When people were dying from AIDS in the 1980s and 90s, Congress found a way to expedite the drug approval process and saved countless lives. Established in 1992, the Accelerated Approval Program allows the FDA to speed approval of drugs for patients with serious and life-threatening conditions. In this episode we talk with the father of children with a rare disease, a company CEO working to treat rare diseases and two policy experts on Accelerated Approval.
When people were dying from AIDS in the 1980s and 90s, Congress found a way to expedite the drug approval process and saved countless lives. Established in 1992, the Accelerated Approval Program allows the FDA to speed approval of drugs for patients with serious and life-threatening conditions. In this episode we talk with the father of children with a rare disease, a company CEO working to treat rare diseases and two policy experts on Accelerated Approval.
Accelerating Hope: The Pathway for Cures
Speaker 1 (00:06): It's mysterious, it's deadly, and it's baffling medical science. Acquired Immune Deficiency Syndrome once thought to affect only promiscuous homosexual males, AIDS is now spreading in epidemic proportions to other segments of the population.
John Crowley (00:23): Where did accelerated approval come from? It was a piece of Congressional legislation that came about during the AIDS and HIV crisis in the late 1980s, early 1990s. And you have to think back to that time, you know, this was a health scourge, HIV, it was devastating communities, killing hundreds of thousands, millions of people worldwide. It was an absolute death sentence and there were no treatments, there were no cures.
(00:49): If you were diagnosed with HIV AIDS, you were going to suffer and you were going to die. And what it did was over the next decade or more, it set the pharmaceutical and the biotechnology industry ablaze with research, with innovation, with new therapies to the point where we ended up a little more than a decade later having dozen or more treatments approved for HIV AIDS and then combinations of treatments.
Rachel King (01:16): The government got it right. When people were dying from AIDS in the 1980s and 90s, Congress found a way to expedite the drug approval process and saved countless lives. The accelerated approval pathway was created in 1992. It allows the FDA to speed approval of drugs for patients with serious and life threatening conditions. And for HIV infected patients, it was the difference between life and death. I'm Rachel King and you are listening to I Am BIO.
(02:09): Although the accelerated approval pathway was designed for the fight against HIV, in the years since it was established, nearly 300 new drugs have come to the market through this pathway. Most have been for rare cancers. The vast majority would not exist without this expedited process.
(02:27): Today we talk about how the program works, who benefits, and why it is under threat. We meet a courageous and loving father who devoted his life to finding treatments for his children with a rare disease, and we hear from a founder and CEO of a company developing drugs for rare and ultra rare diseases. Finally, we talk with two policy experts on accelerated approval.
(02:52): In 2010, Extraordinary Measures starring Harrison Ford, Brendan Fraser, and Keri Russell was released. Based on a true story, the film follows the journey of John and Aileen Crowley as they face the worst news of their lives: their two children have a rare disease that will likely kill them before their 10th birthdays. John Crowley is our guest.
John Crowley (03:16): Hi, I'm John Crowley. I'm the Founder and Executive Chairman of Amicus Therapeutics.
Rachel King (03:22): John explains why and how he came to be a leader in biotech.
John Crowley (03:26): Candidly, I knew very little about the world of biotechnology until 25 years ago this year. It was back in March of 1998 when our then 15 month old daughter, Megan, was diagnosed with a rare form of muscular dystrophy known as Pompe disease. And there's no history in our family. Like all of us, we are carriers for any number of rare genetic diseases and not until we have a child with someone else who's also a carrier, in the case of many of these disorders, do any of the diseases manifest themselves. So there's no history of Pompe in our family and Megan was born seemingly healthy.
(04:02):By about a year of age, she wasn't pulling up in the crib, wasn't taking her first steps. And so we went from pediatrician, to pediatrician, to neurologist. From blood tests, to deep muscle biopsy, to diagnosis. And we were told that day that our daughter had this rare form of muscular dystrophy, that there was very little research, and there was no treatment, there was no cure, and that we should go home and enjoy the time we had, that she would get very weak very soon.
(04:30):And for us, it was particularly challenging because we had appointment that day, our then seven day old son, Patrick, and we were told there was a one in four chance that he could also have the disease and that he should be tested. And very quickly after that at Duke University, Patrick was tested and we were told that not only Megan, but Patrick, had the same disease and we should expect the same outcome.
Rachel King (05:03): Despite the doctor's prognosis, John and his wife refused to sit back and watch their children suffer and deteriorate.
John Crowley (05:11): Eventually, we pretty quickly settled on determination. And it was determination first to learn everything we could about this disease to find any researcher who may have any ideas or any work that could be directed toward a life saving therapy. And there were very few, but there were a handful. And so that launched us into this whole world of biotechnology and we just threw ourselves into it.
(05:33): I think like many moms and dads in that situation, you wanna balance giving all the time, and care, and love, and attention you can to your children. But for us, also looking to try to find that treatment, to find that cure or something that could give the kids some hope, some strength, give us more time. And that is what brought us to biotechnology and we learned pretty quickly that biotechnology is just a great big word that, for many people, just means hope. And that's what it was for us in those very early days.
Rachel King (06:05): Fast forward 25 years and John's children are still with us, both working full time jobs. They still have Pompe disease and they still face challenges, but the family's perseverance gave them more time together. The first company that John founded developed an enzyme replacement therapy that saved his children.
John Crowley (06:25): For a time, the medicine made them stronger and their skeletal muscle strength improved, particularly in Megan. And then after about a year, it stabilized. And that's when I realized we didn't have a cure, we probably also didn't have the most effective treatment we could ever have. But again, it gave us time, it gave our children quality of life, gave them time with each other, with our families, with our friends. But it also gave us time as innovators and entrepreneurs to go back to the drawing board and to think about, "Okay, while they're living and while they're thriving, what else can we do to make them live even longer and even healthier?"
Rachel King (07:01): There are 7,000 rare diseases and as John's story demonstrates, the impact is felt far beyond the people living with the disease. Families and companies are in a race against time. The accelerated approval pathway is a critical tool to find cures and treatments faster. BIO's Chief Scientific Officer, Cartier Esham, explains what the pathway is.
Cartier Esham (07:28): The accelerated approval pathway provides early access to treatments for patients with serious and life threatening conditions. It is granted based on substantial evidence that a surrogate, or intermediate endpoint, is reasonably likely to predict clinical benefit. This pathway allows for approval when a medicine has shown a change to a biologic or physical response.
(07:49): For example, improved T cell counts were determined to reliably predict fewer infections in AIDS patients and was eventually accepted as a surrogate endpoint that could be used to support approval of HIV and AIDS medicines. Some examples of surrogate endpoints that have been used as a basis for approval are: the demonstration that a medicine reduces amyloid beta plaques in Alzheimer's patients. And the likely clinical benefit is slowing the progression of the disease measured by a decrease in cognitive decline.
(08:20): Durable complete remission rate is an example of an accelerated approval endpoint for leukemia. In sickle cell disease, a medication was approved under accelerated approval that works by binding to hemoglobin and increasing its affinity to oxygen to prevent it from clumping and sickling. This is measured by improved hemoglobin levels.
Rachel King (08:42): Our next guest is singularly focused on rare disease.
Emil Kakkis (08:46): My name is Emil Kakkis, I'm the CEO and President of Ultragenyx. The name Ultragenyx stands for ultra rare genetic diseases as a contraction. The goal of the company is to establish new ways to develop rare and ultra rare disease to make it more efficient, and more productive, and to treat a variety and types of diseases that had no prior treatments.
Rachel King (09:07): Emil believes the biomarker framework of the accelerated approval pathway could transform the drug development process for rare diseases.
Emil Kakkis (09:16): The accelerated approval pathway is critically important at allowing drugs, based on the precise measures of disease, to be approved and, subsequently, then validated as clinical effective drugs. So while accelerate approval is thought of as being easier or cheaper, the truth is, it's a more precise way to measure diseases and get them approved.
(09:38): The standards for accelerate approval are based on a biomarker that's reasonably likely to predict clinical benefit and this can be subjective. And for a rare disease for which there isn't a lot of history, there may be difficulty in understanding the relationship between the biomarker and clinical outcomes.
(09:53): But that said, many of these diseases have very clear connections between the underlying biomarker which is really a measure of disease cause and where that cause leads to clinical outcomes. Now what most people think is that the biomarkers are an estimation like a compromise, but in many rare diseases, they are a more accurate measure of underlying disease.
(10:14): To provide a comparison, for example, if you took a car analogy it's like the brakes. The brakes of a car, obviously, are important whether you have a car crash or not. If the brakes are broken, your likelihood of having a car crash goes up. But a car crash is like a clinical outcome. If your brakes are broken, you will have car crashes. Now, it's a lot easier to measure brakes than car crashes. You can measure how good the brakes are, how powerful they are, and do it very precisely. And you know if you fix the brakes, you will prevent car crashes.
(10:48): But if you try to measure your brake repairs based on car crashes, it'd be very inefficient because not everyone is gonna crash. It depends on the driver, the car, and the setting. Just like in clinical medicine, the background genetics, what the patient's experiences are, and other factors will cause noise in clinical outcomes. But measuring underlying disease is far more powerful.
(11:09): So I say that the biomarker approvals used for accelerated approval are not a compromise, they're actually superior. And the transformation of HIV, Hep C, as well as oncology through accelerated approval pathway is a shining example of how accelerated approval can transform the development of powerful new drugs.
Rachel King (11:34): When we return from a break, we'll talk to the author of a study that examined what would happen if proposals to limit the accelerated approval program were implemented? And we ask our guests to weigh in.
(11:59): It's not too early to start planning for the world's most influential biotech meeting, BIO 2023. Held in Boston from June 5th trough June 8th, the conference will highlight our theme, Stand Up For Science. Come join us to learn, network, and stand up for innovation. Register today at bio.org/events.
(12:33): In a moment, we will talk with the data analyst who calculated the impact of misguided proposals to weaken accelerated approval. But first, let's hear from BIO's Chief Scientific Officer, Cartier Esham, on discussions in Washington about changing or limiting this valuable pathway.
Cartier Esham (12:51): There are some concerning challenges relating to the accelerated approval pathway today. For instance, misinterpretations about what this pathway is and what it is not. Headlines criticizing the use of this pathway without closely examining how it has benefited patients and advanced our understandings of complex and life threatening diseases which, at times, are being driven by other agendas, are not taking into account the importance of getting medicines to patients as efficiently and effectively as possible.
Rachel King (13:19): Recently, the Centers for Medicare and Medicaid Services, or CMS, unilaterally decided to limit coverage for two Alzheimer's drugs that had been approved through accelerated approval. The CMS decision is not only problematic because it introduces uncertainty regarding FDA decisions, but also because CMS does not have the scientific expertise to make this kind of determination. Now, only patients enrolled in clinical trials for these breakthrough drugs will be eligible for coverage under Medicare. Here's Cartier again.
Cartier Esham (13:52): Medicines approved under accelerated approval are approved using the same gold standard for safety and effectiveness as any other medicine. Patients should have access, the same access, to these medicines as any other medicine approved under any other pathway. And as always, patients and their families should work with their physicians to determine their best treatment options. But let's not undermine the importance of choices.
(14:17): Dr. Pazdur, FDA's Oncology Director, once explained during a meeting held by the Friends of Cancer Research in 2021, "If you only view things from one lens, the problems of the accelerated program, you miss the entire big picture of what has happened in ecology." He noted that accelerated approval has. "Allowed important oncology drugs to enter the market years earlier than had the pathway not existed."
(14:43): If there are concerns about the accelerated approval pathway, such as how can we get post approval studies done in a timelier fashion, then let's work on that to things like enabling the studies to use real world evidence to verify clinical benefit. Let's not prevent earlier access to medicines for life threatening diseases or for diseases where there are no current options. I think you have to look back and ask, "Would improvements in the treatments we have today for oncology diseases like multiple myeloma or for sickle cell anemia exist without the accelerated approval pathway?" The answer is no.
Rachel King (15:14):The data bears this out.
Duane Schulthess (15:16):My name is Duane Schulthess, I'm the CEO of Vital Transformation.
Rachel King (15:21): Duane's firm recently published a study that calculated the value and impact of accelerated approvals and what would happen if proposals to limit the program were implemented.
Duane Schulthess (15:31): The study looked at several aspects of accelerated approvals. We looked at a historical cohort over the last 10 years to see how it actually functioned and to test some of the criticisms of the program regarding changes that were being made, or at least proposed, in the U.S. Congress as well as by Health and Human Services.
(15:50):So we did a retrospective analysis looking at what the behavior of the accelerated approvals were as well as what would happen if some proposed changes were to have occurred. And we then compared the impacts on basically what we think would've happened within drug development.
(16:07): I'd say that top level finding, overall, was that a lot of the assumptions about delays. There's a real belief, particularly among several folks in the U.S. Congress, there was a bill by Representative Pallone that was looking at putting a hard cap of five years for a data collection part of the accelerated approval.
(16:28): And what we found was a lot of these assumptions were really not on the mark. For example, 75% of accelerated approvals register within four years. So if you were to put a five year hold, you're really only talking about a handful of drugs that are taking long to register. And overwhelmingly, the ones that are taking longer than five years are very, very small micro orphan conditions. Uh, Gaucher disease where the entire clinical trial was an outcomes trial with only 40 people.
(16:57): So the idea that you're going to be able to put a hard cap what that means is one, it's not going to impact 80, 90% of the cohort. And the other problem is what you're going to overwhelmingly have is a negative drain on those very small orphans that require longer to register. It's really gonna have an overwhelmingly deleterious impact on small orphan drugs, which is where we need the most innovation right now and is often were the best science is going.
(17:24): The other thing we found was that of the drugs that have come out, 80% or more are for orphan conditions. So really, this is an overwhelmingly dominant pathway looking at orphan conditions and subpopulations and very, very small hard to treat conditions where there's high unmet medical need and a lack of current therapeutic treatment.
Rachel King (17:45): John Crowley knows firsthand the importance of supporting this program. He agrees that the public is often misled into the wrong assumptions.
John Crowley (17:54): You have to realize that in many of these diseases where there has been an approval based on an accelerated approval pathway, it was done so because there just isn't any good clinical endpoint or it's gonna take a really long time to see, you know, an outcome like survival. And there are a lot of different ways that we can look at clinical outcomes.
(18:13): I think all companies in this field it's in their interests, and certainly in patient interests, to continue to do the research, to understand the molecules that are approved under accelerated approval, but to also understand the diseases, the biology of disease, to try to come up with newer and better treatments.
Rachel King (18:31): Duane's Vital Transformation study also reveals data that counters the argument that drug developers are ignoring the responsibility to conduct aftermarket research.
Duane Schulthess (18:40): What we saw in the data was overwhelmingly 80% of all clinical trials filed within five years. That we know for sure. We also know that those that extend out further statistically have, without question, very small populations; very, very small. And in fact, this is predictable. You can model this, you can actually determine how long a clinical trial is going to take to confirm based on the size of the population that the disease addresses.
(19:11): So if an indication is for a very large ontological treatment with thousands of patients in the clinical trial, statistically those go very fast. Where we see very small populations, those take longer. And also, by the way, they're less likely to be profitable. The longer it takes and the smaller the population, we see a lower net present value, we see a lower return on investment.
(19:34): So I don't think it's necessarily in the drug company's favor to be delaying these applications. And in that case, we're talking maybe delays of five, 10%. Now is every one of those folks who's running a clinical trial out in that length beyond five years? Are we gonna say they're all bad actors? I find that hard to believe because that's not what the data says. The data says there's a logical pattern of behavior here.
Rachel King (19:58): From Emil Kakkis's perspective, accelerated approval should be strengthened, not weakened. Here's Emil again.
Emil Kakkis (20:05): I think right now, accelerated approval's not being used very often in rare disease and it's an unfortunate reality. The idea now that they're gonna limit it further, I think is misguided. But the truth is, if you look at all the rare disease drugs and all the ones approved using biomarker endpoints, whether accelerated or not, the consistency of success in predicting clinical outcome has been 100%. There haven't been any rare disease drugs approved with biomarker endpoints, whether accelerated or standard approval, that haven't proven to be effective in long run. And we think that record should change minds about what we do in the rare disease world where I think the probability of success is much higher and the value so critical to getting those drugs approved.
(20:48): I think the public doesn't understand what accelerated approval really means and I think there's many people who are critiquing the program, failing to realize that these accelerated approvals are not a compromise but, in fact, a more effective, more efficient way to do drug development.
Rachel King (21:03): John Crowley sums it up this way.
John Crowley (21:06): And that's what's really exciting about the potential for accelerated approval is not just to get approval for a medicine today, but to lay the groundwork just like it did in HIV AIDS. For the next 10, 20 years of research through accelerate approval of many new treatments.
Rachel King (21:21): John also mentioned that we have treatments for only about 5% of rare diseases. As a society, we should strive to improve that percentage. FDA's accelerated approval has proven to be successful. It's our responsibility to strengthen and broaden it and ask regulators to use it more frequently so that we can win the race against time for so many people in need.
(21:47): I want to thank our guests John, Cartier, Emil, and Duane for sharing their perspectives on a program that has worked well and could work even better if people who understand the complexities of drug discovery are empowered and listened to.
(22:04): Make sure to subscribe, rate, and/or review this podcast and follow us on Twitter, Facebook, and LinkedIn @iambiotech and subscribe to Good Day BIO at bio.org/goodday.
(22:18): This episode was developed by Executive Producer, Theresa Brady, and Producers, Lynne Finnerty and Rob Gutnikoff. It was engineered and mixed by Jay Goodman with theme music created by Luke Smith and Sam Brady. (singing)