Understanding the U.S. Food and Drug Administration

Join us as Kelly Stone, MD, PhD, FAAAAI, explains the evolution of the U.S. Food and Drug Administration and its central role in ensuring the safety and efficacy of therapeutics in the United States. We discuss the modern drug approval process from preclinical development through clinical trials and post-marketing surveillance  and explore what makes this pathway different for biologics and biosimilars so you have a better understanding of the therapeutics that we prescribe every day in the clinic.

Biosimilars

MedWatch:The FDA Safety Information and Adverse Event Reporting Program

FDA History

Drug Development Process

Transcript

Rebecca Saff, MD, PhD, FAAAAI 0:09

Hello and welcome to Conversations in the World of Allergy, a podcast produced by the American Academy of Allergy, Asthma & Immunology. I am your host, Rebecca Saff. I am a board certified allergist and immunologist and a fellowship director who always enjoys learning more about the exciting field of allergy and immunology. Our podcast series will use interviews with thought leaders to keep you up to date on new developments and to review core topics. Today we'll take a look at how medications make their way from discovery to our patients. The FDA approval process is critical to ensuring safety, quality, and efficacy, but it can also be complex and it's evolving. We'll discuss how the FDA evaluates new drugs from early clinical trials through post-marketing surveillance and explore what makes this pathway different for biologics and biosimilars. I hope this conversation will help you better understand the science and regulation behind the treatments you use in clinic every day. Today's guest is Dr. Kelly Stone. After completing allergy immunology fellowship at Boston Children's Hospital, Dr. Stone was on faculty at Children's National Hospital before joining the NIAID Laboratory of Allergic Diseases, where he served as director of the NIAD's Allergy and Immunology Clinical Fellowship Program, as well as director of the NIH Allergy and Immunology Consultation Service. He joined the FDA in 2019 as the Associate Director of the Division of Pulmonary Allergy and Critical Care in the FDA Center for Drug Evaluation and Research, or CEDAR. At the FDA, he works to ensure our field has safe and effective drugs approved by the FDA to improve the quality of care we can provide in allergy immunology. Dr. Stone, thank you so much for taking the time to join us today.

Kelly Stone, MD, PhD, FAAAAI 1:37

Thank you so much for having me, Rebecca. It's a real pleasure.

Rebecca Saff, MD, PhD, FAAAAI 1:41

I'd like to start by getting to know you a little better. Can you tell us a little bit about yourself, including something you like to do outside of medicine?

Kelly Stone, MD, PhD, FAAAAI 1:48

So as I get older, I'm I'm looking for hobbies. I've realized I haven't had time for hobbies through much of my career. Um so outside of work, I I now enjoy native gardening. Um and I'm also um studying art history, particularly modern contemporary art history.

Rebecca Saff, MD, PhD, FAAAAI 2:04

That's great. When you do native gardening, do you think about the pollen being produced and put out as an allergist?

Kelly Stone, MD, PhD, FAAAAI 2:10

I I do think about that, but I I also think about other considerations and try to let my mind wander to other other things for a while.

Rebecca Saff, MD, PhD, FAAAAI 2:19

I love it. So what made you choose allergy immunology as a field?

Kelly Stone, MD, PhD, FAAAAI 2:25

So I have to say it was a little bit of a journey. As I um went into medical school, I thought I was interested in pediatrics. When I did my pediatric rotation, I was convinced that I wanted to do pediatrics. Um I loved working with kids, I loved working with parents, uh, and I loved my colleagues. Um I had worked at um Johns Hopkins with Kurt Seven and Mike Kasten in pediatric oncology, and was convinced that was going to be my career. But my first rotation in pediatric residency at Children's National was on the HEMOC board, and I quickly realized that was not the career path that I wanted to follow. So we did not have an allergy immunology program that was active in educating pediatric residents, but I was very much influenced by a symposium I had attended in the early 90s at NIH on gene therapy for primary immunodeficiencies. And I really liked sort of the evolving science around gene therapy. Um, I like the technology thinking about these diseases, but I also realized I really love being a pediatrician. And allergy immunology for me allowed me to merge the two where I had long-term relationships with patients with atopic dermatitis, food allergy and asthma, but I also could think about primary immunodeficiency and sort of evolving therapies in that space. I ended up teaching myself a lot through residency and had a very steep learning curve when I started my fellowship at Children's Boston.

Rebecca Saff, MD, PhD, FAAAAI 3:58

That's great. And then what led to your kind of transition from the academic uh position at the NH then to the FDA?

Kelly Stone, MD, PhD, FAAAAI 4:08

Yeah, so I I started my academic career um both at Children's Boston and Children's National, and um had the opportunity to move to the NIH uh both to run the um Algae Immunology Fellowship Program there, which I ran for 12 years, but also to be involved in clinical research. And um over my time at the NIH, uh I gained more and more hats, administrative hats. And um uh during my time there, I had served on FDA advisory committees, including the Pulmonary Allergy Drugs Advisory Committee. I knew many people at the FDA, and I reached a point where I was ready for a change, and I really liked what I had heard about the mission at FDA, the environment. So um made that move in 2019 and couldn't be happier with the move.

Rebecca Saff, MD, PhD, FAAAAI 4:58

Well, tell us a little bit about the history of the FDA and particularly the Center for Drug Evaluation and Research that you work at.

Kelly Stone, MD, PhD, FAAAAI 5:06

Yeah, so um so FDA history, it's it's a long story. Um, and I'll give you the abbreviated version um leading up to Cedar. So the origins of the FDA really um started with Harvey Wiley, who was a chemist in the Bureau of Chemistry in the Department of Agriculture, uh, and he was very concerned about foods and use of preservatives and things like strawberry jam that had no strawberries in it, um, that was advertised as strawberry jam. And he became very passionate about the need for regulating foods. In 1902, he formed the Poison Squad, which were a group of healthy young volunteers. Uh, most of them worked at the Department of Agriculture, and they agreed to receive free meals that were laced with preservatives at various concentrations, things like borax and formaldehyde benzoic acid, and document the adverse uh events. And these experiments provided crucial scientific evidence supporting the need for food safety regulation. And then in 1906, with the publication of The Jungle by Sinclair Lewis, Congress passed the um 1906 Pure Food and Drugs Act that prohibited interstate commerce of mislabeled and adulterated food and drugs. It did not include evaluation of safety and efficacy of drugs. But this was the first federal law regulating food and drugs and was really the start of the FDA. And the modern FDA, the way we regulate drugs really started in 1937 with the tragedy around more than 100 deaths, mostly children from sulfonilamide elixir that had been compounded with diaphylene glycol to give it a sweet raspberry flavor to make it more palatable. But as a result of those deaths, Congress passed the Food, Drug, and Cosmetics Act in 1938. It was signed by President Roosevelt, and it required that all new drugs be tested for safety before marketing. It also required that drugs adequately be labeled for safe use and authorized factory inspections. So from 1938 on wards, all drugs to be marketed had to be shown to be safe, but efficacy was not part of that. And there had been some interest in Congress, it never made its way through to require demonstration of efficacy. But again, another tragedy precipitated a change, and that was in the late 1950s, early 1960s. The FDA received a new drug application for thalidomide for the treatment of morning sickness. And as a sleep aid, it was given to a new clinical reviewer at the FDA, Frances Kelsey, who's a hero to many of us. And it was considered a safe review for her because thalidomide had already been approved through much of the world and was thought to be an easy review. But thanks to her efforts, uh, she refused to approve that new drug application. And by late 1961, the association of thalidomide with birth defects, including focamelia, were very clear with 10 to 20,000 children worldwide affected. But thanks to Francis Kelsey, it wasn't approved. And that near miss sort of precipitated another change to the Food, Drug, and Cosmetic Act, and that was the Kef Ever Harris Amendment in 1962. And this was the first time that it was mandated that manufacturers demonstrate that products are not only safe, but they also have to be effective through adequate and well-controlled investigations. So clinical trials demonstrating efficacy were now required. And then through the years, um, there's a long, interesting history here. There are very good books that describe the history of the FDA, but there were other modifications. So 1984, uh the Hatch Waxman Act passed, which established generic drugs. You asked about Cedar. So biologics and drugs historically had been regulated by separate parts of the FDA. In 1982, they were brought together into a natural center for drugs and biologics. But in 1987, they were separated again with the development of the Center for Drug Evaluation and Research, where I am, and the Center for Biologics Evaluation and Research. And there are many other acts that have sort of modified the way that the FDA regulates drugs, including streamlining the approval process, expanding access to experimental treatments, giving us the authority to require post-marketing studies, expanding pediatric drug testing requirements. So altogether, these landmarks, these landmarks reflect the FDA's evolution from what began as a small agency focused on preventing food adulteration to a comprehensive body that oversees approximately 20% of consumer spending in the United States. Efforts continue to advance regulatory science, improve efficiency, to speed the time for drugs to become available for patients and to improve affordability and access to drugs. So that's the short, long version of the FDA history, but it really is hard to understand what we do with understanding where we came from and sort of looking forward, what additional changes are needed so that we can adequately fulfill our mission.

Rebecca Saff, MD, PhD, FAAAAI 10:41

Someone who's really interested in learning more about the history, is there a book you would recommend that they check out?

Kelly Stone, MD, PhD, FAAAAI 10:47

Many of our new reviewers, I um before they started here, I bought them a copy of a book called Protecting America's Health by Philip Hilts, which is a hundred-year history of the FDA. And it really is fascinating to see sort of the changes, the evolution of the agency, changing thinking, and how we got to where we are now.

Rebecca Saff, MD, PhD, FAAAAI 11:07

That's perfect. And then when in the process of drug development does the FDA start to get involved?

Kelly Stone, MD, PhD, FAAAAI 11:14

So the FDA is not involved in drug discovery, early development. We become involved when sponsors approach us because they have products that they've developed that they're interested in studying them in humans. So the interactions usually start with pre-IND meetings, pre-investigational new drug meetings. And sponsors request those meetings with us. And at those meetings, we discuss their program, including sort of the drug product itself, and whether or not it's adequate to advance the human studies, non-clinical data that they have, for example, from animal studies demonstrating toxicity, whether there are monetrable toxicities, what dose would be safe for a first in human study. And then frequently they want to discuss sort of their overall development program and considerations and as they move forward. So that's sort of a first interaction with them. But we're once we have those interactions, we're involved from that stage through the investigational new drug application stage, you know, first in human phase two, phase three pivotal studies through marketing applications for those products that get their either new drug applications or biological license agreements, BLAs.

Rebecca Saff, MD, PhD, FAAAAI 12:37

Really the entire spectrum, starting from the very beginning of its introduction in humans, it sounds like involved in making sure that it really kind of is well evaluated.

Kelly Stone, MD, PhD, FAAAAI 12:45

Exactly.

Rebecca Saff, MD, PhD, FAAAAI 12:47

And then how does the FDA determine what safety and efficacy look like for a new drug?

Kelly Stone, MD, PhD, FAAAAI 12:53

The fascinating thing with moving to the FDA, I have to say when I moved from the NIH to the FDA, I was a little bit intimidated because I wasn't sure that I was qualified to really do this work. But what I realize is that we have this real depth of knowledge. We have a multidisciplinary team that reviews every product and every indication for safety and efficacy. So we have medical officers who look at clinical data. And in the clinical data, we're looking at both safety and efficacy of the trials. We have non-clinical reviewers, pharmacologists, toxicologists who look at animal data, uh, preclinical data. We have chemists who look at product quality and manufacturing standards, statisticians, clinical pharmacologists who help us with pharmacokinetic, pharmacodynamic studies, drug-drug interactions, and then other specialists is needed, including microbiologists, people who understand how people interact with drugs, human factors, labeling review. And we have set criteria that we use when we're reviewing these. So for safety, um, we look at adverse events reported from the clinical trials. Uh, we look at um serious and life-threatening uh risks that were identified in the trials, drug-drug interactions, review of special populations such as children, pregnant women, and the elderly. For efficacy, we um determine whether a drug demonstrates a clinically meaningful benefit. And the term that we use is substantial evidence of effectiveness. So has the trial been adequately designed with an appropriate population, appropriate endpoints that are clinically meaningful, usually meaning how a patient feels, functions, or survives? And is there a statistically significant and clinically meaningful benefit in that population that was studied? And the results of that ultimately lead us to a benefit risk assessment. Do the demonstrated benefits of the drug relative to the risk and the ability to mitigate those risks demonstrate a favorable benefit risk profile that justifies approval and availability on the market? So that that's a very quick summary, but it's a multidisciplinary theme that looks at all aspects of drug development from the product to the clinical trial. And then we have inspections, we inspect facilities, we inspect clinical trial sites to make sure that good clinical practice is followed. We may have advisory committees with outside experts that help advise us on particular applications, extensive labeling review. And then the final piece of this is um we now have requirements under the Pediatric Research Equity Act that any product that's submitted for approval has to have a plan for how they're gonna develop it for children. So, as part of that, applicants are required to provide a pediatric study plan for how they're gonna develop it for children, what the timelines are. And if they don't think that it should be developed for children or waived at certain ages, they have to uh provide justifications for that. So it's a thorough review process and um uh the bar is very high for products getting to get on the market.

Rebecca Saff, MD, PhD, FAAAAI 16:21

Okay, we talk about medicine being a team sport, but that is certainly a team sport at the FDA to get a drug all the way through the process.

Kelly Stone, MD, PhD, FAAAAI 16:29

Absolutely.

Rebecca Saff, MD, PhD, FAAAAI 16:30

Yeah. And then are there different regulatory considerations for biologics versus regular medications versus kind of these small molecules we're now using these days?

Kelly Stone, MD, PhD, FAAAAI 16:40

Yeah, so um there are definitely differences. So from a regulatory perspective, they're regulated under uh different parts. Um small drugs are are regulated under the Food, Drug, and Cosmetic Act, whereas um biologics are approved under the Public Health Service Act. So that's uh a detail. But you know, biologics, monoclonal antibodies are complex molecules. They're, you know, they're produced by by cells as a result. Um, there's a variability in post-translational modifications that add a level of complexity to them, whereas small molecules are a little bit easier to characterize. There are predictable um safety concerns. So with uh monoclonal antibodies, for example, you worry about anti-drug antibodies, hypersensitivity reactions, anti-drug antibodies that may affect both the efficacy and safety of the product. We don't see that as much with small molecules. With the monoclonal antibodies, we worry a little bit more about the target rather than off-target effects. Small molecules, on the other hand, you worry about off-target effects. You want to understand the product, you worry about age-related changes in metabolism and clearance of the drug. Uh, you worry more about drug-drug interactions, and you worry more about dose adjustments, particularly for renal or hepatic impairments. So there are different differences, but in the end, the way that we evaluate them for safety and efficacy for marketing approval really is the same process. There are just differences based on unique qualities of small molecules versus um uh versus biologics.

Rebecca Saff, MD, PhD, FAAAAI 18:23

I thought it would be good to kind of walk through how the process has worked recently. We have this nasal formulation that was of epinephrine that was just approved by the FDA, um, and it's now available, which is great for our patients. But I know initially it was submitted and then it was actually rejected. So I'm curious what the kind of key steps were in walking the nasal epinephrine through the FDA and to the approval process and how the FDA decided, okay, additional data is needed before we can approve this.

Kelly Stone, MD, PhD, FAAAAI 18:52

Yeah, so so you trust a rather complicated example to go through um the process. So epinephrine is a little bit unique in that it's um it's indicated for emergency treatment of anaphylaxis and it's been around since 1905. So when I talked about the history of the FDA, it predated 1938, and certainly um sort of the evaluations uh for efficacy in 1962. So there have never been um trials in the setting of anaphylaxis for epinephrine. It's just based on 100 years. We know how it works, we know the physiologic effects of epinephrine, we have data from animal models, and um, it's been on the market. The first real approval of epinephrine was in 1987 for the epipen when auto injectors became available, and approval of the epipen and subsequent in auto injectors have not required clinical trials. It's really based on sort of the bioequivalence that it has epinephrine. The device is reliable to a high degree, and that um patients can use it adequately. So that's how epinephrine is on the on the market. So um epinephrine products that rely on alternative routes of administration, like nasal epinephrine, really rely on the safety and efficacy that was demonstrated by epinephrine by that long history that I talked about. And with all companies, we interact with them throughout development. So it's years and years and years of talking to the companies as they go through different phases of development. And the challenge with the epinephrine is um the difficulty with doing a true clinical trial in the setting of anaphylaxis. So we've relied on PK matching in this setting. So for the approved epinephrine product, the requirement was that they demonstrated that the pharmacokinetics, the concentration over time is bracketed by approved epinephrine injection products. In addition, we look at pharmacodic uh pharmacodynamic responses, particularly blood pressure, pulse rate, to make sure that we're seeing um responses that are supportive of what the PK is demonstrating. So that's the basis for evaluating these programs. Then when it comes to nasal administration, there are unique things. So an injection, you're injecting it, there's a depot, it's being absorbed over time. Whereas in the nose, there may be different circumstances. With acute rhinitis, for example, you may have nasal congestion and rhinorrhea that affect absorption or more rapidly clear the epinephrine from the nasal cavity and may affect absorption. So as part of the development program, applicants need to look at absorption, PK and PD, not only under normal conditions, but also under conditions. Of acute rhinitis, usually in the setting of allergic rhinitis, allergen exposure, and um, how does that uh affect drug absorption?

Rebecca Saff, MD, PhD, FAAAAI 22:10

And certainly you can get acute rhinitis and congestion with a reaction. So that also is going to play into it.

Kelly Stone, MD, PhD, FAAAAI 22:17

Exactly. And, you know, so in terms of the requirement for additional data, in the setting that we're relying on this approval pathway based on PK bridging, uh, we really require certainty that we understand how it's absorbed, we understand how it would be absorbed under different conditions, and we understand it well enough to label it so that patients can use it safely and effectively. So at times we don't approve products where additional data is needed to fill gaps where there's uncertainty in the data. And that's what you're referring to, I think, in this question.

Rebecca Saff, MD, PhD, FAAAAI 22:54

And then once the drug is approved, such as with the nasal epinephrine, how then does the FDA continue to monitor for safety during this post-marketing period?

Kelly Stone, MD, PhD, FAAAAI 23:04

So there's several answers to this. So for all drugs, safety reported to the manufacturer that they're required to report to to FDA. Um, there are also reports that go through MedWatch directly from providers or for patients. And we really rely on those reports. So the one plug I would like to put in is sort of the um how absolutely critical it is when there are adverse events that are identified, that they are reported. It's the only way that we're aware in most settings. And with those reports, we have groups that are routinely looking at safety reports from products that are approved and on the market looking for safety signals. So in the allergy and immunology space, for example, the most recent example is with citirazine, where there's now a warning and precaution for rebound paritis. And that was the result of routine pharmacovigilance over many years, reports following up on data and sort of determining that there really is a safety concern here that needs to be labeled for providers to be aware of. So routine pharmacovigilance is one. Sometimes we require post-marketing requirement studies where there's an identified safety concern that we don't think prevents the product from being approved, but we think that we need additional data and we require that sponsors conduct those trials. They have to give us specific details of what the trial is going to include, dates when they'll be completed. Um, so that's that's another way that we we monitor safety. And then another area is in pediatric. So every drug that's approved, as I said before, sponsors have to study it in children unless there's a good reason why we should waive that requirement. And in those cases, to um assess the safety and efficacy in that new pediatric population, we can require one of these post-marketing requirements specifically for pediatrics.

Rebecca Saff, MD, PhD, FAAAAI 25:10

I'm curious, recently the FDA approved a biologic that actually has a half-life of six months, or you know, it can only be administered for six months. How do the regulations differ for these products that are available for so long?

Kelly Stone, MD, PhD, FAAAAI 25:24

So um these are incredibly interesting products. So um compliance with treatment is always a concern, and certainly there are advantages to drugs that can be administered uh much less frequently. And and these drugs, monoclonal antibodies, have modifications in the FC region that increase their affinity for the n-atal FC receptor. So you get increased recirculation and extends the half-life of the product. So in the clinical trials, um, they have to conduct them um the same way that the product would be used when it's approved. So most products, I mean, you're talking about multiple doses over, you know, the conduct of a trial. Um, in a 52-week trial with these products, you know, you're talking about two doses. So, you know, it is different in that way. With these products, um, they're in the bloodstream for a prolonged period of time. You know, so certainly there are concerns if there's lack of efficacy, you know, the opportunity to uh adjust treatment. Can you adjust treatment while you still have the prior treatment in your system? Those factors come in. And then the labeling for the product that was recently approved includes um information to um highlight for providers potential risk of use during pregnancy. So the the binding to the neonatal FC receptor that allows the half-life to be extended and for the dosing interval to be extended also has the potential to um increase um transplacental transfer and potential prolonged exposure in the newborn. So, you know, that safety concern, you know, is unique to these products. It sort of alters a little bit the safety there. Um so we look very carefully at sort of the non-clinical data that comes in with fetal toxicity, it's etc. So they're interesting products. I'm sorry, they're they're interesting products, but they are challenging.

Rebecca Saff, MD, PhD, FAAAAI 27:27

We're all very excited because a biosimilar or omalizumab was approved in March of 2025 and should be available this fall. I know that I didn't quite understand exactly the difference between a biosimilar and other medications. And so I wonder if you could walk us through exactly what a biosimilar is and how it differs from a generic.

Kelly Stone, MD, PhD, FAAAAI 27:46

Yeah, so um so the biosimilars are to biologics as generics are to small molecules. So, you know, that's sort of the overall framework to have a think about it. Um, the definition of a biosimilar um is in in in regulation uh in the Public Health Service Act, and the definition is that a biosimilar is highly similar to an approved reference biologic product, and it has no clinically meaningful differences. So highly similar. I've had someone recently say, well, similar isn't the same as the same, but similar in this case really should be viewed as the same. So the language highly similar is there because um as a complex molecule, unlike a small molecule where you can have the exact same molecule, it's very difficult to reproduce the exact molecule with the same post-translational modifications. So biosimilar is to biologics, what a generic is this small molecule. The origin of biosimilars is an act that was passed in 2010, the Biologics Price Competition and Innovation Act, which was part of the Affordable Care Act, and it mandated a development pathway for biosimilars. It established an abbreviated approval pathway for biologic products. Um and the purpose really was to increase competition in the biologics market, to reduce healthcare costs while maintaining safety and efficacy standards, but also to balance innovation incentives for the companies that develop the innovator with access to more affordable biologic therapies. And the the final thing that I'll say there in that description of biosimilars, they use three terms. One is reference product, which is the original approved product that goes through extensive testing for every indication that's approved. Biosimilar, which is the biosimilar that's highly similar, and then there's a term interchangeable biosimilar. So an interchangeable biosimilar was put in the initial regulations. And the definition, an interchangeable biologic biosimilar can be given by a pharmacy. So if you write for a drug, the pharmacy can exchange the biosimilar, the interchangeable biosimilar for the uh reference product. With the original approved biosimilars, that was not possible. Providers would have to be the ones to decide that the biosimilar was appropriate for that patient. And this has evolved over time where most biosimilars being approved today are interchangeable. Sort of the requirements there have changed significantly. So it's a long answer to your question.

Rebecca Saff, MD, PhD, FAAAAI 30:29

That's right. How does a company prove that they have a biologic that is highly similar to the approved product?

Kelly Stone, MD, PhD, FAAAAI 30:38

Yeah, so the basis for um demonstrating biosimilarity, there are um different components to it. Uh the first is looking at product quality. The second, and really the crux of approval of biosimilars, is um comparative analytical assessment. They look at the reference product compared to the biosimilar. Does it have the same primary structure, secondary, tertiary structure, effector functions, charge, they go through all sorts of analytical tests, and it's a very sensitive way to identify differences between the two molecules. The second level of testing that they have to do in clinical studies is comparative clinical pharmacology studies. So if you look at the PK of the reference product to the biosimilar, do you get the same exposure? And it has to be similar within certain uh parameters. And then historically, for the um, you know, the first 80 or so biosimilars approved, there had to be a comparative efficacy study where the biosimilar was compared to the reference product in a clinical trial, and it only had to be for one indication for which that drug was approved. And if they demonstrated comparative efficacy there, then the approval really applied to all indications for that drug. But what's happened over time is that as we've been more experienced, we realize that the comparative analytical assessments really are the most sensitive assay. Combining analytical assessment with a PK study really is sufficient to demonstrate um biosimilarity. Um the requirement for a comparative efficacy study, a clinical trial, really has been sort of minimized, and it's only for situations where there may be some residual uncertainty. So, what this isn't doing is it's providing a very abbreviated pathway to get biosimilars that behave exactly like the reference products. You know, again, sort of their exposure, pharmacodynamic effects are the same. Analytically, they're the same, but by providing an abbreviated pathway, it allows them to get on the market that um is is meant to provide cheaper uh products with greater accessibility.

Rebecca Saff, MD, PhD, FAAAAI 33:04

And has that been shown to be true that these biosimilars are they more accessible and less expensive for patients?

Kelly Stone, MD, PhD, FAAAAI 33:11

So they have. So um so the first biosimilar approved in the US was in 2015 for Phil Grasstum for a GMCSF product. There have been studies demonstrating significant savings up to um uh I'm gonna get these numbers wrong, but um well, so I'm not gonna quote a number, but there have been significant savings, and the projections are that there's gonna be really significant savings by having these on the market. So with generics, the lessons have been that when generics go on the market, when there are one or two generics, it can bring the price down somewhat, say 20%. Um, but as you have three, four, or more generics available, competition intensifies significantly, and prices can fall as much as 80 to 90 percent or more below the brand price. So for biosimilars, at the point of market entry, biosimilars are typically priced about 40 to 50 percent below the reference biologic product. So it has more become available, the expectation is that there's going to be more downward uh pressure on prices. So currently, biosimilars hold less than 20% of the market share compared to generic, which have about 90% of prescriptions uh for small molecule drugs. The trajectory is expected to improve, creating uh further downward pressure as we go from 20% of the market to a larger share of the market. On a national scale, since approval of the first biosimilar product in 2015, which was for fograstin uh or GMCSF, biosimilars have generated over 56 billion in cumulative healthcare savings. And in 2024 alone, the savings was 20.2 billion. So this underscores a positive trend, and these savings should continue to compound as adoption expands and additional products receive regulatory approval. And then the final thing that I would say is on the development side, uh bringing a biosimilar to market has typically required about five to eight years and can cost up to $300 million in investment. And of that cost, a substantial portion has been attributable to the comparative efficacy studies. Um, so this was a long, expensive process to get a biosimilar to market. Uh, with the regulatory reforms that I discussed, um, streamlining how biosimilars are produced, not requiring the comparative efficacy studies, this should significantly reduce the development cost. Um, and the timelines should be reduced by two to four years, and the cost, you know, potentially 150 million or more per product. So these are efficiencies that ultimately should be passed through the healthcare system in the form of competitive pricing. So, you know, together, I think the expectation is that prices as biosimilars come on the market uh will bring prices down as there are more biosimilars and as they're a larger part of the market share, you know, prices should come down significantly from what we've had.

Rebecca Saff, MD, PhD, FAAAAI 36:31

Um and do you think it'll bring the price down for patients, just having one approved, or do we need to kind of wait until we have multiple approved to really see the savings?

Kelly Stone, MD, PhD, FAAAAI 36:40

Yeah, so um I'm I'm certainly not a health economist, but the intent really is that it it will um make these more affordable and more accessible.

Rebecca Saff, MD, PhD, FAAAAI 36:49

Yeah. And do you think there's other biosimilars that are on the near horizon in our field?

Kelly Stone, MD, PhD, FAAAAI 36:54

Um so so there are others that are likely um uh to be coming out, you know, in the next uh few to 10 years.

Rebecca Saff, MD, PhD, FAAAAI 37:02

That'll be great. Great for our patients, hopefully, and uh great for the healthcare system. And have there been changes in FDA regulations that have occurred recently or that are likely to occur in the next few years that we should be aware of?

Kelly Stone, MD, PhD, FAAAAI 37:17

Yeah, so as I said at the beginning, the agency continues to evolve. And uh before I answer the specific question, um you know, we we work uh based on law, which are passed, laws based passed by Congress, uh, which have legal authority. Uh regulations are interpretations of the law by specific agencies. Most of the changes that you see and hear about are changes in guidance from the FDA, which are sort of our current thinking on interpretation of the regulations. So there have been many changes, and certainly is sort of different administrations have different priorities, different commissioners have different priorities. Some of the recent changes have been uh sort of a focus on reducing use of animals in in drug development using new approach methodologies or NAMS as alternatives to animal testing. The um commissioner recently had a um a review in the New England Journal talking about the shift from we historically have required two adequate and well-controlled trials for an indication to approve a drug. Each trial had to independently demonstrate efficacy. And with the new thinking, um, it's really shifting towards, in most cases, a single adequate and well-controlled trial that's well designed to um answer the clinical question with little residual uncertainty. That may be all that's needed. So that's a significant change. You you've you've heard of the commissioner's priority voucher. So there's now an attempt to try to improve efficiency and reduce the time it takes from the FDA receiving an application for a new drug application or a BLA in the actual approval. So the changes that you're gonna see, I think, are really around trying to um improve efficiency, incorporate things like artificial intelligence in the way that we do regulatory reviews, looking at different ways to use real-world evidence, real-time political trials. So I think you're gonna see a lot of changes um, you know, in in the next few years as sort of, you know, again, sort of we progress in the way that um, you know, both regulatory science and also um sort of uh policies.

Rebecca Saff, MD, PhD, FAAAAI 39:44

Yeah, no, I think it's this very difficult balance between really needing to ensure safety, but also needing to ensure efficacy, but also streamlining the process so new drugs can get to patients as quickly as we can. So I imagine that balance can be so complicated.

Kelly Stone, MD, PhD, FAAAAI 40:00

You know, the other focus um um also uh we'll be looking at over-the-counter drugs. Are there drugs that are currently prescription only that may be sort of appropriate to be available over-the-counter again as an attempt to improve accessibility to drugs and potentially to make it uh more affordable for patients? So all of these things I think are things on the horizon that um you're probably gonna see.

Rebecca Saff, MD, PhD, FAAAAI 40:26

And how does the drug get to be over the counter? What are the what are the things that have to be put forward in order to get it rather than needing a prescription?

Kelly Stone, MD, PhD, FAAAAI 40:35

Yeah, so I mean the key concept that needs to be addressed is whether the drug can be used safely without a learned intermediary. Um, so can't can a patient go into a pharmacy? Can they read a drug fact label, which is very abbreviated compared to what you're used to seeing with prescription information? And can they know how to use that drug, when to use that drug, um, how to use it safely and effectively? And there are different ways that this is done. So um companies can come in with a new drug application specifically to go directly over the counter. There are drugs that go from prescription to over-the-counter, nasal steroids is a good example of products that we're familiar with. Um, where there were prescription and then I forget the exact date, but 10, 10, 12 years ago, they became available over the counter. So, so there are opportunities for that as well. But again, anything that goes over the counter, patients have to be able to know when to use the drug and how to use the drug without a uh provider instructing them.

Rebecca Saff, MD, PhD, FAAAAI 41:46

And then we talked about you know things like oral immunotherapy. How are those approved differently than all these other medications that we're talking about, biologics and small molecules, because a lot of them are food.

Kelly Stone, MD, PhD, FAAAAI 41:59

Yeah, so um I'm gonna be very careful um in discussing these. So um so so the oral immunotherapy products are regulated by SIBER by the Center for Biologics Evaluation and Research. And the way that they're viewed is is a little bit different, but um I I can put this. So are you talking specifically for food allergy or for allergic rhinitis as well?

Rebecca Saff, MD, PhD, FAAAAI 42:25

For food allergy.

Kelly Stone, MD, PhD, FAAAAI 42:27

Yeah, so for food allergy, you know, I can comment. So there are two products that are approved with an indication for food allergy. Uh the first was pelforzia, which is specific for peanut allergy, and it's intended to reduce the risk from uh anaphylax of anaphylaxic accidental exposure to the food, and it requires continued avoidance of the food. The second product that was approved in um 2024 was omolizimab, uh, which is unique in that it's agnostic to the food. It's for IGE mediated food allergy, but it's not specific to a particular food. So there are differences in the way from a um chemical manufacturing component between allergenics and drugs. And I'm not going to comment on that. There are different, you know, potential um uses of the drug. So both of them are to prevent accidental exposure, uh accidental exposure, but oral immunotherapy potentially is immunomodulatory, whereas drugs typically aren't, at least now we don't think that they're immunomodulatory, they're different. But in the way that we regulate them and review them, you know, they're they're food allergy development programs. So as of now, we use food challenges as a primary endpoint, as a surrogate for sort of endpoints that are clinically meaningful, preventing anaphylaxis in the community, improving quality of life, things like that, that um from a practical Standpoint are challenging. So we work very closely between with our colleagues in SEBR and CEDR or our group to try to encourage consistency in the way that we view development of products for food allergy from considerations of population. Do studies enroll patients that are highly sensitive to the food or sort of a broader population endpoints. What's a clinically meaningful change in that threshold? Is there a specific threshold target that you should be looking at? When we do these studies, we talk about dose limiting toxicities, dose limiting symptoms. How do you define that? And there's variability across trials. So I think that there is areas for improvement in sort of how we view sort of food allergy development programs, improving consistency, getting feedback from patients, from academicians, from industry, really to try to make sure that we're being rigorous in the way we review these products, but also we're facilitating development of products. In the end, we want to help companies develop products in a way that will lead to sort of getting it on the market and benefiting, benefiting patients. So it's a little bit of a long answer to your question about oral immunotherapy specific, Lee. But I do defer specifics of allergenics to my colleagues in SIBR.

Rebecca Saff, MD, PhD, FAAAAI 45:35

Fair enough. And working at the FDA is somewhat of an unusual career path for an allergy immunology physician. What makes working at the FDA so rewarding?

Kelly Stone, MD, PhD, FAAAAI 45:45

Yeah, it's kind of funny. So I didn't, and I don't think anyone grew up telling their mother that they wanted to be a clinical reviewer at the FDA when they grew up. So having said that, FDA is a terrific place for allergist immunologists and for clinicians in general to make contributions to the public health, but also to have rewarding careers. We have allergist immunologists throughout the agency, including review divisions from drugs to generic drugs to gene and cell therapies, vaccines and allergenics, as well as drug policy and others. And it's really a remarkable institution with remarkable people. So the things that really make it an outstanding place to work to me, one is the mission. I like being a public servant. I know my colleagues like being public servants, and they take their job very seriously. And our job really is to um work with companies, as I said, to facilitate development of products, to make sure that development of products is done safely, to protect subjects in clinical trials, but also to make sure that products that go on the market truly do demonstrate safety and efficacy. So, you know, the mission is central to what I think makes FDA a great place to work at. Another area is intellectual stimulation. We see a lot of really interesting products that are at different points in development, innovations that, you know, as they go through development, you're not sure whether they're going to be beneficial or not. But from someone who likes technology and data, it's just a fascinating place to be. But I think that the most important thing that makes FDA an outstanding place to work really is the people. I talked about the depth of expertise, but you know, I work with a group of people who really are dedicated public servants, who um value their job, they understand the importance of their job. And um, you know, it really I can't imagine a better place to work. So public service remains um an honorable career path, and the community and public really should be reassured by the expertise and commitment that the public servants that I work with sort of the exhibit ensuring that um, you know, drugs are are safe for patients. So I can't say enough about what a terrific environment it is. And sort of my transition to the FDA has certainly been a plus.

Rebecca Saff, MD, PhD, FAAAAI 48:24

We certainly appreciate the work that you do and the work that everyone at the FDA does to both keep us safe and bring these efficacious drugs to market. Um, so thank you so much for talking with us, and we look forward to seeing more biosimilars on the market in our field, and hopefully that really benefits our patients.

Kelly Stone, MD, PhD, FAAAAI 48:41

Great. Thank you so much again, uh Rebecca, for having me on the podcast.

Rebecca Saff, MD, PhD, FAAAAI 48:46

We hope you enjoyed listening to today's podcast. Please visit aaaai.org for show notes and any pertinent links from today's conversation. As a reminder, this podcast is not intended to provide any individual medical advice to our listeners. We do hope that our conversations provide evidence-based information. Any questions pertaining to one's own health should always be discussed with our personal physician. The Find an Allergist search engine on the Academy website is a useful tool to locate a listing of board certified allergists in your area. Use of this audio program is subject to the American Academy of Allergy, Asthma & Immunology Terms of Use Agreement, which you can find aa aai.org. If you like the show, please take a moment to rate and subscribe through wherever you download your podcast. Thank you again for listening.