heard from experts in infant formula and what things FDA should know about infant formula.
And finally, we actually held our first CEO listening session. And you and I are going to go on the road next week. We're going to be in California. And the week after in Boston, and we're going to listen to CEOs to hear their concerns. So today I guess we're going to talk about all three of these. 
Yeah. This is a listening FDA.
We are on a listening tour and we're getting some really good ideas. Yeah. 
It was a really energizing week. I just have to say, I mean, just to see all the great energy and ideas. I mean, I'm really excited about it. 
And this place runs like 24/seven. Like new announcements come out, you know, new approvals get released.
And so it's just so energizing to be here. Beautiful day on the campus today. So great to be with you guys. 
Yeah. So let's start with maybe cell gene therapy because I think, you know, and I did a great job moderating that. There were a lot of great people in the room. We had the entire HHS leadership there as well, which is so powerful to see all the agencies talking about this issue together.
You don't really see that often, but what were some of your takeaways? 
Well, the first success was we had 25 speakers and we stuck to time. So it is always a success. But we had, you know, 23 experts and we had our internal speakers, who came in and they basically told us different perspectives of cell and gene therapy.
You have a researchers who are doing the laboratory science that underpins chimeric antigen receptor T cells. You have Carl June and Crystal Mackall. You've also got this gentleman came from UC Berkeley, who is one of the pioneers of individual patient, bespoke like, custom tailored for that patient gene editing delivered to a baby with a particular deficiency. 
And there was a big milestone announced this week, a big milestone day for the FDA and for this family and for gene therapy.
Baby KJ. So baby KJ was discharged from CHOP Hospital in Philadelphia after a custom, gene editing therapy for a very rare genetic defect based disease in infancy. And it's really the first ever. It's the first ever. And the FDA was able to tailor the regulatory policy to enable this to happen. 
I mean, Marty, you've talked a lot about this idea of possible mechanisms and pathways.
So tell us, does that kind of, is this an example of that? 
It's basically the spirit of a the plausible mechanism pathway. You can't expect to do a trial. You can, come up with a mechanism of action that is plausible. And also suggests safety based on the mechanism and based on other studies that can be extrapolated to this particular gene editing tool in this location.
And the result is a pretty impressive, outcome where the baby went home after, hospitalization that sometimes can be fatal because of this gene defect. 
So my understanding is this baby is born, and by all accounts, the delivery is normal. And the parents didn't suspect anything. But a few days after the baby's born, the baby's lethargic and not acting quite healthy and normal.
Doctors start to draw blood tests, and they find that the ammonia level is off the charts high, suggesting a problem with protein, breakdown in the liver. They actually sequence the baby and they discover it has a the baby has a he has a carbamoyl-phosphate synthetase deficiency, and they have a particular genetic mutation in the baby that's responsible for this condition.
In a world just a year ago, what do you do for a baby? You restrict the protein intake. You follow the ammonia level, you gradually try to wean them up on protein. You give them nitrogen scavenging drugs. I mean, you really just kind of treat the symptoms of the disease. You don't treat the root cause. 
And with a big risk of liver failure along the way.
And even with that, 50% of the babies are dead in a month. You know, it's a terrible condition, you know, even with those things. Yeah. And the liver failure will inevitably proceed. What these researchers did was they took a CRISPR gene editing. They packaged it in a lipophilic nanoparticle. They infused it in the baby first at a low dose, then at a higher dose.
Now, the nice thing here, scientifically, is we used to use an adeno viral vector gene delivery system. But the problem with that is if you re-exposed a person to that many times, they develop antibodies against the gene delivery system because it is a sort of a virus derived product. But this lipophilic delivery we don't have, we've not yet seen evidence of auto immunity against it.
So you can dose a kid many, many times with different doses. So that I think that's one advance.  It goes presumably to the liver, edits the gene. And now the baby is able to tolerate a lot more protein and the ammonia level has fallen. The baby's healthy and discharged and we see good clinical outcomes. What we don't have yet is this baby has been very vulnerable.
So we haven't yet done a liver biopsy to prove that the gene is edited. I suspect at some point they will want to do that when the baby's healthy and strong, just to confirm that what we're seeing is, in fact, the reality that the gene has been properly edited. Now, what are the lessons here? One FDA rapidly made available this product to this baby and the family.
We have allowed a drug to be given that can only be given to this baby. You know, it is like a suit you had a tailor make.  Talk about suit.  A suit you had a tailor make for one person. And the question that we're going to face at FDA is, how can we do this for many, many kids?
Everyone getting an individual therapy and the usual regulatory thinking has to go out the window. 
That's right. 
And Vinay, did I hear correctly that it took about a week to approve this therapy. 
Yeah. I mean we accelerated this as rapidly as possible. I think, one of the reassuring things that I heard at the meeting was, that, you know, the FDA got a lot of praise for bringing this very quickly to to the to the patient.
Kudos to the career staff here that were, hand-holding the family and the researchers along the way and involved and, doing what we want to see more of at the FDA. And that is custom tailoring a regulatory process to the condition based on the need, the unmet need in particular, and the individual situation and the relatively safety, the relative safety profile of the intervention.
And treating root causes, rather than just masking the symptoms, which is a philosophy that you extend across all sorts of regulatory thinking at FDA, including food and and the issues that are more discussed in in 
Kind of a big win for medical science.
Yeah, absolutely. And so that's just one of the stories we heard yesterday. And then we hear from people who are developing CAR T cell therapies that have resulted in the cure for historically incurable leukemias. And we've heard from people whose own children or loved ones suffer from genetic diseases for which there is not yet a cure, but they are in vigorous pursuit of the cure.
And I think we learned a lot at FDA about things that we could perhaps improve upon. We also got some reassurance that we had been going in the right direction, I think, on some of these issues.
You know, what's really sort of shaped some of my thinking, if I'm being very honest in, in sort of how I think about regulation is when you have to break bad news to a family and the the person reaches it comes back with the response of, gosh, is there anything that we can do?  When you when you have to give that bad news and you don't have any tools in the toolbox to be able to offer it, it
has an impact on you. I mean, emotionally, it I mean, there's no training in medical school for this. It's the hardest part of being a doctor, I think, is breaking bad news, especially when it's surprise, bad news. And you can't help but ask yourself, is there anything in the world that can be done still maintaining our mission to safeguard public safety?
Right. 
That, you know, we should be thinking about why does it take ten years or more on average for a drug to come to market? You know, these are questions I think, that we are asking as we ask ourselves, what processes here can we rethink and do smarter?
Well, Marty and I are both oncologists, so we both had a lot of these kind of discussions.
And exactly as you say, it is heartbreaking for the doctor and for the patient and the family when you get in situations where they'd be willing to try, you know, whatever options are out there. And I guess one other point to make here is that, you know, sometimes I see people say, how do you reconcile your philosophy on the Covid 19 booster shots, where we've written about the need for randomized studies, but also a baby like baby KJ where we're saying you're never going to get a randomized study and it's okay.
And the answer is, just look at the differences. One, a healthy 20 year old kid, a healthy person who has, no medical problems. The burden of proof for such a kid is very high that they would benefit from an additional dose of a product.
And sample size, right?
And sample size. And there's many, many millions of these healthy, you know, millions of people like a healthy.
Baby KJ just one, you know, 50% mortality rate. No ability to do a randomized. It's not even possible. 
Did anyone suggest, oh, you really should have done a randomized controlled trial for, you know, this gene therapy before you gave it to baby KJ? 
Thankfully, no one did. But I guess I just want to explain our philosophy.
You know, we're going to be flexible based on the condition, the frequency, how dire things are, how unique the situation is. That's not a departure. That's not an inconsistency. That's just medicine 101. 
And I think it's a good harmonization of common sense.
Right. 
And just makes sense. 
Yeah. Big theme, common sense and so so hopefully we can see more innovation in that space.
We'd like to move it along. I think it's an amazing expert panel that I just absolutely loved. And soaked every minute of. So I would encourage people to look at that FDA expert panel.
Maybe just add one more thing about the expert panel before we move to the next topic is that we also have the secretary. Secretary, Robert F Kennedy Jr came.
We had Mehmet Oz come from CMS. We had Jay Bhattacharya come from NIH. I think I've never seen at FDA, the NIH director, the CMS director, and the, HHS secretary and the FDA commissioner, all in the same place at once. So advocates not only got to say what they thought we should do better at FDA, but also what CMS could do about making payment for gene therapies, where the gene therapy may cost $2 million, but that condition will be cured, and the health care system may save 4 or $5 million in lifetime health care expenditure.
How do we pay for that in a regulatory environment? Doctor Oz was able to comment. What about somebody brought up the issue of organ transplant? How do we increase organ supply? Well, of course you know tissues falls under FDA but organs falls elsewhere. But we had Bobby Kennedy to listen to that. So we really assembled, you know, the the audience you most want.
If you are somebody who's concerned about these things. So people could directly appeal to the relevant stakeholders. 
And I love that approach. Right. A coordinated research, approval and payment strategy around a new therapy, because it's been so clunky, it's been so sort of, you know, parsed out and and not streamlined that you have these situations where you have this great irony of a health care system that spends over $4 trillion, and yet a kid with a rare condition will be told there is a treatment, but you can't have it because it's not covered.
And so that makes no sense, right? In a modern world, we should be able to fix that problem. And it's not a matter of simply, you know, oh, the insurance company's bad. They need to be. Well, it's a broader strategy of how we make sure that there's access, and that includes financial affordability. To a lot of these therapies.
So that was a part of the expert panel yesterday, a great expert panel. I loved it, learned a lot. This is sort of the exciting, fast growing area right now. And I think, laboratory life sciences. So I got a lot out of it. And I'm glad we did it. And hopefully it lets people know this is a priority area for us, for you, for CBER.
And, hopefully we'll see more cool stuff. Come coming. Not just baby KJ.  
And the Secretary spoke with baby KJ's parents and maybe the doc and the doctor. And shared some of that, conversation at the expert panel. That was cool. 
That's amazing. Well, speaking of babies, I think we should talk about infant formula.
That's why we love Sanjula.  So this is part of a broader initiative we have across kind of HHS around, operation stork speed. But, Marty, maybe share a little bit about kind of why we're even talking about baby formula. Well, there's been almost no innovation in the baby formula space since 1998, with the exception of adding selenium, the FDA has not updated its recipe
for, what you must include in baby formula for it to come and get. 
There's one recipe. 
There's one recipe. The government issues a recipe of this is what needs to be, you know, these are the criteria of the ingredients.
When you say recipe, you mean kind of like you need to have X amount of this vitamin or these nutrients in these quantities is that?
It gets very wonky into the complexity.
But yes, exactly the ingredients. And so that, it's called a monograph. Technically. And that's been sort of this system of regulatory approval. Well, if you have an idea to use a different fatty acid or a different, a non seed oil, alternative, then you, you don't meet the recipe. And so therefore it's very hard to come to market.
You have to almost submit it as a new drug and run a like a phase three clinical trial and run off. So it's like we have got to promote more innovation. So there's more competition, there's more types of baby formula, and we can meet the demand that moms have in America to have baby formula with no seed oil, baby formula without corn syrup, baby formula without added sugar, baby formula without heavy metals.
So those there is now an increased awareness, not just in the nutrition science community that we heard about, that we heard from in that FDA expert panel. 
Maybe a broader point here is that, you know, there definitely, probably ways to make a baby formula that's not good. Maybe he's not going to gain weight, not going to grow healthy.
So there are lots of ways to mess it up. But we are not even close to having the audacity. Like we have the audacity claim that we have the perfect recipe. We don't know that to be true. It's very plausible that we can improve baby formula in many different ways through these sorts of substitutions. FDA doesn't know, you know, so I think we do have to allow.
And we're also seeing that moms are buying baby formula from other countries because they feel those products are healthier or don't have some of these ingredients. And so I think there is a there's a lot of desire for, for us to to think about this. And I don't know, I, I learned so much. I mean, the fact that, you know, there were studies presented from the 1980s that were really compelling, and yet we really haven't acted on some of those.
I saw that I was like, oh my gosh, this study is amazing. And then it was like 1984 or something. It's like, how do we not? And I assumed it just came out because it was so mind boggling. But I don't know if you're referring to the study on visual acuity. 
Yeah, it was a visual acuity study done with rhesus monkeys, and it looked at the seed oils.
Right. And it compared, safflower oil against soy oil to see how that impacted visual acuity. And you saw that safflower oil actually had kind of lower visual acuity than the soy oil. And so there's a lot of discussion about the right kind of fats and oils. And my takeaway was, well, you know, not all seed oils are equal, right.
So there's different compositions of the fats and have different impacts. And those of you, the ratio of the omega threes, the omega sixes. And so I mean there's a lot we can learn from that. 
It's amazing that the visual acuity say on an eye chart was lower for the primates fed, when their mothers in pregnancy were eating, the safflower flower oil low in omega threes.
And when the babies had the same safflower oil lower in omega threes. And so, you know, one of the experts said think of omega threes important for brain health. And omega six is more important for body health. And so there's actually this incredible data that shows that the types of fats consumed in pregnancy and in childhood affect your visual acuity.
And there's a whole science to it. And when I read the paper about the photoreceptors in the retina, and, you know, one of the precursors of one of those molecules is linoleic acid. But, I mean, how do I how did I not learn about that in medical school? I mean, never once did we talk about seed oils
And how have we not tried to improve upon formula, development and giving people and giving consumers different options that are all, you know? 
Some of these regulatory guidelines have been pretty rigid, right?
And just kind of putting out that monograph to your point. But there's so much more evidence now that we can build off of. Right. So seed oil was also a big piece of it talking about the sugars. And so lactose came up. You know, I know lactose is kind of used a lot. There are a lot of infant formulas out there that are lactose reduced or lactose free.
You know, what surprised me was that the experts said that there are more infants who are consuming lactose reduced or lactose free formula than maybe what is medically necessary. And I think some of that comes out of how these products are being marketed to families to say, hey, this is gentler on the stomach, and so you have babies out there that ...
Which is not a substantiated claim.
Right.
Right. 
So there's babies out there getting a lactose free formula who probably could get a lactose formula. They've been, in some ways a bit, captured by the narrative that lactose free is better, but it likely is not better, particularly if you can tolerate lactose. 
A lot of experts had commented, I think that lactose is a very good, powerful, complex carbohydrate important for infants in their development.
And so you've got to get carbohydrate somehow, right? So I mean, fat, it can be a source. But also, a lot of people do not like the idea of corn syrup. I mean, this is not natural, right? This is not how when cavemen, you know, delivered babies, they didn't immediately give the babies corn syrup. Right?
Right. So, we have to think about not just what makes sense in a maturing nutrition science field. If we didn't get the recipe perfect in 1998 and it's like, okay, we don't need to touch it now, we're good for the next thousand years. No, the field is evolving like we have a lot of learnings in that space.
We heard from those experts at the Infant Formula Round Table.  
And the corn syrup piece is interesting, right? Because as you know very well, you know, the impact on those added sugars early in, in life sets you up in this trajectory for a longer term. Chronic conditions, obesity, diabetes, all of that. And that was a lot of what the panelists were talking about is we have to get this right early on.  That early nutrition is really important.
And I just the marketing piece of this on the labeling and the guidelines, I mean, on seed oils is one part. The lactose is another piece. Another thing that surprised me was this, they were saying there are claims that this is basically equivalent to breast like human breast milk. Right. And some of these things are not actually well substantiated.
Or there were other claims around this formula can stop your baby from crying in 24 hours, right? Things that have no basis in kind of what the in science. 
That's right. Most experts say that breast milk is better for a baby than formula. And of course, that needs to come with the important footnote that some women cannot produce breast milk physiologically or for other reasons, are not able to breast feed their babies.
And so, that's when we need to acknowledge that we need good infant formula options out there. 
Breastfeeding should be encouraged and supported but can't be mandated, obviously. 
And that's what the CDC has been doing for a long time, actually, in the CDC. I think it's the healthy people 2030 goals. There are goals for increasing breastfeeding rates in the United States.
That's been a long standing, sort of, goal of the CDC. There's also the issue of the supply chain getting when you have fewer options and less product competition. 
You can run an infant formula shortages. 
Exactly. And that's of course, that's what happened a few years ago. 
Four major players who control about 70 to 80% of the market.
And so we need to see more options.
See more options. At the same time, we want to encourage those companies to keep producing, high quality infant formula because we don't want to see another shortage because, you know, there's a saying, I know, we use in the operating room a lot. You've heard it. Don't let perfect be the enemy of good.
Right? So if we create these very stringent, standards by which now that infant formula issue the shortage, there was also a contamination issue. Of course, that's serious and separate. But when you have a just you don't have a lot of competition on the market and you have this supply chain that's sort of narrow. What you can see is that it becomes flimsy where it can be disrupted with a single, you know, event.
But the real story is why why don't we have more infant formula products on the market? 
Yeah. I mean, a misuse of government and regulation is always too overregulated space where you you're not really sure you're optimized. You know, that's always a misuse. 
That's right. Perfect. Could be the enemy of good. Of course, when when people didn't have infant formula, they were using things that were terrible for babies.
Right? Right. I don't even want to say them, but they were right alternatives that no baby should be getting. 
And every year there's some babies who suffer because the infant formula that people dilute the powder too much, for instance, and that that can be quite dangerous, you know. So, there are clearly, you know, some important safeguards that need to be in place, but also we can't pretend that we have, as Marty says, the perfect infant formula in 1998.
And it can never be improved upon. 
Great points, great panel. Encourage everybody to watch it again. FDA Expert Panel on Infant formula. And, this should be up now. I think we posted it on our social media accounts.
And YouTube. 
YouTube. Good. 
Now the CEOs and they were the last to enter the room. They were just here last night.
So this is our third event this week. And it was a CEO roundtable sort of listening session with CEOs from pharmaceutical manufacturers.
Big and small. I mean, we had the big some of the big players were in the room, but some of the small players in the room, people usually from the DC, New York area next week were going on the West Coast, and we're gonna go back to the Northeast in Boston, and then we might go to Atlanta by the end of the summer.
And we had, how many people were there like 55 or 60 people?
Seemed like more.  
It's close to 70.
Seventy people. And, we, you know, met with everyone there. We let everyone have the microphone. We went around the room and everyone gave 1 or 2 points that they thought the FDA could do a better job.
Now, what were the ground rules? Of course, no one was allowed to talk about their specific medical product or their specific thing that they're working with the FDA on. It was about high level, you know, pan company kind of concerns. And we heard a lot of things in different domains, communication ways in which it could be improved between the FDA and the between the reviewers and then the company.
And a lot of those points I thought were fair points. 
Yeah. They said like a five minute call could save them two months of back and forth with letters or uncertainty or how do we do the application or what do you want in this clinical trial design? Very good points about increased communication could help innovation.
But I want to double click into that because I think we experience this every day.
Right. If I have a question instead of me emailing you, I'm just going to walk down to your office and it's much faster. Right. And so I didn't realize that you have this interaction where company sponsors are waiting. I think that I can't remember the number now, but it was up to ninety days 
There's a tiered system of communication.
Yeah. We're just you know, they have a clarifying question that to your point, could have an answer in two minutes. Five minutes and then nine days goes by. And then to your ultimate question about why does it take ten years? It's these little incremental kind of steps that they add up over time. 
They add up. So, companies and developers deserve an instant response to their questions.
And of course, we can't let them abuse it where they're calling five times a day with every little detail. But a couple quick response communications would go a long way. So we're going to work on that. 
We're going to work on that. And then another big theme that came up was, the CMC chemistry manufacturing and controls processes.
Now this is sort of the nitty gritty of how things are actually made and the quality testing that goes into FDA. And, you know, there's just there's there's a depth of quality testing here that I don't think I fully appreciated. For instance, when you take a pill and you split it, you assume that half the active ingredient is in both halves of the pill.
But we have people here whose job is to ensure that that's true, even if it's split in a different direction, that you know the active ingredient didn't precipitate to one corner or the other.
So if you cut it horizontally or vertically...
You might get all, you know. But these are the little things. It's it's a little things that we actually care about, extremely important.
But the industry people, their point of view is that this meeting, all of these standards can be extremely onerous and costly and time consuming, cost tens of millions of dollars per product. So we're so and we hear them. But we have to balance two things. One, the products that we have in this country have to be the highest quality sterility when necessary.
We need to take these things into account. They are important. At the same time, I'm sure the industry has a point that our paperwork is at times overly bureaucratic, too many forms and too much, you know...
Pages and pages.
A hundred thousand pages sometimes.  Some applications have been 100,000 pages.  So we have to ensure ...
That's the reason why we can't review fast, because it's 100,000 pages.
But then you say, well, why does have to be a hundred thousand pages? I mean, we have to introduce a radical, innovative concept called the page limit. 
Yeah, we really do. I mean, I think that it's important to be, to have information available if you want to dig deeper, but to routinely read, you know, you say 100,000, but I've heard some applications are 800,000.
Wow. 
And it's this crazy perpetual, dog chasing its own tail because the companies don't want to be stuck in a gotcha moment where a reviewer might say, oh, where's this information? So they figure just include a 100% of every single thing they have. 
You know, it's like a medical chart really. You know, sometimes when you get when you get the medical chart from the outside hospital and it tells you all these notes on what he or she may have eaten six weeks ago, what the blood pressure was on a Tuesday.
It's not usable. It's just too much information. 
That's right. Yeah. It's like the presentation in the emergency department where they they take you all the way around the barn at the very end and has pancreatitis. You're like, okay, you could have started off like that. Yeah. 
I think that's why I heard some of the CEOs are really supportive of us using AI in some of those administrative review kind of tasks, where you can kind of help summarize many of those 100,000 pages.
And of course, this week was the big rollout.
For Elsa. Yeah. 
So Elsa is our AI, powered scientific review tool that the scientific reviewers use food inspectors. And so they use that to, help them with the scientific review. And sometimes it's summarizing a lot of that background information. Also, you know, our reviewers are very good at double checking, sometimes triple checking all of the data and making sure it is formatted or they reformat it into certain tables.
And that was another piece of feedback we got in the CEO forum. Is the data in the tables could benefit from a standardized format where they are not spending a tremendous amount of time, taking data and putting it in an FDA format. When we have a tool that can do that. 
And then I think the third big category that came up was end points control, arms randomization when you need it when you don't.
And earlier in this video we talked about baby KJ. And let's say hypothetically you have a child with an enzymatic deficiency. You know exactly what the gene is. That's the implicated in that.  You deliver targeted gene editing. You see that the enzymes are corrected, the levels all start to normalize, and then later you biopsy the tissue and show the gene is edited.
I think in those cases, we're going to be completely satisfied that scientifically, you've proven that this baby is better off as a result of the therapy n of one equals approval. But there are also cases to push back a little bit on the industry where they some people went a little too far and told anecdotal stories about products, where somebody has a disease that deteriorates slowly.
But of course there's a range of presentations. Of course, some people will deteriorate faster and some slower. They administer a product that they say is responsible for a slower deterioration. But in that case, it's very difficult to know. Is it the product? Did you just happen to find somebody whose disease is progressing more slowly? And if you don't have all those biological correlates along the way, it's harder for us to know.
And maybe in those cases, n of one isn't enough. So this is sort of the nuance of science and regulation and understanding cause and effect. 
You got me thinking. If when I deteriorate, if I want to deteriorate fast or slowly. 
Oh, well, it's an interesting question. Well, I mean, you're talking about really like what Peter talks about, lifespan.
Yeah. 
Which is that I think we don't just want to live longer. We want to live a long, healthy life. And for many of us, I think we'd rather if we were to deteriorate at the end of life, rather have it be more abrupt. That's my personal view, actually. But but but these kind of chronic conditions, they're talking about, like, early lifelong deterioration.
And if there were really a drug that would slow it, we would approve it. I mean, of course, the question is, how do you use anecdotes for a, slowly debilitating condition? That's a challenge we face at FDA and maybe with biological correlates, we would be open to that, but with no clear biological correlates. Anecdotal testimony. And let me give one more example.
Sometimes in cancer you can measure the tumors shrink. Well, that's a that's that is a proof that the drug has activity.
Surrogate endpoints.
Surrogate endpoints. And that that's something that, you know, we've always embraced at FDA and will continue to. 
So what I'm hearing is the industry wants a little bit more of that kind of predictability.
And you know, what we're looking for in these different, tailored cases. 
Yeah, that came up. 
And I think they'll get it when they have a you know, when we think about ways we can have a faster talking back and forth with our reviewer staff. 
I think anything we can do to reduce mind reading at the FDA, the better.
I mean, predictability is important. It's important not just for companies and developers. It's important for investment, right? We want to encourage investment in innovation. And so predictability, it sort of cuts through one of the big problems in life in all aspects of life. And that is making assumptions. Right. So the more we can do to let folks know this is exactly what we are thinking.
And that was in part the idea behind our New England Journal paper on, Covid vaccine regulation. 
And the letter in reply to these responses we got is going to come out soon in the doing the journal and even these videos, I think, let people know what we're thinking and how we're thinking about it.
And maybe we can think creatively of other ways, you know, maybe if they can understand what reviewers in a particular division are thinking, I think we should take a hard look at that.
Well, that's something that came up, which is that the industry felt like you're sitting on a treasure trove of data. Of course, there all those drugs that came to market, but there's thousands or tens of thousands of drugs that never came to market. And there are different reasons why they didn't come to market. Manufacturing reasons, efficacy reasons, endpoint reasons.
There's got to be a way that we can learn from all that information and that the industry doesn't have to, you know, they can benefit from this information we have at FDA.
Yeah, that developers can know those reasons.
You want to repeat the mistakes that others have already made, right? Yeah. 
And we're thinking about ways to do that. 
Radical transparency I love it.
One of the big themes common sense, radical, transparent. 
And that came up yesterday in the forum to I think a lot of CEOs please, you know, continue to provide that transparency. We're seeing a difference. And, you know, if there are other ways to do that. So I think we'll have to think more about it. 
And then maybe a last point is that, this came up in the morning and in the afternoon is that, you know, some of the people were worried about where is the the center engine of innovation going to be globally.
And in the morning session, people talked about development of gene therapies in China. And in some ways it's it's accelerating. And I think it's we should be very clear that it is your position that the United States will remain the center of biomedical progress and the engine of biomedical, innovation. And there are lots of things a regulator can do to improve that.
Yeah, people have significant concerns of phase three clinical trials where the vast majority or all the patients, were are in China and, can we use that data to make, inferences for regulation in the United States with Americans? And so I think the general feeling that came out in that oncology advisory committee was, no, we cannot accept a trial where all the patients or that vast majority are, in a in China.
And that's for many reasons. Sometimes you can't trust the GDP numbers that come out of China. Why would we trust, why would we make decisions based solely on phase three clinical trials done in China. 
You know, and I just want to add to that, which is that, you know, sometimes I read a newspaper and they talk about an amazing trial finding.
And you look and you see and you, you see that there's a high accrual rate in China. And I do think people should think critically. And it's it doesn't mean you're always skeptical, but you should think critically about those things. 
Yeah. 
I think on the topic of trials, a couple had also recommended, you know, can we change the requirements of 2 to 1, clinical trials as well?
Yeah. And we do use one for, I don't know, maybe half of new drugs. But it was a very good point. Something that, we've been talking about and thinking about is that clinical trial requirement. So something to work on, something to think about. We got a lot to think about. Anything else? 
I think there is I'm just looking at, you know, some of the things I noted down, the idea of scaling up some of the priority review.  A lot of interest in accelerated reviews, priority reviews, rare diseases.
And so building on those successes, we are not going to, change any of those very, great pathways that exist. We want to build on those successes and see what what else we can do. 
I think that the biggest thing was across all these meetings is that people felt like this is a new FDA, that we're listening to people in a way they and they felt like they haven't been listened to in quite some time.
And so we're going to continue. We're going to talk to more CEOs, we're going to have more roundtable discussions, and we're going to try to, continue to do these videos where we are broadcasting exactly what we're thinking minute by minute, think, yeah. 
I just think the other takeaway I would add to that is I walked away from this week thinking there's this desire to really modernize the agency, right?
With all of these processes and technology that we have to bring the agency into the 21st century. 
And, you know, the stuff I heard the CEO roundtable yesterday was not that different from some of the conversations I had at the Jefferies health care conference, this week on Wednesday. It'll be interesting if the West Coast developers and companies have the same ideas and suggestions as we heard yesterday.
We'll find out Thursday at your old turf. 
San Francisco.
San Francisco, Bay area.
But we'll be down in the Stanford campus area. Great. And then, Friday in San Diego. 
Cool. I'm really looking forward to it. It's going to be great. All right, so great conversation. Three big things actually more than three big events. We had the rollout of AI agency wide.
We had the Jefferies health care conference on Wednesday afternoon. We had those three big events. We talked about the Infant Formula Expert Roundtable, the cell and gene therapy event, which was just amazing. And it just couldn't be, more sort of, a better timed unintentionally, as it was with the announcement of baby KJ, getting discharged from the hospital.
And then our CEO roundtable yesterday. So great week. All right. Thanks, everybody. We'll do it again.I'm Marty Makary.  Vinay Prasad, Sanjula Jain-Nagpal. Great to see you guys. So, busy week at the FDA. 
Yeah. We're going to talk about the three big panels we heard from selling gene therapy experts, patients, advocates. We heard from experts in infant formula and what things FDA should know about infant formula.
And finally, we actually held our first CEO listening session. And you and I are going to go on the road next week. We're going to be in California. And the week after in Boston, and we're going to listen to CEOs to hear their concerns. So today I guess we're going to talk about all three of these. 
Yeah. This is a listening FDA.
We are on a listening tour and we're getting some really good ideas. Yeah. 
It was a really energizing week. I just have to say, I mean, just to see all the great energy and ideas. I mean, I'm really excited about it. 
And this place runs like 24/seven. Like new announcements come out, you know, new approvals get released.
And so it's just so energizing to be here. Beautiful day on the campus today. So great to be with you guys. 
Yeah. So let's start with maybe cell gene therapy because I think, you know, and I did a great job moderating that. There were a lot of great people in the room. We had the entire HHS leadership there as well, which is so powerful to see all the agencies talking about this issue together.
You don't really see that often, but what were some of your takeaways? 
Well, the first success was we had 25 speakers and we stuck to time. So it is always a success. But we had, you know, 23 experts and we had our internal speakers, who came in and they basically told us different perspectives of cell and gene therapy.
You have a researchers who are doing the laboratory science that underpins chimeric antigen receptor T cells. You have Carl June and Crystal Mackall. You've also got this gentleman came from UC Berkeley, who is one of the pioneers of individual patient, bespoke like, custom tailored for that patient gene editing delivered to a baby with a particular deficiency. 
And there was a big milestone announced this week, a big milestone day for the FDA and for this family and for gene therapy.
Baby KJ. So baby KJ was discharged from CHOP Hospital in Philadelphia after a custom, gene editing therapy for a very rare genetic defect based disease in infancy. And it's really the first ever. It's the first ever. And the FDA was able to tailor the regulatory policy to enable this to happen. 
I mean, Marty, you've talked a lot about this idea of possible mechanisms and pathways.
So tell us, does that kind of, is this an example of that? 
It's basically the spirit of a the plausible mechanism pathway. You can't expect to do a trial. You can, come up with a mechanism of action that is plausible. And also suggests safety based on the mechanism and based on other studies that can be extrapolated to this particular gene editing tool in this location.
And the result is a pretty impressive, outcome where the baby went home after, hospitalization that sometimes can be fatal because of this gene defect. 
So my understanding is this baby is born, and by all accounts, the delivery is normal. And the parents didn't suspect anything. But a few days after the baby's born, the baby's lethargic and not acting quite healthy and normal.
Doctors start to draw blood tests, and they find that the ammonia level is off the charts high, suggesting a problem with protein, breakdown in the liver. They actually sequence the baby and they discover it has a the baby has a he has a carbamoyl-phosphate synthetase deficiency, and they have a particular genetic mutation in the baby that's responsible for this condition.
In a world just a year ago, what do you do for a baby? You restrict the protein intake. You follow the ammonia level, you gradually try to wean them up on protein. You give them nitrogen scavenging drugs. I mean, you really just kind of treat the symptoms of the disease. You don't treat the root cause. 
And with a big risk of liver failure along the way.
And even with that, 50% of the babies are dead in a month. You know, it's a terrible condition, you know, even with those things. Yeah. And the liver failure will inevitably proceed. What these researchers did was they took a CRISPR gene editing. They packaged it in a lipophilic nanoparticle. They infused it in the baby first at a low dose, then at a higher dose.
Now, the nice thing here, scientifically, is we used to use an adeno viral vector gene delivery system. But the problem with that is if you re-exposed a person to that many times, they develop antibodies against the gene delivery system because it is a sort of a virus derived product. But this lipophilic delivery we don't have, we've not yet seen evidence of auto immunity against it.
So you can dose a kid many, many times with different doses. So that I think that's one advance.  It goes presumably to the liver, edits the gene. And now the baby is able to tolerate a lot more protein and the ammonia level has fallen. The baby's healthy and discharged and we see good clinical outcomes. What we don't have yet is this baby has been very vulnerable.
So we haven't yet done a liver biopsy to prove that the gene is edited. I suspect at some point they will want to do that when the baby's healthy and strong, just to confirm that what we're seeing is, in fact, the reality that the gene has been properly edited. Now, what are the lessons here? One FDA rapidly made available this product to this baby and the family.
We have allowed a drug to be given that can only be given to this baby. You know, it is like a suit you had a tailor make.  Talk about suit.  A suit you had a tailor make for one person. And the question that we're going to face at FDA is, how can we do this for many, many kids?
Everyone getting an individual therapy and the usual regulatory thinking has to go out the window. 
That's right. 
And Vinay, did I hear correctly that it took about a week to approve this therapy. 
Yeah. I mean we accelerated this as rapidly as possible. I think, one of the reassuring things that I heard at the meeting was, that, you know, the FDA got a lot of praise for bringing this very quickly to to the to the patient.
Kudos to the career staff here that were, hand-holding the family and the researchers along the way and involved and, doing what we want to see more of at the FDA. And that is custom tailoring a regulatory process to the condition based on the need, the unmet need in particular, and the individual situation and the relatively safety, the relative safety profile of the intervention.
And treating root causes, rather than just masking the symptoms, which is a philosophy that you extend across all sorts of regulatory thinking at FDA, including food and and the issues that are more discussed in in 
Kind of a big win for medical science.
Yeah, absolutely. And so that's just one of the stories we heard yesterday. And then we hear from people who are developing CAR T cell therapies that have resulted in the cure for historically incurable leukemias. And we've heard from people whose own children or loved ones suffer from genetic diseases for which there is not yet a cure, but they are in vigorous pursuit of the cure.
And I think we learned a lot at FDA about things that we could perhaps improve upon. We also got some reassurance that we had been going in the right direction, I think, on some of these issues.
You know, what's really sort of shaped some of my thinking, if I'm being very honest in, in sort of how I think about regulation is when you have to break bad news to a family and the the person reaches it comes back with the response of, gosh, is there anything that we can do?  When you when you have to give that bad news and you don't have any tools in the toolbox to be able to offer it, it
has an impact on you. I mean, emotionally, it I mean, there's no training in medical school for this. It's the hardest part of being a doctor, I think, is breaking bad news, especially when it's surprise, bad news. And you can't help but ask yourself, is there anything in the world that can be done still maintaining our mission to safeguard public safety?
Right. 
That, you know, we should be thinking about why does it take ten years or more on average for a drug to come to market? You know, these are questions I think, that we are asking as we ask ourselves, what processes here can we rethink and do smarter?
Well, Marty and I are both oncologists, so we both had a lot of these kind of discussions.
And exactly as you say, it is heartbreaking for the doctor and for the patient and the family when you get in situations where they'd be willing to try, you know, whatever options are out there. And I guess one other point to make here is that, you know, sometimes I see people say, how do you reconcile your philosophy on the Covid 19 booster shots, where we've written about the need for randomized studies, but also a baby like baby KJ where we're saying you're never going to get a randomized study and it's okay.
And the answer is, just look at the differences. One, a healthy 20 year old kid, a healthy person who has, no medical problems. The burden of proof for such a kid is very high that they would benefit from an additional dose of a product.
And sample size, right?
And sample size. And there's many, many millions of these healthy, you know, millions of people like a healthy.
Baby KJ just one, you know, 50% mortality rate. No ability to do a randomized. It's not even possible. 
Did anyone suggest, oh, you really should have done a randomized controlled trial for, you know, this gene therapy before you gave it to baby KJ? 
Thankfully, no one did. But I guess I just want to explain our philosophy.
You know, we're going to be flexible based on the condition, the frequency, how dire things are, how unique the situation is. That's not a departure. That's not an inconsistency. That's just medicine 101. 
And I think it's a good harmonization of common sense.
Right. 
And just makes sense. 
Yeah. Big theme, common sense and so so hopefully we can see more innovation in that space.
We'd like to move it along. I think it's an amazing expert panel that I just absolutely loved. And soaked every minute of. So I would encourage people to look at that FDA expert panel.
Maybe just add one more thing about the expert panel before we move to the next topic is that we also have the secretary. Secretary, Robert F Kennedy Jr came.
We had Mehmet Oz come from CMS. We had Jay Bhattacharya come from NIH. I think I've never seen at FDA, the NIH director, the CMS director, and the, HHS secretary and the FDA commissioner, all in the same place at once. So advocates not only got to say what they thought we should do better at FDA, but also what CMS could do about making payment for gene therapies, where the gene therapy may cost $2 million, but that condition will be cured, and the health care system may save 4 or $5 million in lifetime health care expenditure.
How do we pay for that in a regulatory environment? Doctor Oz was able to comment. What about somebody brought up the issue of organ transplant? How do we increase organ supply? Well, of course you know tissues falls under FDA but organs falls elsewhere. But we had Bobby Kennedy to listen to that. So we really assembled, you know, the the audience you most want.
If you are somebody who's concerned about these things. So people could directly appeal to the relevant stakeholders. 
And I love that approach. Right. A coordinated research, approval and payment strategy around a new therapy, because it's been so clunky, it's been so sort of, you know, parsed out and and not streamlined that you have these situations where you have this great irony of a health care system that spends over $4 trillion, and yet a kid with a rare condition will be told there is a treatment, but you can't have it because it's not covered.
And so that makes no sense, right? In a modern world, we should be able to fix that problem. And it's not a matter of simply, you know, oh, the insurance company's bad. They need to be. Well, it's a broader strategy of how we make sure that there's access, and that includes financial affordability. To a lot of these therapies.
So that was a part of the expert panel yesterday, a great expert panel. I loved it, learned a lot. This is sort of the exciting, fast growing area right now. And I think, laboratory life sciences. So I got a lot out of it. And I'm glad we did it. And hopefully it lets people know this is a priority area for us, for you, for CBER.
And, hopefully we'll see more cool stuff. Come coming. Not just baby KJ.  
And the Secretary spoke with baby KJ's parents and maybe the doc and the doctor. And shared some of that, conversation at the expert panel. That was cool. 
That's amazing. Well, speaking of babies, I think we should talk about infant formula.
That's why we love Sanjula.  So this is part of a broader initiative we have across kind of HHS around, operation stork speed. But, Marty, maybe share a little bit about kind of why we're even talking about baby formula. Well, there's been almost no innovation in the baby formula space since 1998, with the exception of adding selenium, the FDA has not updated its recipe
for, what you must include in baby formula for it to come and get. 
There's one recipe. 
There's one recipe. The government issues a recipe of this is what needs to be, you know, these are the criteria of the ingredients.
When you say recipe, you mean kind of like you need to have X amount of this vitamin or these nutrients in these quantities is that?
It gets very wonky into the complexity.
But yes, exactly the ingredients. And so that, it's called a monograph. Technically. And that's been sort of this system of regulatory approval. Well, if you have an idea to use a different fatty acid or a different, a non seed oil, alternative, then you, you don't meet the recipe. And so therefore it's very hard to come to market.
You have to almost submit it as a new drug and run a like a phase three clinical trial and run off. So it's like we have got to promote more innovation. So there's more competition, there's more types of baby formula, and we can meet the demand that moms have in America to have baby formula with no seed oil, baby formula without corn syrup, baby formula without added sugar, baby formula without heavy metals.
So those there is now an increased awareness, not just in the nutrition science community that we heard about, that we heard from in that FDA expert panel. 
Maybe a broader point here is that, you know, there definitely, probably ways to make a baby formula that's not good. Maybe he's not going to gain weight, not going to grow healthy.
So there are lots of ways to mess it up. But we are not even close to having the audacity. Like we have the audacity claim that we have the perfect recipe. We don't know that to be true. It's very plausible that we can improve baby formula in many different ways through these sorts of substitutions. FDA doesn't know, you know, so I think we do have to allow.
And we're also seeing that moms are buying baby formula from other countries because they feel those products are healthier or don't have some of these ingredients. And so I think there is a there's a lot of desire for, for us to to think about this. And I don't know, I, I learned so much. I mean, the fact that, you know, there were studies presented from the 1980s that were really compelling, and yet we really haven't acted on some of those.
I saw that I was like, oh my gosh, this study is amazing. And then it was like 1984 or something. It's like, how do we not? And I assumed it just came out because it was so mind boggling. But I don't know if you're referring to the study on visual acuity. 
Yeah, it was a visual acuity study done with rhesus monkeys, and it looked at the seed oils.
Right. And it compared, safflower oil against soy oil to see how that impacted visual acuity. And you saw that safflower oil actually had kind of lower visual acuity than the soy oil. And so there's a lot of discussion about the right kind of fats and oils. And my takeaway was, well, you know, not all seed oils are equal, right.
So there's different compositions of the fats and have different impacts. And those of you, the ratio of the omega threes, the omega sixes. And so I mean there's a lot we can learn from that. 
It's amazing that the visual acuity say on an eye chart was lower for the primates fed, when their mothers in pregnancy were eating, the safflower flower oil low in omega threes.
And when the babies had the same safflower oil lower in omega threes. And so, you know, one of the experts said think of omega threes important for brain health. And omega six is more important for body health. And so there's actually this incredible data that shows that the types of fats consumed in pregnancy and in childhood affect your visual acuity.
And there's a whole science to it. And when I read the paper about the photoreceptors in the retina, and, you know, one of the precursors of one of those molecules is linoleic acid. But, I mean, how do I how did I not learn about that in medical school? I mean, never once did we talk about seed oils
And how have we not tried to improve upon formula, development and giving people and giving consumers different options that are all, you know? 
Some of these regulatory guidelines have been pretty rigid, right?
And just kind of putting out that monograph to your point. But there's so much more evidence now that we can build off of. Right. So seed oil was also a big piece of it talking about the sugars. And so lactose came up. You know, I know lactose is kind of used a lot. There are a lot of infant formulas out there that are lactose reduced or lactose free.
You know, what surprised me was that the experts said that there are more infants who are consuming lactose reduced or lactose free formula than maybe what is medically necessary. And I think some of that comes out of how these products are being marketed to families to say, hey, this is gentler on the stomach, and so you have babies out there that ...
Which is not a substantiated claim.
Right.
Right. 
So there's babies out there getting a lactose free formula who probably could get a lactose formula. They've been, in some ways a bit, captured by the narrative that lactose free is better, but it likely is not better, particularly if you can tolerate lactose. 
A lot of experts had commented, I think that lactose is a very good, powerful, complex carbohydrate important for infants in their development.
And so you've got to get carbohydrate somehow, right? So I mean, fat, it can be a source. But also, a lot of people do not like the idea of corn syrup. I mean, this is not natural, right? This is not how when cavemen, you know, delivered babies, they didn't immediately give the babies corn syrup. Right?
Right. So, we have to think about not just what makes sense in a maturing nutrition science field. If we didn't get the recipe perfect in 1998 and it's like, okay, we don't need to touch it now, we're good for the next thousand years. No, the field is evolving like we have a lot of learnings in that space.
We heard from those experts at the Infant Formula Round Table.  
And the corn syrup piece is interesting, right? Because as you know very well, you know, the impact on those added sugars early in, in life sets you up in this trajectory for a longer term. Chronic conditions, obesity, diabetes, all of that. And that was a lot of what the panelists were talking about is we have to get this right early on.  That early nutrition is really important.
And I just the marketing piece of this on the labeling and the guidelines, I mean, on seed oils is one part. The lactose is another piece. Another thing that surprised me was this, they were saying there are claims that this is basically equivalent to breast like human breast milk. Right. And some of these things are not actually well substantiated.
Or there were other claims around this formula can stop your baby from crying in 24 hours, right? Things that have no basis in kind of what the in science. 
That's right. Most experts say that breast milk is better for a baby than formula. And of course, that needs to come with the important footnote that some women cannot produce breast milk physiologically or for other reasons, are not able to breast feed their babies.
And so, that's when we need to acknowledge that we need good infant formula options out there. 
Breastfeeding should be encouraged and supported but can't be mandated, obviously. 
And that's what the CDC has been doing for a long time, actually, in the CDC. I think it's the healthy people 2030 goals. There are goals for increasing breastfeeding rates in the United States.
That's been a long standing, sort of, goal of the CDC. There's also the issue of the supply chain getting when you have fewer options and less product competition. 
You can run an infant formula shortages. 
Exactly. And that's of course, that's what happened a few years ago. 
Four major players who control about 70 to 80% of the market.
And so we need to see more options.
See more options. At the same time, we want to encourage those companies to keep producing, high quality infant formula because we don't want to see another shortage because, you know, there's a saying, I know, we use in the operating room a lot. You've heard it. Don't let perfect be the enemy of good.
Right? So if we create these very stringent, standards by which now that infant formula issue the shortage, there was also a contamination issue. Of course, that's serious and separate. But when you have a just you don't have a lot of competition on the market and you have this supply chain that's sort of narrow. What you can see is that it becomes flimsy where it can be disrupted with a single, you know, event.
But the real story is why why don't we have more infant formula products on the market? 
Yeah. I mean, a misuse of government and regulation is always too overregulated space where you you're not really sure you're optimized. You know, that's always a misuse. 
That's right. Perfect. Could be the enemy of good. Of course, when when people didn't have infant formula, they were using things that were terrible for babies.
Right? Right. I don't even want to say them, but they were right alternatives that no baby should be getting. 
And every year there's some babies who suffer because the infant formula that people dilute the powder too much, for instance, and that that can be quite dangerous, you know. So, there are clearly, you know, some important safeguards that need to be in place, but also we can't pretend that we have, as Marty says, the perfect infant formula in 1998.
And it can never be improved upon. 
Great points, great panel. Encourage everybody to watch it again. FDA Expert Panel on Infant formula. And, this should be up now. I think we posted it on our social media accounts.
And YouTube. 
YouTube. Good. 
Now the CEOs and they were the last to enter the room. They were just here last night.
So this is our third event this week. And it was a CEO roundtable sort of listening session with CEOs from pharmaceutical manufacturers.
Big and small. I mean, we had the big some of the big players were in the room, but some of the small players in the room, people usually from the DC, New York area next week were going on the West Coast, and we're gonna go back to the Northeast in Boston, and then we might go to Atlanta by the end of the summer.
And we had, how many people were there like 55 or 60 people?
Seemed like more.  
It's close to 70.
Seventy people. And, we, you know, met with everyone there. We let everyone have the microphone. We went around the room and everyone gave 1 or 2 points that they thought the FDA could do a better job.
Now, what were the ground rules? Of course, no one was allowed to talk about their specific medical product or their specific thing that they're working with the FDA on. It was about high level, you know, pan company kind of concerns. And we heard a lot of things in different domains, communication ways in which it could be improved between the FDA and the between the reviewers and then the company.
And a lot of those points I thought were fair points. 
Yeah. They said like a five minute call could save them two months of back and forth with letters or uncertainty or how do we do the application or what do you want in this clinical trial design? Very good points about increased communication could help innovation.
But I want to double click into that because I think we experience this every day.
Right. If I have a question instead of me emailing you, I'm just going to walk down to your office and it's much faster. Right. And so I didn't realize that you have this interaction where company sponsors are waiting. I think that I can't remember the number now, but it was up to ninety days 
There's a tiered system of communication.
Yeah. We're just you know, they have a clarifying question that to your point, could have an answer in two minutes. Five minutes and then nine days goes by. And then to your ultimate question about why does it take ten years? It's these little incremental kind of steps that they add up over time. 
They add up. So, companies and developers deserve an instant response to their questions.
And of course, we can't let them abuse it where they're calling five times a day with every little detail. But a couple quick response communications would go a long way. So we're going to work on that. 
We're going to work on that. And then another big theme that came up was, the CMC chemistry manufacturing and controls processes.
Now this is sort of the nitty gritty of how things are actually made and the quality testing that goes into FDA. And, you know, there's just there's there's a depth of quality testing here that I don't think I fully appreciated. For instance, when you take a pill and you split it, you assume that half the active ingredient is in both halves of the pill.
But we have people here whose job is to ensure that that's true, even if it's split in a different direction, that you know the active ingredient didn't precipitate to one corner or the other.
So if you cut it horizontally or vertically...
You might get all, you know. But these are the little things. It's it's a little things that we actually care about, extremely important.
But the industry people, their point of view is that this meeting, all of these standards can be extremely onerous and costly and time consuming, cost tens of millions of dollars per product. So we're so and we hear them. But we have to balance two things. One, the products that we have in this country have to be the highest quality sterility when necessary.
We need to take these things into account. They are important. At the same time, I'm sure the industry has a point that our paperwork is at times overly bureaucratic, too many forms and too much, you know...
Pages and pages.
A hundred thousand pages sometimes.  Some applications have been 100,000 pages.  So we have to ensure ...
That's the reason why we can't review fast, because it's 100,000 pages.
But then you say, well, why does have to be a hundred thousand pages? I mean, we have to introduce a radical, innovative concept called the page limit. 
Yeah, we really do. I mean, I think that it's important to be, to have information available if you want to dig deeper, but to routinely read, you know, you say 100,000, but I've heard some applications are 800,000.
Wow. 
And it's this crazy perpetual, dog chasing its own tail because the companies don't want to be stuck in a gotcha moment where a reviewer might say, oh, where's this information? So they figure just include a 100% of every single thing they have. 
You know, it's like a medical chart really. You know, sometimes when you get when you get the medical chart from the outside hospital and it tells you all these notes on what he or she may have eaten six weeks ago, what the blood pressure was on a Tuesday.
It's not usable. It's just too much information. 
That's right. Yeah. It's like the presentation in the emergency department where they they take you all the way around the barn at the very end and has pancreatitis. You're like, okay, you could have started off like that. Yeah. 
I think that's why I heard some of the CEOs are really supportive of us using AI in some of those administrative review kind of tasks, where you can kind of help summarize many of those 100,000 pages.
And of course, this week was the big rollout.
For Elsa. Yeah. 
So Elsa is our AI, powered scientific review tool that the scientific reviewers use food inspectors. And so they use that to, help them with the scientific review. And sometimes it's summarizing a lot of that background information. Also, you know, our reviewers are very good at double checking, sometimes triple checking all of the data and making sure it is formatted or they reformat it into certain tables.
And that was another piece of feedback we got in the CEO forum. Is the data in the tables could benefit from a standardized format where they are not spending a tremendous amount of time, taking data and putting it in an FDA format. When we have a tool that can do that. 
And then I think the third big category that came up was end points control, arms randomization when you need it when you don't.
And earlier in this video we talked about baby KJ. And let's say hypothetically you have a child with an enzymatic deficiency. You know exactly what the gene is. That's the implicated in that.  You deliver targeted gene editing. You see that the enzymes are corrected, the levels all start to normalize, and then later you biopsy the tissue and show the gene is edited.
I think in those cases, we're going to be completely satisfied that scientifically, you've proven that this baby is better off as a result of the therapy n of one equals approval. But there are also cases to push back a little bit on the industry where they some people went a little too far and told anecdotal stories about products, where somebody has a disease that deteriorates slowly.
But of course there's a range of presentations. Of course, some people will deteriorate faster and some slower. They administer a product that they say is responsible for a slower deterioration. But in that case, it's very difficult to know. Is it the product? Did you just happen to find somebody whose disease is progressing more slowly? And if you don't have all those biological correlates along the way, it's harder for us to know.
And maybe in those cases, n of one isn't enough. So this is sort of the nuance of science and regulation and understanding cause and effect. 
You got me thinking. If when I deteriorate, if I want to deteriorate fast or slowly. 
Oh, well, it's an interesting question. Well, I mean, you're talking about really like what Peter talks about, lifespan.
Yeah. 
Which is that I think we don't just want to live longer. We want to live a long, healthy life. And for many of us, I think we'd rather if we were to deteriorate at the end of life, rather have it be more abrupt. That's my personal view, actually. But but but these kind of chronic conditions, they're talking about, like, early lifelong deterioration.
And if there were really a drug that would slow it, we would approve it. I mean, of course, the question is, how do you use anecdotes for a, slowly debilitating condition? That's a challenge we face at FDA and maybe with biological correlates, we would be open to that, but with no clear biological correlates. Anecdotal testimony. And let me give one more example.
Sometimes in cancer you can measure the tumors shrink. Well, that's a that's that is a proof that the drug has activity.
Surrogate endpoints.
Surrogate endpoints. And that that's something that, you know, we've always embraced at FDA and will continue to. 
So what I'm hearing is the industry wants a little bit more of that kind of predictability.
And you know, what we're looking for in these different, tailored cases. 
Yeah, that came up. 
And I think they'll get it when they have a you know, when we think about ways we can have a faster talking back and forth with our reviewer staff. 
I think anything we can do to reduce mind reading at the FDA, the better.
I mean, predictability is important. It's important not just for companies and developers. It's important for investment, right? We want to encourage investment in innovation. And so predictability, it sort of cuts through one of the big problems in life in all aspects of life. And that is making assumptions. Right. So the more we can do to let folks know this is exactly what we are thinking.
And that was in part the idea behind our New England Journal paper on, Covid vaccine regulation. 
And the letter in reply to these responses we got is going to come out soon in the doing the journal and even these videos, I think, let people know what we're thinking and how we're thinking about it.
And maybe we can think creatively of other ways, you know, maybe if they can understand what reviewers in a particular division are thinking, I think we should take a hard look at that.
Well, that's something that came up, which is that the industry felt like you're sitting on a treasure trove of data. Of course, there all those drugs that came to market, but there's thousands or tens of thousands of drugs that never came to market. And there are different reasons why they didn't come to market. Manufacturing reasons, efficacy reasons, endpoint reasons.
There's got to be a way that we can learn from all that information and that the industry doesn't have to, you know, they can benefit from this information we have at FDA.
Yeah, that developers can know those reasons.
You want to repeat the mistakes that others have already made, right? Yeah. 
And we're thinking about ways to do that. 
Radical transparency I love it.
One of the big themes common sense, radical, transparent. 
And that came up yesterday in the forum to I think a lot of CEOs please, you know, continue to provide that transparency. We're seeing a difference. And, you know, if there are other ways to do that. So I think we'll have to think more about it. 
And then maybe a last point is that, this came up in the morning and in the afternoon is that, you know, some of the people were worried about where is the the center engine of innovation going to be globally.
And in the morning session, people talked about development of gene therapies in China. And in some ways it's it's accelerating. And I think it's we should be very clear that it is your position that the United States will remain the center of biomedical progress and the engine of biomedical, innovation. And there are lots of things a regulator can do to improve that.
Yeah, people have significant concerns of phase three clinical trials where the vast majority or all the patients, were are in China and, can we use that data to make, inferences for regulation in the United States with Americans? And so I think the general feeling that came out in that oncology advisory committee was, no, we cannot accept a trial where all the patients or that vast majority are, in a in China.
And that's for many reasons. Sometimes you can't trust the GDP numbers that come out of China. Why would we trust, why would we make decisions based solely on phase three clinical trials done in China. 
You know, and I just want to add to that, which is that, you know, sometimes I read a newspaper and they talk about an amazing trial finding.
And you look and you see and you, you see that there's a high accrual rate in China. And I do think people should think critically. And it's it doesn't mean you're always skeptical, but you should think critically about those things. 
Yeah. 
I think on the topic of trials, a couple had also recommended, you know, can we change the requirements of 2 to 1, clinical trials as well?
Yeah. And we do use one for, I don't know, maybe half of new drugs. But it was a very good point. Something that, we've been talking about and thinking about is that clinical trial requirement. So something to work on, something to think about. We got a lot to think about. Anything else? 
I think there is I'm just looking at, you know, some of the things I noted down, the idea of scaling up some of the priority review.  A lot of interest in accelerated reviews, priority reviews, rare diseases.
And so building on those successes, we are not going to, change any of those very, great pathways that exist. We want to build on those successes and see what what else we can do. 
I think that the biggest thing was across all these meetings is that people felt like this is a new FDA, that we're listening to people in a way they and they felt like they haven't been listened to in quite some time.
And so we're going to continue. We're going to talk to more CEOs, we're going to have more roundtable discussions, and we're going to try to, continue to do these videos where we are broadcasting exactly what we're thinking minute by minute, think, yeah. 
I just think the other takeaway I would add to that is I walked away from this week thinking there's this desire to really modernize the agency, right?
With all of these processes and technology that we have to bring the agency into the 21st century. 
And, you know, the stuff I heard the CEO roundtable yesterday was not that different from some of the conversations I had at the Jefferies health care conference, this week on Wednesday. It'll be interesting if the West Coast developers and companies have the same ideas and suggestions as we heard yesterday.
We'll find out Thursday at your old turf. 
San Francisco.
San Francisco, Bay area.
But we'll be down in the Stanford campus area. Great. And then, Friday in San Diego. 
Cool. I'm really looking forward to it. It's going to be great. All right, so great conversation. Three big things actually more than three big events. We had the rollout of AI agency wide.
We had the Jefferies health care conference on Wednesday afternoon. We had those three big events. We talked about the Infant Formula Expert Roundtable, the cell and gene therapy event, which was just amazing. And it just couldn't be, more sort of, a better timed unintentionally, as it was with the announcement of baby KJ, getting discharged from the hospital.
And then our CEO roundtable yesterday. So great week. All right. Thanks, everybody. We'll do it again.