S.Hrg.119-415

1[Senate Hearing 119-415]2[From the U.S. Government Publishing Office]34                                                     S. Hrg. 119-41556                      FROM REGULATOR TO ROADBLOCK:7                          HOW FDA BUREAUCRACY8                           STIFLES INNOVATION9=======================================================================1011                                HEARING1213                               BEFORE THE1415                       SPECIAL COMMITTEE ON AGING1617                          UNITED STATES SENATE1819                    ONE HUNDRED NINETEENTH CONGRESS2021                             SECOND SESSION2223                               __________2425                             WASHINGTON, DC2627                               __________2829                           FEBRUARY 26, 20263031                               __________3233                           Serial No. 119-253435         Printed for the use of the Special Committee on Aging3637[GRAPHIC NOT AVAILABLE IN TIFF FORMAT]3839        Available via the World Wide Web: http://www.govinfo.gov4041                               __________4243                 U.S. GOVERNMENT PUBLISHING OFFICE4463-835 PDF              WASHINGTON : 202645=======================================================================4647                       SPECIAL COMMITTEE ON AGING4849                     RICK SCOTT, Florida, Chairman5051DAVE McCORMICK, Pennsylvania         KIRSTEN E. GILLIBRAND, New York52JIM JUSTICE, West Virginia           ELIZABETH WARREN, Massachusetts53TOMMY TUBERVILLE, Alabama            MARK KELLY, Arizona54RON JOHNSON, Wisconsin               RAPHAEL WARNOCK, Georgia55ASHLEY MOODY, Florida                ANDY KIM, New Jersey56JON HUSTED, Ohio                     ANGELA ALSOBROOKS, Maryland57                              ----------58                McKinley Lewis, Majority Staff Director59                Claire Descamps, Minority Staff Director6061                        C  O  N  T  E  N  T  S6263                              ----------6465                                                                   Page6667Opening Statement of Senator Rick Scott, Chairman................     168Opening Statement of Senator Kirsten E. Gillibrand, Ranking69  Member.........................................................     27071                           PANEL OF WITNESSES7273Annie Kennedy, Chief Mission Officer, Everylife Foundation for74  Rare Diseases, Washington, D.C.................................     475Jeremy Schmahmann, MD, Director, Massachusetts General Hospital76  Ataxia Center, Boston, Massachusetts...........................     677Bradley Campbell, President and CEO, Amicus Therapeutics,78  Princeton, New Jersey..........................................     879Cara O'Neill, MD, FAAP, Chief Science Officer, Co-Founder, Cure80  Sanfilippo Foundation, Columbia, South Carolina................    108182                                APPENDIX83                      Prepared Witness Statements8485Annie Kennedy, Chief Mission Officer, Everylife Foundation for86  Rare Diseases, Washington, D.C.................................    3487Jeremy Schmahmann, MD, Director, Massachusetts General Hospital88  Ataxia Center, Boston, Massachusetts...........................    4189Bradley Campbell, President and CEO, Amicus Therapeutics,90  Princeton, New Jersey..........................................    4591Cara O'Neill, MD, FAAP, Chief Science Officer, Co-Founder, Cure92  Sanfilippo Foundation, Columbia, South Carolina................    519394                        Questions for the Record9596Annie Kennedy, Chief Mission Officer, Everylife Foundation for97  Rare Diseases, Washington, D.C.................................    9398Bradley Campbell, President and CEO, Amicus Therapeutics,99  Princeton, New Jersey..........................................    96100101                       Statements for the Record102103ALS Association Statement........................................   101104Huntington's Disease Society of America Statement................   103105Jeremy D. Schmahmann, M.D., Statement............................   115106Little Hercules Foundation Statement.............................   165107Individuals with Rare Diseases' Statements for the Record........   169108Taxpayer Protection Alliance Statement...........................   452109110                      FROM REGULATOR TO ROADBLOCK:111                          HOW FDA BUREAUCRACY112                           STIFLES INNOVATION113114                              ----------115116                      Thursday, February 26, 2026117118                                        U.S. Senate119                                 Special Committee on Aging120                                                    Washington, DC.121    The Committee met, pursuant to notice, at 9:35 a.m., Room122216, Hart Senate Office Building, Hon. Rick Scott, Chairman of123the Committee, presiding.124    Present: Senator Scott, McCormick, Johnson, Moody,125Gillibrand, Kim, and Alsobrooks.126127                 OPENING STATEMENT OF SENATOR128                      RICK SCOTT, CHAIRMAN129130    The Chairman. Good morning. The U.S. Special Committee on131Aging will now come to order. Today we are here to ask a simple132but important question, is the FDA doing everything Congress133intended it to do to quickly get safe, effective treatments to134patients with rare diseases who cannot afford to wait?135    For more than 30 million Americans living with a rare136disease, making sacrifices every day is just a part of life,137but something they cannot afford to give up is time. Time means138the ability to walk. Time means independence. Time means being139able to speak, eat, or even recognize a loved one, and too140often, time is exactly what patients lose while therapy sit in141regulatory limbo. Growing up, I saw firsthand how a rare142disease can affect a family. My family didn't have health143insurance, and my brother had a rare hip disease. My mom had to144drive 200 miles round trip just so he could get the care he145needed. She made that sacrifice because care couldn't wait.146    My brother couldn't afford to sacrifice time. Congress has147been clear. On an overwhelmingly bipartisan basis we have given148the FDA flexibility to move faster for patients with serious149and life-threatening conditions.150    In 2016, Congress passed the 21st Century Cures Act. In151that bill and other bills that followed, Congress gave152direction to the FDA, encouraged the use of real-world153evidence, highlighting that rare disease drug development154requires adaptability and urgency.155    These laws are meant to help cut through bureaucratic156delays and give patients access to the care and cures they so157desperately need. Yet here we are, 10 years later, hearing from158patients, physicians, and drug developers that the system is159not working as Congress intended.160    I have heard from Commissioner Makary that he is working161hard to fix longstanding problems at the FDA and I want to162thank him for the work he is doing to try and make a strained163system work better for patients. However, advocates here today164will describe inconsistent review practices, shifting165standards, and redundant, often late appearing data requests166that in many cases may not be driven by safety concerns but by167an overly cautious and rigid approach that puts bureaucratic168processes ahead of patients.169    As we will hear, the human cost of this regulatory slow170walking is real. Many of the patients affected by these delays171have no other treatment options. Patients from every State come172and talk to our offices, and I am sure the same thing with the173Ranking Member, sharing their irreversible declines in health174that happen while they or someone they care about waits for a175treatment that might never come.176    It is heartbreaking to hear from families who are left177watching their loved ones deteriorate, while promising178therapies remain stuck in review. Meanwhile, small biotech179companies struggle to survive years of uncertainty, even when180their science is sound. Beyond individual patients, there are181serious national security consequences that come with the FDA's182inaction and delays.183    Our adversaries have been accelerating their drug184development and approval, attracting investment, talent, and185clinical trials. FDA inaction here at home creates an economic186and national competitive issue. Let me be clear, this hearing187is not about weakening safety standards. Safety must always188come first, but safety and speed are not mutually exclusive.189    A system can protect patients while still acting with190urgency, transparency, and common sense. Some of you may be191asking why the Senate Aging Committee is tackling this issue192when so many of those impacted by issues with rare disease193treatments are young. Here is why. Part of caring for America's194aging population is making sure that more Americans are given195the opportunity to grow old.196    It may sound cliche, but we are all aging. If something is197standing in the way of a younger American making it to their198senior years, it is absolutely the business of this Committee199and something we need to try and fix. It is my hope that200today's hearing will serve as a useful tool to help us201understand what we can do to bring accountability,202transparency, and efficiency to the process.203    We are joined by an incredible panel of witnesses here204today representing a wide range of perspectives, but all205working toward a better future for people living with rare206diseases. Now, we have a lot of members in the crowd that are207here because rare disease drugs are very important to them, and208I want to thank everybody for being here. Now, I would like to209recognize Ranking Member Gillibrand for her opening statement.210211                 OPENING STATEMENT OF SENATOR212             KIRSTEN E. GILLIBRAND, RANKING MEMBER213214    Senator Gillibrand. Thank you, Chairman Scott. I really215appreciate you calling today's hearing. Thank you to our216witnesses and the advocates who are here for Rare Disease Day217on the Hill. It makes a big difference that you come together218to make sure your loved ones are being heard and that the219challenges and struggles that you go through as families and220supporters are being understood by lawmakers.221    Every one of us in this room today knows that when we have222a friend, or a loved one, or a family member who has a rare223disease, that the most important thing is finding a cure,224getting the treatment, and making sure they survive. A disease225is considered rare if it affects fewer than 200,000 people, but226rare diseases actually aren't that rare. One in ten Americans227is living with a rare disease.228    As you know, many of these patients face substantial unmet229medical needs. Because it can be really difficult and expensive230for companies to develop these treatments and the FDA to231evaluate them, Congress has provided the agency with232significant regulatory flexibility to encourage both biotech233innovation and rare disease therapies.234    These include authorizing the accelerated approval pathway235to speed up the drug review, establishing programs like the236Rare Disease Endpoint Advancement Pilot to bolster novel237endpoint development, and strengthening and expanding the use238of patient experience data and real-world evidence in drug239reviews.240    These mechanisms are designed to help improve access to241novel treatments for our patients, and they are supposed to242provide drug sponsors with a predictable and consistent243approach to addressing regulatory science challenges that are244unique in rare disease therapy development and review, like245designing complex clinical trials, developing appropriate246endpoints, and using real world evidence, but it is not working247how it should be. FDA's approach, transparency, and flexibility248varies widely between its offices, divisions, and centers. I249have seen a pattern of hesitation to use authorized250flexibilities, limited communication with drug sponsors,251failure to incorporate patient experience in real world252evidence reviews, and FDA shifting its regulatory position on253trial design at the last minute, rejecting drug applications,254and requiring new clinical trials the sponsor may be unable to255perform. This is heartbreaking for patients, and it is why we256can't afford delays and disruptions in treatment.257    Rare diseases can progress rapidly, cause irreversible258harm, and in some cases premature death. This is also259frustrating for drug sponsors who face increased costs and260delayed timelines that impact the viability of their clinical261trials, particularly in the United States. Uncertainty shapes262behavior across the biotech ecosystem.263    Without consistency and predictability, drug sponsors will264continue to struggle with seeking FDA approval and will take265their clinical trials elsewhere, like to China. This is bad for266business, and it is bad for patients. If we want the U.S. to267remain the global leader in biotech and we want American268patients to have access to these novel treatments, things need269to change.270    Congress must hold the FDA accountable. We must make sure271FDA fixes its inconsistent and unpredictable application of272regulatory flexibility. It is essential for supporting273innovation, while upholding the highest standard for safety and274efficacy, in the approval of these rare disease drugs.275    FDA appears to be moving in the right direction. With the276rare disease evidence principles, the rare disease innovation277hub, proposing new pathways for approval and trying to hire278more reviewers, but it doesn't matter what agency leadership279puts in a press release. It is about execution and280implementation across all levels of that agency. Consistency281from top to bottom.282    Congress will ensure that happens by conducting oversight,283encouraging application of authorized flexibilities, and284providing adequate resources to restore agency capacity. I look285forward to hearing from our witnesses and working with this286committee to hold the FDA accountable because rare disease287patients cannot wait.288    The Chairman. Thank you, Ranking Member. I would like to289welcome our witnesses, experts who are here to talk about how290serious this issue is and the steps we can take to ensure291patients with rare diseases are not left behind by regulatory292delay. First, I want to recognize Annie Kennedy, Chief Mission293Officer at the EveryLife Foundation for Rare Diseases.294    Ms. Kennedy is a nationally recognized leader in rare295disease policy and patient advocacy and works directly with296patients, caregivers, and families navigating the drug297development and approval process.298    EveryLife represents the voices of rare disease communities299across the country, and has long advocated for patients300centered policies, regulatory flexibility, and timely access to301life-saving therapies. Thank you for being here, and please302begin your testimony.303304           STATEMENT OF ANNIE KENNEDY, CHIEF MISSION305306               OFFICER, EVERYLIFE FOUNDATION FOR307308                RARE DISEASES, WASHINGTON, D.C.309310    Ms. Kennedy. Thank you, Chairman Scott, Ranking Member311Gillibrand, and distinguished members of the Committee for312convening this critical hearing. I am Annie Kennedy, Chief313Mission Officer for the EveryLife Foundation for Rare Diseases.314I am honored to be here alongside the hundreds of advocates who315have joined us for Rare Disease Week on Capitol Hill.316    Collectively, we are representing the more than 30 million317Americans living with rare diseases. Today, there are more than31810,000 known rare diseases, about 70 percent of which start in319childhood. For small patient communities facing progressive320diseases, time is a commodity.321    Traditional large placebo-controlled trials are often322neither feasible nor ethical when considering the challenges323and urgency of rare diseases. Beginning with the passage of the324Orphan Drug Act in 1983, your leadership has provided tools325that have rocketed the U.S. into the most competitive developer326of rare disease products. Each landmark law since has reshaped327our landscape.328    In fact, tomorrow marks an anniversary of another watershed329moment for our community here on Capitol Hill. The MD Care Act330hearing convened in this exact same hearing room, presided over331by Senator Arlen Specter, included a 13-year-old named Benjamin332Cumbo. Twenty-five years ago, I watched with great pride as Ben333asked Congress for actions that could help cure him and his334friends so that he could achieve his dreams of growing up,335having a girlfriend, and serving his country.336    Congress did respond. In that time, Congress has built a337framework that incentivizes rare product development,338authorizes regulatory flexibility, creates new pathways to339approval, and embeds patient experience into review. While340fewer than five percent of rare diseases currently have an FDA341approved treatment, nearly 1,400 orphan-designated therapies342are now changing the lives of patients and families.343    Recently, this momentum has shifted. We are here today344because our community has experienced worrisome trends with345devastating consequences. While we are heartened by recent346announcements of therapy development initiatives, such as the347Rare Disease Evidence Principles Framework and the Plausible348Mechanism Pathway and are eager to work with the agency on349their implementation, our rare disease community has350experienced a series of product application actions that seem351misaligned with these recent public pledges to expand the use352of regulatory flexibility.353    Since the start of 2025, we have seen at least 23 complete354response letters declining to approve rare disease therapies,355many under accelerated approval, that suggest a hesitation to356apply regulatory flexibility through surrogate endpoints,357natural history studies, and external controls.358    At that same time, advisory committee meetings for drugs359and biologics declined by 65 percent compared to 2024, reducing360opportunities for external expertise and patient insights to361inform complex rare disease product decisions. We asked362families who would been personally affected by recent363regulatory decisions to reflect on their impact. These stories364will be shared for the record. Story after story spoke to365chilling consequences of recent regulatory delays and clinical366trial hurdles.367    As one mom shared about her son, Stone. My son is now368receiving this experimental treatment, and he is thriving. For369the first time since his diagnosis, his doctors have told us,370with this treatment, a near normal lifespan is within reach for371a disease that once came with a teenage expiration date that is372nothing short of extraordinary. We are now living in fear, not373because science failed, not because companies stopped fighting374rare diseases, but because of regulatory inconsistency.375    We are here today because congressional action is needed to376ensure that this generation of patients will benefit from our377existing rare disease treatment pipelines. We ask that Congress378engage FDA to clarify its approach to accelerated approval for379rare diseases, its consistent application of regulatory380flexibility, and to urge the resumption of advisory committee381meetings so that external expertise informs complex reviews.382    We also urge Congress to resource the Rare Disease383Innovation Hub to strengthen cross center coordination and to384establish the Rare Disease and Condition Advisory Committee and385a science focused drug development initiative. In closing, 25386years ago, I stood in this room filled with rare families.387    Today, advances in science have put life-altering388treatments within reach for many, but those advances were not389in time for those who were in this with me 25 years ago. While390Ben achieved many of his dreams, he died two days before391receiving his master's degree. We now have the opportunity to392ensure that this generation of rare disease patients will393benefit from today's therapy development pipelines.394    Each time a promising therapy faces delays or demise,395investment wanes, future scientific promise is unfulfilled, and396lives are lost. Time is the most precious commodity for our397rare disease community.398    As Stone's mom implored while writing from his hospital399bedside, we are closer than ever to rewriting the future of400these diseases. Please don't let my generation become the next401group of mothers who stand at gravesides instead of402graduations. Thank you.403    The Chairman. Thank you. Thank you, Ms. Kennedy. Now, I404would like to introduce Dr. Jeremy Schmahmann, Professor of405Neurology at Harvard Medical School, Founding Director of the406Ataxia Center at Massachusetts General Hospital, and Principal407Investigator for the Laboratory for Neuroanatomy. I said that408correct, right?409    He is a leading neurologist who treats patients with410progressive and neurodegenerative diseases where time and411access to treatment are critical. He has seen firsthand the412consequences of delayed access to care and the irreversible413loss patients can experience while waiting for regulatory414decisions.415    His testimony will round today's discussion and the real-416world clinical impact these regulatory delays have on patients417and families. Thank you for being here. Please begin your418testimony.419420         STATEMENT OF JEREMY SCHMAHMANN, MD, DIRECTOR,421422             MASSACHUSETTS GENERAL HOSPITAL ATAXIA423424                 CENTER, BOSTON, MASSACHUSETTS425426    Dr. Schmahmann. Chairman Scott, Ranking Member Gillibrand,427members of the Committee, thank you for convening this hearing,428and for the opportunity to testify, and for your remarkable429opening statements.430    My name is Jeremy Schmahmann. I am the Martha and Robert431Fogelman Chair in Ataxia, and Cerebellar Neurology at432Massachusetts General Hospital, and Professor of Neurology at433Harvard Medical School. I started the first Ataxia Center in434the country, and I have cared for patients with spinocerebellar435ataxias for 45 years.436    I am the site principal investigator for Biohaven's study437of troriluzole in ataxia and my comments today reflect my438personal and professional opinion, not necessarily that of my439employer.440    Senators, please help us fix the FDA. It has rejected441troriluzole, a drug that is safe--the first treatment to442improve quality of life and slow progression in spinocerebellar443ataxia. My patient Steve, for example, developed444spinocerebellar ataxia type 3, also known as Machado-Joseph445disease, in his late 30's.446    Like his mother before him, he will become increasingly447disabled, will need to use a wheelchair, become bedridden, and448die young, but since starting troriluzole a year ago, he has449not changed. Mary, in her late 40's, has type two. After six450and a half years on troriluzole, she has not change.451    These inherited neurodegenerative diseases worsen452inexorably and in this business, staying the same is success.453Like other rare diseases, ataxia is difficult to study,454deteriorates slowly, and manifests differently even within455families. There are 15,000 ataxic patients in America. Some456affect hundreds of people, some just a few.457    Now, Congress, as you have told us, recognized these458challenges and passed legislation mandating that FDA use459regulatory flexibility and real-world evidence in rare diseases460like ataxia. The drug riluzole, used to treat ALS for 50 years,461was reported to improve ataxia.462    Based on this, and the plausible mechanism of action in463spinocerebellar ataxia, Biohaven developed troriluzole, which464metabolizes into riluzole, but is taken once a day with better465brain penetration and fewer side effects. Early in the drug's466development, an ataxic patient who stopped treatment after a467year of open label therapy insisted they go back on troriluzole468because they told us their condition worsened after stopping469the drug.470    Biohaven, to their credit, provided troriluzole to these471patients and ran a one-year, double-blind placebo-controlled472study. Patients with spinocerebellar ataxia type three improved473compared to placebo. They were falling less, and they had fewer474injuries. Biohaven requested approval of troriluzole for475spinocerebellar ataxia type three based on these results.476    The FDA refused to review the new drug application.477Biohaven obtained FDA feedback and used a revised protocol to478follow patients on drug for another three years, comparing them479with patients in two natural history studies. In this real-480world evidence study, troriluzole showed significant481improvement across nine pre-specified FDA endpoints, slowing482disease by 50 to 70 percent.483    This is a dramatic result that was supported by patient and484physician feedback. We were all shocked when FDA denied485approval of this safe drug that makes people better. I wrote486six letters to FDA leadership between 2023 and 2025, co-signed487by 17 ataxia colleagues, asking FDA to review the application488again and work with Biohaven to make the drug available, if489necessary performing post-marketing studies. I never heard490back.491    Now, 300 patients, stable on troriluzole, will have to come492off drug, and they are distraught. I met three times with FDA's493Center for Drug Evaluation and Research. On each occasion, they494did not heed the patients or the experts or considered the495science. One panel member said to me, why should I listen to496you?497    The FDA's proposed path forward is another placebo-498controlled trial that will take five to eight years, or a499randomized withdrawal of the drug from patients benefiting from500it. If this happens, patients on placebo will die. I believe501this to be unethical, lacking charity, mercy, or kindness.502    Senators, please, save our patients' lives. Use your503authority to require that FDA consider real-world evidence and504applies the regulatory flexibility you have legislated, and in505so doing restore transparency, integrity, and competence to the506agency. Thank you.507    The Chairman. Now, I would like to recognize Ranking Member508Gillibrand to introduce our next witnesses.509    Senator Gillibrand. Thank you, Mr. Chairman. I want to510introduce our next witness, Bradley Campbell. Mr. Campbell is511the President and CEO of Amicus Therapeutics, a biotechnology512company focused on discovering and developing new medicines for513people living with rare diseases.514    During his tenure at Amicus, he led the global515commercialization of Galafold, a medication used to treat Fabry516disease in adults, which was approved by the U.S. Food and Drug517Administration on an accelerated basis. Mr. Campbell brings518over 20 years of experience in the rare and orphan disease519fields. You may begin your testimony.520521       STATEMENT OF BRADLEY CAMPBELL, PRESIDENT AND CEO,522           AMICUS THERAPEUTICS, PRINCETON, NEW JERSEY523524    Mr. Campbell. Thank you very much, Chairman Scott, Ranking525Member Gillibrand, the rest of the Senators on the Committee.526It is my privilege to be here today to speak to you about our527experience in developing drugs for people living with rare528diseases. I am also honored to be alongside my fellow529panelists.530    I feel far less qualified than they to speak today, but I531hope I can share some perspectives on the challenges and532opportunities we have to help fix the system. I have had the533privilege to work at Amicus for the last 20 years and have534dedicated most of my professional career to developing new535treatments for people living with rare diseases.536    I thought I could begin with a patient story that I think537captures the spirit of the testimony here today and the538conversation we are having. At a recent patient meeting, we539were discussing patient experience data and how we might make540endpoints for clinical trials more meaningful for patients.541    During a break, a young woman with Pompe disease took me542aside and said, what would be most meaningful for her is if she543could breathe on her own for just one minute. That would make544the difference between her life and her death. This is not an545approvable endpoint in Pompe disease, of course, but she546depends upon a mechanical ventilator to breathe.547    If that ventilator fails, if the battery dies, if an aid548fails to clear a mucus plug, just that 60 seconds of her own549breath could make the different between her life and death. I550think that comment is a very powerful reminder of why patients551and caregivers must help us design better clinical studies with552real endpoints that make a difference for them.553    We can't ask patients to wait for years before approved554treatments come when the difference between life and death can555be that single breath. I think the rare disease innovation556ecosystem in the United States has made enormous progress over557the last 20 years, but it must now again adapt in speed,558agility, and flexibility to keep the pace of innovation.559    One of our own development experiences at Amicus I think560sheds light on how regulatory flexibility and working together561with sponsors and regulators can make a real difference in drug562development. When we were developing our medicine Galafold for563Fabry disease, we learned in early studies that in some564patients the drug worked and some patients it didn't.565    Through careful data analysis and close collaboration with566the FDA and regulators around the world, we developed an assay567that could identify which of the thousands of genetic variants568that cause Fabry disease might best respond to the therapy, and569just as importantly, which ones may not.570    The FDA ultimately incorporated that assay into our label571and approved the first ever oral precision medicine for people572living with Fabry disease. What does that mean? That means when573sponsors and regulators work together, the result was an oral574treatment option that has saved thousands of patients' years of575biweekly infusions.576    We know rare diseases are biologically complex. We know577they are difficult to study. As we sit here today, 95 percent578of the more than 10,000 known rare diseases lack an FDA-579approved treatment. I think that is statistic many of us are580familiar with, but if you fast forward that pace of581development, it will take us 150 years to only treat half of582the remaining rare diseases.583    Small and mid-sized biotechnology companies like Amicus,584Biohaven, and others are the engine of rare disease innovation,585but they can only succeed if the regulatory system adapts along586with unmet medical need. I think there are three practical587areas that we can work together to improve that very system.588    First, we must start clinical trials faster. We know in589other countries, those trials start in weeks, not months. We590can reduce administrative requirements, leverage single IRBs,591use AI and other digital tools to get into the clinic faster.592We also must find better ways to measure efficacy. We can use593biomarkers, innovative endpoints, accelerated approvals.594    These are things the FDA has at its disposal right now, but595we must use them more and we can make manufacturing inspections596and rules work better. The single biggest delay oftentimes is597inspections for getting patients access to medicines.598    The FDA has tools like remote interactive inspections and599relying on global regulators to reduce that inefficiency and600let me close with just one final story. At a patient meeting601last year, a man with Fabry disease told us when he was602diagnosed in his 30's, he stopped saving for retirement because603he thought there was no reason to think he could live that604long. Fast forward 15 years, Fabry disease is now a treatable605disease.606    Advancement in treatments have changed that trajectory and607for the first time he is thinking about a future he thought he608would never have. I look forward to working together with the609members of this Committee, and indeed with the regulators, the610broad community here focused on rare diseases to find ways to611ensure that we have a flexible, adaptable, agile regulatory612system that can keep pace with modern innovation.613    Thanks so much for the opportunity to testify and I look614forward to taking your questions.615    Senator Gillibrand. Thank you, Mr. Campbell. I want to move616to introduce our next witness, Dr. Cara O'Neill. Dr. O'Neill is617the Co-Founder and Chief Science Officer at the Cure618Sanfilippo--the Cure Sanfilippo Foundation, dedicated to619accelerating scientific development on disease and empowering620families with the resources they need to navigate their621journey.622    Dr. O'Neill founded the foundation after receiving her623daughter, Eliza, Sanfilippo's diagnosis in 2013. At the624foundation, Dr. O'Neill leads patient focused research efforts625and awareness, working to bridge the gap between scientists,626clinicians, industry, and family.627    She was awarded the International 2020 Patient Advocacy628Leader Award by World Symposium for exceptional contributions.629You may begin your testimony.630631           STATEMENT OF CARA O'NEILL, MD, FAAP, CHIEF632633          SCIENCE OFFICER, CO-FOUNDER, CURE SANFILIPPO634635              FOUNDATION, COLUMBIA, SOUTH CAROLINA636637    Dr. O'Neill. Thank you, Chairman Scott, Ranking Member638Gillibrand, and members of the Committee. On behalf of 15639million children with rare diseases in this country, I thank640you truly for your concern.641    I am Cara O'Neill, Chief Science Officer at Cure Sanfilippo642Foundation, a Pediatrician, and mom to Eliza who has an ultra-643rare genetic disease called Sanfilippo Syndrome, or MPS3, one644of many forms of childhood dementia leading to progressive,645irreversible brain damage. I would like to first acknowledge646the critical public service of FDA and its staff who shoulder647complex and heavy workloads every day.648    We know the pressures are significant because we feel it649too. Of late, we have seen many press releases highlighting new650FDA policies and programs, which encourage us to look out into651the future with hope, but today, the Committee has called us652here with the recognition that current regulatory barriers are653significantly impacting patients right now, and never more654starkly than for degenerative conditions where time is the most655crucial factor and where every regulatory flexibility must be656leveraged to meet this uniquely urgent need.657    We can see this illustrated in a story of three girls with658the same deadly disease, but very different lives. Isabelle, or659Izzy, was the first child with Sanfilippo that my husband and I660met after our own daughter Eliza's diagnosis. Izzy was just 11,661and the disease had already taken a tremendous toll. She could662no longer walk independently, taking only a few steps if her663mom held most of her weight.664    Izzy had lost the ability to speak years before and could665no longer eat or drink without choking, so relied on a feeding666tube. She had seizures and increasingly severe abnormal667movements that twisted her arms and legs into painful668positions.669    During one visit, Izzy's mom shared that she had come to670accept this disease would take her daughter's life, but what671she said next has always stuck with me. She said, in truth, I672fear her suffering more than I fear death. At that time, my673Eliza was close to four and in an extremely hyperactive stage674of the disease, but she sang and talked with us. She played675dress up and clapped around the house in my high heels. She676rode her tricycle everywhere. She looked so healthy, but what677was going on inside her body and brain was a much different678picture.679    Meeting Izzy put us face to face with Eliza's future, the680concrete and cruel reality of what this disease would do. A681medicine didn't come in time for Izzy. She suffered greatly and682passed away just a few weeks before her 15th birthday. For683decades, we have known the cause of this disease. We can684precisely measure the levels of toxic biomarker to determine685whether a treatment is working and now we have the science to686treat it.687    Thanks to NIH funding and support from nonprofit688foundations, including our own, a promising gene therapy was689developed and propelled toward clinical trial at nationwide690Children's Hospital in Ohio. While we anxiously were awaiting691news the trial will begin, back at home we watched Eliza's692sentences becoming shorter, her words less frequent. She became693agitated and hardly slept.694    The disease was taking hold. Two years later, in May 2016,695the clinical trial finally began and Eliza, then six and a696half, was so very lucky to be the first child to receive that697gene therapy. It was her chance at a life different from698Izzy's--a chance to grow up. Now at 16, it is clear that699therapy changed her life. She surpassed average life700expectancy, runs on the beach, plays in the water, uses picture701cards to tell us how she is feeling and what show she wants to702watch on TV. She can feed herself and goes to school every day.703    These are simple but incredibly meaningful abilities that704have a huge impact on her daily life, and children treated with705higher doses earlier in life have even more remarkable706outcomes. Like Caroline, who is now 10. She can read, play on a707softball team, and learn to ski on her recent family vacation.708    Despite these breakthroughs and nearly 10 years after the709trial began, families outside the trial are still waiting for710access. Why? Because last summer the drug was denied approval,711not because of safety or how the children were benefiting, but712for questions about manufacturing.713    While this is an important issue, FDA could have used its714flexibility to continue reviewing the application while715addressing questions in parallel. You see, early on, trial data716confirmed the drug's mechanism was more than just plausible, it717was biologically effective, showing significant reduction of718toxic biomarker within just six months after treatment in all719the children.720    Granting accelerated approval based on this biomarker would721have brought treatment access to children years earlier,722preventing further brain damage and changing the lives of so723many children, like Sadie, who is here today--who is still724waiting. This same drug application was recently resubmitted,725but FDA issued another denial asking for yet more paperwork726before agreeing to review it again.727    Congress has given FDA the tools of flexibility it needs to728accelerate approvals for these devastating diseases, but sadly729flexibility and speed are not actually what most rare disease730patients are witnessing.731    Transformative therapies are at FDA's doorstep and so, with732great respect, families are pleading for FDA to unlock the door733and move with urgency so that our children can have a chance at734the life they deserve. Thank you.735    The Chairman. Thank you for your testimony. Thank you, Mr.736Campbell, for your testimony. Now we will go to questions.737Senator Johnson.738    Senator Johnson. Thank you, Mr. Chairman. Again, I have to739commend you for another excellent hearing here. At the start of740the hearing, I received a text from Laura McLinn, who reminds741me that 10 years to this day, as Chairman of Homeland Security742I held a hearing titled, Connecting Patients to New and743Potential Life Saving Treatments. Her son, Jordan, who suffered744from Duchenne Muscular Dystrophy testified at hearing--was745certainly present there.746    Two years later, that resulted in Right to Try, which was747not easy to pass. I had to hold up the FDA user fee bill, had748to water down Right to Try quite a bit to make sure that Big749Pharma wouldn't sabotage it. They did sabotage it over in the750House, but because of President Trump's leadership, he forced751the House to pass the Senate version. Its main benefit is its752name. It is very limited in its application, unfortunately.753    People have the right to try. Laura has also begged me,754begged me in a text to mention Ataluren and Deramiocel, two755investigatory drugs that are also being held up by the FDA for756Duchenne Muscular Dystrophy. I think we probably are going to757need another piece of legislation, probably Right to Try 2.0--758something that is going to be far more effective than the759current Right to Try, but I will tell you, reading this760testimony this morning, you can maybe tell just by my passion,761it enraged me.762    It enraged me that these families, these patients are being763denied effective treatments because of the regulatory764roadblocks. Quick story and again, I want to ask questions, but765a quick story. After I met the Duchenne Muscular Dystrophy766community, they went up before a panel of FDA--this was767probably in 2016, 1917, or 1918--begging. There are about 60768Duchenne Muscular patients' families begging the FDA, please769approve this investigatory drug for our children.770    Again, time is muscle, time is brain and that panel, I771don't know who sat on it, listened to those 60 families begging772them and said no, just like they said no--and I can't even773pronounce these diseases and drugs. They say no time and time774and time again. That has to change. Congress is directing the775FDA, be more flexible--say yes.776    You know, these patients understand the risks. They ought777to have the right to try. Dr. Schmahmann--am I pronouncing that778right?779    Dr. Schmahmann. Yes, sir.780    Senator Johnson. I don't want you throwing anybody under781the bus because I don't want this to impact future approvals782but describe your meetings with CDER. To me, it is shocking to783have one of those members of that panel say, why should we784listen to you? Well, because you are a doctor at Harvard.785    You are treating patients. You are having success. You are786giving them a new lease on life, and you have got bureaucrats787inside these agencies saying, why the hell should we listen to788you? I want you going into greater detail--describe what those789meetings are like.790    Dr. Schmahmann. Thank you, Senator. We have heard a few791words a few times. Heartbreaking as the experience of patients792and families going through this and the compassion that is793required.794    I saw none of that in the three meetings with the FDA. The795members of the panel were like talking to a brick wall. There796was no engagement, no dialog. In fact, they said as much, this797is not a dialog, this is not a collaboration. They do not seem798to see the suffering of the patients, and they didn't hear the799science.800    They were rigid and inflexible and unyielding. The FDA801worked with the company initially, but then they changed their802mind later, and so, as the studies unfolded, everything came to803a grinding halt. This drug in particular is safe. It804metabolizes into a drug that has been there for 30 years in the805market and is safe. Patients say it works. The doctors say it806works. The study shows it works.807    The double-blind first study showed it worked. The real-808world evidence shows it works. Patients behind me, every one of809them, talking to them yesterday, say it works. This drug works.810    To paraphrase the Senator, what is their problem? My811experience of the people on that panel, three times, as a812private citizen coming for the first time to the FDA, was813deeply distressing.814    Senator Johnson. I have already texted Dr. Tracy Beth Hoeg815and told her I have read your testimony. I will be sending her816your testimony. I hope she listens to this. If I could just817take a couple more minutes, Dr. O'Neill, you are obviously818personally impacted by this.819    Can you describe any meetings you have had similar to what820we just heard? Again, the American people need to understand821what these regulators are doing and not doing. Dr. O'Neill.822    Dr. O'Neill. Thank you. You know, I will say that my823interactions with regulators have been kind, so maybe a bit of824a different perspective is they have listened. They have been825interested to hear what we had to say. To hear the patient826perspective. I think where we are challenged is that we don't827see that translated into regulatory action.828    Some of the decisions that are coming out are not829benefiting patients right now. Listening is great, but two-way830conversation and collaboration is actually what is needed, and831greater transparency in how patient experience data and patient832input is actually being integrated into these decisions.833    Senator Johnson. My guess is that panel for Duchenne834Muscular Dystrophy back in 2017 or whatever probably listened835very nicely to the families, but they still said no. That is an836unacceptable answer.837    Again, you have my commitment. I am going to delve into838this. We are going to right these wrongs. Thank you. Mr.839Chairman, this is again an excellent hearing. We have got to840followup on this. This is just completely unacceptable. Thank841you842    The Chairman. Thank you, Senator Johnson. Senator843Alsobrooks.844    Senator Alsobrooks. Thank you so much, Chair Scott. Also845Ranking Member Gillibrand. I am so grateful to be here today846joined by so many patient advocates, caregivers, family847members.848    I have heard from many Marylanders living with rare849diseases and from their families, including dozens who have850visited my office this week to share their priorities and their851concerns. As I underscored with the NIH Director a few weeks852ago, patients suffering from devastating diseases do not have853time to wait for needless delays to critical cures. For854Marylanders with rare diseases, delayed access is not just an855inconvenience, it is a matter of life or death.856    For many with rare conditions, clinical trials are their857last and best hope. These patients also depend on a regulatory858process that is science driven and capable of turning research859into real treatment. Instead of strengthening those860foundations, this Administration is constantly disrupting861clinical trials, slowing innovation, and undermining the862pipeline to cures.863    Scientific integrity should always guide decision-making,864and we must protect the firewall between the Food and Drug865Administration and political influence. President Trump and866Secretary Kennedy continue to decimate critical parts of that867system. The instability they have caused ripples across868families, physicians, researchers, and innovators, and patients869pay the price.870    Ms. Kennedy, I would like to ask, over the past two weeks,871we saw a striking example of political interference at the FDA872involving a seasonal mRNA flu vaccine from Moderna. The agency873first declined even to review the application, then reversed874course just one week later after revised regulatory approach.875    The abrupt change raised serious concerns about876transparency, predictability, and political influence in what877should be a scientific process. An episode many have described878as regulatory whiplash. What does that kind of volatility879signal about how the FDA is functioning right now, and why does880that matter for rare disease reviews that depend on regulatory881consistency?882    Ms. Kennedy. First of all, thank you so much, Senator, for883being here and for all of you being here today, and for this884important issue. I think first it is important to say that I am885not an expert in vaccines, and I am here really to focus on886rare disease, but I appreciate the question really asking about887the trends that we are seeing and us being here really trying888to follow the trends and understand what that means for rare889disease.890    I also agree with Dr. O'Neill that we have seen real891intention from career staff and staff scientists at FDA around892their engagement, but what we are concerned about is, to your893question, what seems to be reversals in decisions, where there894had been previous agreement, previous work with sponsors that895was directing sponsors to move in one direction, and then896regulatory decisions seemed to be yielding different decisions897at this point.898    As I stated in my testimony, we have seen recently 23899complete response letters issued in rare diseases that are900delaying access to the patient community and having devastating901consequences to our community. Many of those actually are902decisions that are reversals in regulatory agreements that have903been made previously.904    Additionally, we are very concerned that previously, if905there were to be a complex decision that needed to be worked906through between a sponsor and the agency, an advisory committee907would have been convened, and we have seen 65 fewer advisory908committees convened in 2025 than 2024.909    In fact, none since July. We are very concerned that the910regulatory tools that are at the disposal of the agency to911really work through some of these really complex decisions912aren't being utilized.913    Senator Alsobrooks. Thank you. Just very quickly, if I can914also go to Ms. O'Neill. Finding new cures doesn't happen915overnight, and it rarely happens in a single year.916    Breakthrough therapies are built over decades of careful917scientific work and discoveries, and NIH funded laboratories918form the foundation for treatments that later move into919clinical trials through regulatory review and ultimately into920patient care.921    When NIH research capacity is disrupted, as we have seen,922and weakened, how does that set back the search for new cures923long before therapies ever reach the FDA?924    Dr. O'Neill. Thank you for your question. The NIH is a925critical source of funding for innovation in this country and926scientific innovation. It is interesting that when there were927disruptions and uncertainty in the funding, we received a flood928of requests about funding from our small non-profit foundation.929I think non-profit foundations across the country were seeing930that and, you know, we are not equipped to take up all of the931pre-clinical and transformative science that NIH can do. The932role of the NIH in supporting innovation is huge.933    Senator Alsobrooks. Thank you.934    The Chairman. Thank you, Senator. Senator McCormick.935    Senator McCormick. Thank you, Mr. Chairman and thanks to936you and the Ranking Member for convening this and thank you all937so much for being here today to help bring some of these938critical issues to Americans and Pennsylvanians to light. Ms.939Kennedy, more than 30 million Americans live with rare940diseases, yet fewer than five percent have an approved941treatment.942    As you mentioned, since early 2025, the FDA has issued at943least 23 complete response letters for rare disease therapies,944while advisory committees use has declined dramatically. When945late-stage rare disease applications raise concerns, what946alternatives to issuing a complete response letter should the947FDA use, including advisory committees or structured post-948approval commitments, to resolve issues without restarting the949entire process?950    Ms. Kennedy. Thank you. We appreciate that question. FDA951has at its disposal, thanks to Congress, many types of952engagements between sponsors and the agency. Many of those have953been made possible thanks to the user fees.954    We are concerned that many of those meetings and meeting955types aren't occurring, and that the CRLs are being utilized as956a way to perhaps maybe even clear the docket or create delays.957There could be a lot of reasons why that might be happening,958but there are meeting types that have been implemented that959could enable engagement to answer questions that sponsors, and960the agency might have.961    We saw actually the agency deploy this during the pandemic,962the COVID pandemic, where we saw real rapid, real time963resolution to a crisis in our country and the agency was able964to interact with sponsors. Get questions answered in real time965and then we saw that CBER tried to operationalize that in other966places and spaces.967    We would really, as a rare disease community, like to see968that operationalized within rare disease because we believe969that our rare disease community has the urgency and unmet need970that matches that of a pandemic, of a crisis.971    We have individuals in this room who have very limited life972expectancies. If we don't address what is happening in rare973diseases with that same sense of urgency, they would not be974here with us if we were to convene this hearing another year975from now.976    Senator McCormick. Thank you. Thank you for highlighting977that urgency, and I think we feel it, and you are helping us to978feel it. Thank you for that. Mr. Campbell, just on the issue of979accelerating the process.980    I was taken by the fact in preparing for this that some981countries are moving much faster on rare disease therapies. The982European Union's FAST-EU program caps multinational clinical983trial authorization at 70 days. Australia allows many trials to984begin almost immediately after an ethics approval.985    What is going on here? What will happen if the United986States fails to keep pace? What policy changes should we987consider in the Congress, given what appears to be a much more988streamlined approach in other places?989    Mr. Campbell. Thank you, Senator. I completely agree. I990think, you know, the United States has been the beacon of991biotechnology innovation for so many decades, and it is part of992why we have more therapies approved today for rare diseases993than we did, you now, decades ago.994    I would acknowledge legislation like the Orphan Drug Act995that led to that. As we said in our testimony and many of the996panelists here today, we have now stopped keeping pace with997innovation and I think one exact point, which I raised in my998testimony as well, is speed to clinical trials. For me, on the999one hand it is time for patients, and taking weeks, 70 days,1000would be a remarkable number.1001    I think Congress could work with the FDA to pass1002legislation to encourage, again, centralized IRBs, leveraging1003digital technology and artificial intelligence to help us do1004that. Reducing regulatory requirements. For sure, those things1005could speed us into the clinic. The other piece, I think, which1006is sitting behind this is our national competitiveness and in1007some ways our national security.1008    When we think about Australia, we think of Europe,1009collaborative nations, etcetera--there are other nations out1010there that perhaps we see in a different way, and from my1011perspective, whether you think of that as a security threat or1012whether you think of that as a threat to getting drugs to1013patients, in either case, I think Congress can take a1014leadership role in helping the FDA to speed through that1015process.1016    Senator McCormick. Thank you all for being here.1017    The Chairman. Thank you, Senator McCormick. Senator Kim.1018    Senator Kim. Thank you, Chairman. Thank you to all of you1019coming out here. A couple words I just heard that I think1020really just hit the nail on the head. I would love your1021reactions to it. When we are talking about all the different1022problems that we are facing with the FDA, the bureaucracy or1023the workforce issues, I think the word that really hits it home1024is urgency.1025    I heard you use that. You know, I heard use that Ms.1026Kennedy. I feel like that is really what we are talking about1027here. Is like we need a government that is moving at the speed1028of urgency that the parents are trying to save their kids,1029right. Like, that we are struggling to understand what the1030actual purpose here is and the speed with which we need to1031move. Look, I got two boys. I got an eight-year-old and a ten-1032year-old. I would do anything for them, you know.1033    I just like, how do we translate that into the urgency of a1034government trying to be responsive? I think that is where some1035of the disconnect hits on so many levels. You know, Mr.1036Campbell, you talked about it. You used the word national1037security. I used to work in national security. I was in1038Afghanistan and Iraq and elsewhere.1039    I saw this government move with urgency when they felt like1040lives were on the line, but like, why is it that we can't1041necessarily translate that to another circumstance where there1042are millions of lives on the lines and people just don't have1043the time to wait for this? I think that that is really a1044purpose. How do we talk about this as a national security1045priority?1046    The same reason we are trying to save lives abroad is the1047same reasons we are trying to save the lives here at home. Does1048that make sense to you, Ms. Kennedy? Am I kind of grasping the1049crux here of what we are trying to push forward?1050    Ms. Kennedy. Yes, Senator, you absolutely are. Congress has1051recognized this urgency in statute and has enabled the use of1052regulatory flexibilities, and that is what is reflected in the1053accelerated approval pathway and the use of surrogate outcome1054measures and biomarkers in clinical trial design in rare1055disease.1056    What we are concerned about is that in many of these1057complete response letters, what we are seeing reflected is FDA,1058especially in one of the medical product centers, CBER, seems1059to be the trend that we are detecting backing away from a1060comfort level or use of the surrogate biomarkers.1061    What we have seen in rare disease is surrogates work.1062Surrogate biomarkers do save lives. We have more than 2501063products that have been approved through the accelerated1064approval pathway, but fewer than 20 percent of those are for1065the non-oncologic, non-infectious rare diseases.1066    Which means there is a distinction between what is1067happening in the rare community that is in this room and the1068broader rare community. It is really important when we look at1069those statistics that we sort of look at what the different1070medical product centers are comfortable with and are doing, and1071that is why we--we know that the tools are available. We want1072to ensure that they are being utilized.1073    Senator Kim. Mr. Campbell, I wanted to bring you in on this1074because, you know, you have talked about this at length. Build1075off of what we just heard. How would expand use of adaptive1076trial designs or surrogate endpoints by the FDA lend itself to1077achieving better outcomes when it comes to rare disease1078approvals?1079    Mr. Campbell. Yes, I think the first step is just use what1080we have available to us, right. If you look at oncology, I1081think in 2024, there were 8,000 different therapeutics in1082clinical trials that dwarfs the number in rare diseases today.1083    I think a large part of that is the much more welcoming use1084of accelerated approval and surrogate biomarkers. Our own1085product, Galafold, was approved on a surrogates biomarker. The1086competitor product also, Fabrazyme, was approved on a surrogate1087biomarker and these things work. I get it, you know, rare1088diseases are biologically complex.1089    It is very difficult to understand how long it is going to1090take. You can't do randomized control studies in the same way1091you can with broader disease populations. When it is done1092right, as in the case of Fabrazyme, 10 years later, after using1093real-world evidence and a registry, they are able to confirm1094the original surrogate endpoint, and now it is a fully approved1095product. For me, the tools are all there. It is really more, as1096we have discussed, consistency and using the tools that exist.1097If we were to--oh please, go ahead, Senator.1098    Senator Kim. I just want to jump in here at the end. I mean1099the urgency on the trials and moving up forward on the1100approvals, but Mr. Campbell, I also want to raise another1101issue, which is just how long it often takes to build1102manufacturing facilities here in the United States.1103    You know, the level of slowness with the inspections1104themselves. I want that urgency on a manufacturing side as1105well. You know, what can you be showing us about the1106decisionmakings that manufacturers are going through especially1107in terms of being able to build this and manufacture this here1108in America.1109    Mr. Campbell. Here at home. Thank you so much for the1110opportunity to address that, so just by background, Amicus, we1111work with external manufacturers. As a small cap company, we1112don't have the capital to build our own manufacturing1113facilities, and we certainly don't have an environment to be1114able to do that.1115    We work outside the United States. It takes three to five1116years to just to build a state-of-the-art manufacturing1117facility for protein therapeutics. It takes another one to two1118years then to get that facility inspected. You are talking five1119to seven years from when we want to do this to when it actually1120has medicine coming off the line for patients. In my mind, it1121is mutually beneficial to all of us, so create incentives--and1122they don't have to be financial incentives. Help with1123permitting. Help with inspections.1124    Give priority to inspections for homegrown manufacturing1125facilities. Create an environment that is actually supportive1126of bringing manufacturing at home, versus using, which is what1127we have seen over the last couple of years, more sticks to try1128to prevent--probably a more qualified person to speak to this,1129speaking in background. Let's use incentives instead of sticks1130to encourage that because I think the United States ecosystem,1131the patients, all benefit from doing that.1132    Senator Kim. Mr. Chair, you know, we have talked at length1133here in this Committee about the benefits on so many levels of1134having that manufacturing here in America, the speed with which1135we can move, the capabilities.1136    You know, these are some very concrete things that I hope1137we can followup on and really come up with a game plan here1138because it is just, honestly, it is just pathetic that we are1139just not able to do this with a greater level of speed given1140the skills and the talent and the resources of our country. We1141can and should be doing better.1142    Thank you for holding this hearing today.1143    The Chairman. Thank you, Senator Kim. Senator Johnson, do1144you have some more questions?1145    Senator Johnson. Yes. Thank you, Mr. Chairman. I mean, I1146think the elephant in the room here is, so we have got the laws1147in place. They maybe could be beefed up, but I think it is a1148personnel issue, right. I fear that not even necessarily the1149heads of the agencies, but possibly bureaucrats that have been1150there for decades, for whatever reason, they don't like a1151particular drug, and so they are able to sabotage it.1152    My question, how can we overcome the inconsistency from,1153you know, one bureaucrat to the next bureaucrat, changing1154administrations, or quite honestly, you know, a particular1155bureaucrat that has been in there for decades that just keeps1156blocking things. I mean, how do you get to the personnel issue?1157I will start with you, Ms. Kennedy.1158    Ms. Kennedy. I think my experience differs from some on1159this panel in that we have seen great examples of models where1160we have had public meetings and public workshops where FDA has1161come together with the patient community, which I think is an1162incredibly important mechanism, to have meetings where we can1163have regulatory agreement around the use of certain innovative1164models in clinical trial design, surrogate endpoints, natural1165history studies as a control arm that had then allowed those1166programs to move forward.1167    Senator Johnson. I pointed out in a meeting like that, a1168panel, for Duchenne Muscular Dystrophy, 50 to 60 families, and1169they still said no.1170    Ms. Kennedy. I love that reference. What you may not know,1171you probably don't know, is prior to being with the EveryLife1172Foundation, I was with the Duchenne community, and so that may1173have been an advisory committee.1174    Senator Johnson. Were you in that meeting?1175    Ms. Kennedy. Yes, I was. Well, it depends on what meeting1176you are referring to. If it was an ADCOM, an advisory committee1177meeting, that advisory committee did vote no, but then the1178agency brought that internally and then overruled that.1179    Senator Johnson [continuing]. overruled it.1180    Ms. Kennedy. That is a perfect example of the agency still1181has the authority to make the decision because they heard from1182the community and what we are concerned about right now is that1183the agency isn't engaging with the patient community.1184    Senator Johnson. Dr. O'Neill, in your testimony you talked1185about, you got your CO, the complete response letter. I mean,1186perfect bureaucratic type of--in other words, the no letter,1187right, and you got the no letter, not necessarily because of1188safety or lack of efficacy. It was because there is something1189in the manufacturing process, which again, a manufacturer, I1190understand that, but can you explain that. It seems like a1191pretty weak excuse where you could, we will fix the1192manufacturing process so this drug can be made available just1193talk about that1194    Dr. O'Neill. Thank you. I am not an expert on gene therapy1195manufacturing, so I will say that. However, the sponsor was1196very transparent in reviewing the full CRL with our community1197so that we could understand truly what the concerns were. Many1198of them were noted to be things like a crack on the floor not1199in the manufacturing area, or a tarp that was out back, or1200things that really are unrelated to our children.1201    Senator Johnson. Trust me, I have been through audits. I1202supplied packaging material for medical devices. You can find1203an excuse to, you know, write something up, pretty flimsy1204excuses.1205    Again, that is my concern. Dr. Schmahmann, in your case, it1206was based on real world evidence. It seems like the real-world1207evidence was completely in favor of allowing patients access to1208this drug. Talk a little bit about, you know, why you got a1209CLR, a no letter.1210    Dr. Schmahmann. Thank you, Senator. You know, one of the1211thoughts that came to me as we are going through this whole1212process and hearing what happened to Sanfilippo with the crack1213in the floor in the factory is that this is a policy of death1214by technicality. These little, tiny glitches that the FDA is1215producing land up not approving drugs and patients die as a1216consequence.1217    I am glad to hear that there are people in the FDA who are1218doing what Congress requires them to do, but that speaks to the1219unpredictability and the erratic nature of the responses and1220the performance of the people in FDA. There are many ways to go1221forwards to use clinical trials and then use the new technology1222to bring treatments to patients faster that are safe and make a1223difference.1224    Science advances. The regulation is keeping up with the new1225advances, but it seems like the FDA is having trouble with1226that. The FDA must keep pace with the updates in science using1227the biomarkers, serum or imaging, using digital markers, using1228patient reported outcomes.1229    I developed the patient reported outcome measure for1230ataxia, understanding what patients are saying. The key issue1231here is that the real experts are the patients. The patients1232are the experts by experience. The patients are our research1233collaborators. We are all patients. Every one of us has1234something.1235    We are all patients. It may not be a rare disease, but this1236applies to us. We are talking about us, whether it is a rare1237disease or not. The approach that can be taken, including what1238was started at our institution, I think called a platform1239trial, where you can have one small group of controls and a1240number of other patient cohorts trying different drugs. There1241are innovations both in the clinical trial design and the1242biomarker space.1243    This is where we need to move, and the urgency is exactly1244what Senator Kim was talking about. There is an urgency now and1245some of the drugs on the table now, the ones you have heard1246about from Dr. O'Neill and myself, these should be approved1247this week. There is no reason not to.1248    Going forward, we need to find a way to enhance, to1249expedite, and make this a better process and have a sense that1250when you are going to the FDA, you know what you are getting.1251It is not just a random scatterplot of who is going to get what1252kind of a person there.1253    Senator Johnson. Isn't another root cause here is literally1254the doctors are no longer at the top of the treatment pyramid?1255They have been replaced by regulators. You talk patients are1256number one, but doctors are the ones that are most1257knowledgeable in this equation, and you are shutting off to the1258side. What you are saying doesn't count because the regulators1259have replaced you in terms of making these decisions for1260patients. Isn't that a big problem?1261    Dr. Schmahmann. You know, Senator, on your wall in your1262office yesterday, I saw your mission statement, which was1263triple, teamwork, respect, integrity, professionalism, loyalty,1264and education.1265    The FDA is not doing that. It is the opposite.1266Communication, dialog, teamwork between the physicians, the1267patients, the pharma who make the drug, the regulators, that is1268a two-way street. It is a dialog. In medicine, when we do1269rounds in the morning on our patients in the hospital, there is1270a discussion.1271    The physician is there, the residents are there, the nurse,1272the nurse practitioner, or the physical therapist, the patient1273and the family. It is a conversation, a discussion. This is not1274what we are hearing from across the board and certainly from1275the other rare diseases. We are here, the few of us.1276    Turns out there are 30 million people behind us, as you1277said. What we are bringing to you is the plea to make the FDA1278what it was supposed to be, which is what you regulated, and1279allow us to work in a collaborative manner across the board,1280not with this kind of hit or miss approach as to who you are1281going to get on a committee. You are looking for1282accountability.1283    In fact the leadership of the FDA, it is their1284responsibility to hold the feet to the fire of the people under1285that person's leadership. Not just to say good things, but to1286actually make them happen and bring new drugs to the American1287population including us, our patients, my patients, that are1288safe and effective.1289    Senator Johnson. Again, thank you, Mr. Chairman. I think1290this is an excellent hearing, excellent testimony. Both you and1291the ranking member, you pretty well diagnosed the problem here.1292I mean, in your opening statements, you laid out the problems.1293This is eminently fixable, and we have to fix it. Again, I am1294committed to working with you to do so but thank you for this1295hearing.1296    The Chairman. Senator Gillibrand.1297    Senator Gillibrand. Thank you. In 1972, the Federal1298Advisory Committee Act established advisory committees within1299the FDA to help provide independent expert scientific input on1300product reviews and policy topics.1301    In 2025, FDA canceled many advisory committee meetings and1302indicated that it would like to move away from involving1303advisory committees in the review of drug applications. For1304each of the witnesses, you can start Ms. Kennedy, how important1305is it to the rare disease community for FDA to restore the use1306of advisory committees?1307    Ms. Kennedy. It is everything. We yesterday had one of our1308communities showcase in front of close to 800 members of the1309rare disease community how an advisory committee meeting helped1310inform a key regulatory decision for the VAR syndrome community1311by showing how an open public hearing enabled members of that1312community illuminate the nuance of a very complex regulatory1313decision in a very complicated regulatory review.1314    As Senator Johnson just highlighted, I have been a part of1315many advisory committee meetings for communities, including the1316Duchenne community, and advisory committees don't always vote1317yes. That is not the point.1318    The point is for external experts, including clinicians,1319including those with statistical expertise and manufacturing1320expertise that are not always internal to the agency, to be1321brought to bear on regulatory decisions because we realize that1322with 10,000 rare diseases, it is not possible for FDA to always1323have all of that expertise internal.1324    Those committee hearings must be at the avail of the1325agency, but also those open public hearings must be available1326so that patient communities who are participating in clinical1327trials can share what their experiences in those clinical1328trials are. One of the challenges we have in clinical trial1329design is we don't always know what we are going to find when a1330clinical trial begins.1331    We design a clinical trial hoping that we are going to be1332able to select the best outcome measures, but sometimes patient1333communities who participate in those trials experience other1334benefits and those hearings enable us to hear from patients1335about what other outcomes were achieved so that we can make the1336best decisions possible for the patient community around safety1337and efficacy.1338    Eliminating those hearings eliminates the chance for FDA to1339make the decisions that are in the best interests of the1340patient communities possible.1341    Senator Gillibrand. Dr. Schmahmann and Dr. O'Neill,1342congressional actions have advanced how patient experience data1343is included in the development and evaluation of rare disease1344therapies. What is the importance of the patient voice in this1345regulatory process, and what more is needed to ensure FDA1346includes this information in its decisionmaking?1347    Dr. Schmahmann. I agree that it is critical, Senator. I1348think that there is a deeper problem. If you don't listen to1349somebody else's advice in a complex story, that is the opposite1350of humility. It is a denial of the patient's humanity and it is1351sort of hubris. You don't want to hear what the patients have1352to say? Who are you? That is the problem.1353    This is all about the patients. To deny the patient voice1354in drug development and in drug design--and I agree completely1355with Ms. Kennedy here. Determining the end point when you start1356is fine if the disease is well known in the millions of people.1357    In our case, for example, the spinocerebellar ataxia, the1358first clinical trials that Biohaven did in the 2016s, we didn't1359know what would change. We had to take a guess and I worked1360with them in devising the scale, devising a trial. The patients1361then told us, you know what, I am falling less, I am not as1362fatigued, and my speech is better. There was a different1363outcome we didn't understand at the beginning. That is the1364epitome of regulatory flexibility.1365    There is a rule in medicine, listen to the patient, they1366are telling you the answer. The second piece is, ignore the1367patients at your peril. What we have here is denying of the1368patient's story. It is the peril not of us, but of the patient1369because now the drugs are not being approved.1370    I think you have hit the nail on the head here. If you are1371ignoring the patient, then why are you getting up in the1372morning and coming to do the work that you do with the FDA?1373    Senator Gillibrand. Well said. Dr. O'Neill.1374    Dr. O'Neill. Thank you. You know, obviously you have heard1375that patients are not outside of the drug development process.1376They are critical to it and advisory committees, as Annie had1377mentioned, are an important place where we can have that1378scientific dialog and hear from patients.1379    Their experience is also science. It is human science. The1380interaction needs to come way before that, because by the time1381we get to an advisory board, tens of millions of dollars have1382been spent, maybe a decade has gone by. We have not treated1383potentially that many patients who needed treatment.1384    Having a true collaborative dialog early in the process is1385essential and something--an opportunity that needs to be acted1386upon within the FDA. I think one other thing that we are1387understanding is key insights around risk tolerance. We also1388want safe medicines, but we also want the opportunity to save1389our children because those answers about a clinical trial come1390way down the road.1391    As Mr. Campbell explained, real-world evidence, post-1392marketing disease monitoring programs, this is where we need to1393be really focusing on these innovative ways. Maybe not so1394innovative, honestly, anymore, but more frequently used and1395supported ways to provide that longer term evidence to support1396accelerated approval.1397    Senator Gillibrand. Mr. Campbell, did you want to add?1398    Mr. Campbell. For sure. I think what we keep coming back1399to, and I think you hear the theme, is you have all the tools1400in place. You have the advisory committees. You have1401accelerated approval pathways.1402    I think the frustration is when they are deployed1403inconsistently and without clarity from the sponsors and from1404the patient community and from the physicians in terms of how1405you end up, you know, meeting the expectation but then not1406coming to a positive resolution. There is one other piece that1407we haven't talked about, if I could just introduce that, which1408is the Rare Disease Innovation Hub. If we want to talk about1409things that Congress could proactively do.1410    We have a tool that is modeled after what was very1411successful in oncology, the Center of Excellence, but my1412observation would be is it is underfunded and probably under1413empowered to do what it needs to do.1414    When we think about advisory committees, when talk about1415staffing at the FDA, when we think consistency between1416reviewers, Congress could directly fund the Rare Disease1417Innovation Hub in a meaningful way that would allow us to train1418rare disease experts that could sit across review teams, across1419review divisions, and bring some of that consistency, that1420humanity, that humility, but that expertise that perhaps each1421of the individual teams or the new reviewer on the team doesn't1422quite have.1423    Again, I think we have a lot of the tools that we need. We1424just need to encourage the FDA to use them in the right way and1425that is one example we haven't talked about here today where1426Congress could fund that directly and allow the FDA to make it1427a much more valuable tool for rare disease drug development.1428    Senator Gillibrand. Thank you, Mr. Chairman.1429    The Chairman. You know, when you hear the testimony, I1430think all of us internalize it. I have got six grandsons and a1431granddaughter and you know, thank God they don't--you know,1432everybody has got problems, right, but you know, they don't1433have a rare disease that is going to shorten their life.1434    I can't imagine what a family is going through when they1435have a family member that has something and then they believe1436there is a possibility that something could change their life,1437and it doesn't happen. I mean, I would be pretty frustrated. I1438would be pretty--more than that. Ms. Kennedy, is it important1439for people to come to Congress and talk about their concerns1440with regard to the drug approval process?1441    Ms. Kennedy. Well, I know you are asking me, but there are1442about 800 people on the Hill that would be happy to answer that1443question as well.1444    Throughout this time here this morning, starting with your1445opening remarks, we have cited many laws that have been1446transformational for our rare disease community, and every1447single one of them started with a member of the community1448meeting with their elected official and talking about a1449roadblock that could be transformed and turn into a resource1450and a tool.1451    Every single one of those laws has transformed lives and1452ultimately has saved lives. So the answer to your question is1453an emphatic yes, and we are so grateful for the time you take1454to be with our community, to listen to our community, to1455engage, and to become partners with all of us, so thank you.1456    The Chairman. Does the FDA appreciate when you guys come1457here?1458    Ms. Kennedy. I think many do, yes. Maybe some no, but I1459think overall, over the years, I have been in this space 301460years and I think we have had strong partnerships with the1461agency and many times the agency has very much appreciated our1462support.1463    The Chairman. Dr. Schmahmann, what--from a clinical1464standpoint, what happens to patients with progressive1465neurologic diseases when access to treatment is delayed due to1466the regulatory process rather than safety concerns?1467    Dr. Schmahmann. They progressively deteriorate. They lose1468function. They can't live their lives, go to work, spend time1469with their family, make a living, be productive citizens of1470society in that way. They become part of the family that people1471have to take care of instead of taking care of the families1472themselves. Then they become progressively debilitated and then1473they die young.1474    Then family members, in our case, see that. They see their1475future in the mirror. There is a high incidence of depression1476and, in fact, suicidality in this patient community as well.1477This is across the spectrum. This is not a motor control1478problem alone. This is a social, emotional, societal issue and1479the issue about medications that improve neurological function1480in real time work at the level of the physiology where brain1481cells are sick before they die.1482    If you have a medication, even though it is not a gene1483therapy, you have medication like troriluzole, where we know1484the mechanism, and you stop the neurons from being so1485hyperactive that they die, you actually improve function and1486you slow disease over time, so you are modifying the disease.1487    The absence of a medication that can treat the disease1488means that each day that this drug, troriluzole, and others1489like it are not being approved means patients are losing brain1490cells and are closer to death. It is heartbreaking to see, as1491you all said at the outset, and we are hoping that this can1492change from today.1493    The Chairman. I think in your testimony you said that the1494FDA suggested withdrawing patients from compassionate use of1495care to evaluate whether their conditions would deteriorate1496despite physicians expressing the harm would be irreversible.1497So tell me about the--what are the ethical implications of1498that?1499    Dr. Schmahmann. If you have a disease where there is a1500symptom like a migraine, for example, you can see if I stop the1501drug, will you get worse for a week or two, or a month, and I1502will put you back on drug, you are okay. In a neurodegenerative1503disease like these, and I am going to be--excuse me if I am1504provocative--the last time we had a catastrophe in medical1505science in the U.S. was between 1922 and 1972.1506    I believe there was like a 40-year period, 1932 to 1972,1507when people with syphilis were not treated so that the doctors1508could see what happened to them, and the patients were not1509told. That is a case study for every person who is going into1510human studies research in the United States.1511    We learn about that case. You cannot treat patients like1512guinea pigs. You have to have them on your story as part of the1513research collaborator, experts by experience. If we have a1514drug, as we do here, that is first safe and that bends the arc1515of the disease, and you want patients to come off that drug so1516you can see if they worsen, in other words if their brain cells1517are dying under your care, that is a poster child--it is1518Tuskegee version two, and it is entirely unacceptable. I reject1519it outright.1520    They should not have recommended that and whoever did, I1521would suggest they take updated education sessions on clinical1522trials and on human studies research. It is not okay, Senator.1523    The Chairman. I can't imagine doing that. Mr. Campbell,1524talk about inconsistent FDA standards, how it impacts1525timelines, costs, the ability of small biotech companies to1526survive. Is it easier to raise money if the FDA is1527inconsistent? Does that make your job easier?1528    Mr. Campbell. No, is the candid answer, and you know, that1529is underlying all of this, right. We have created in the United1530States this rich ecosystem of innovation, which has been1531supported by Congress, supported by FDA over the years,1532supported by modern technology, and that brings in new1533companies that bring in new innovations and offer some of the1534therapies that we have talked about here today that are now1535stuck in front of this regulatory process.1536    The reality is, and this is in my written testimony, the1537reality is for many small and mid-sized biotech companies, it1538takes decades to become profitable, which means we are going1539hand-in-mouth begging for dollars from investors. If there is a1540clear path forward and investors can be confident of an1541eventual return, then they will keep investing and the1542innovation ecosystem keeps going and going.1543    If we continue to create this uncertainty, if we continue1544to create an uncertainty around manufacturing timelines, around1545approval timelines, around changing the goalposts again, I am1546confident that those investor dollars will go somewhere else.1547    I will tell you transparently, having gone to the recent1548J.P. Morgan Healthcare Conference, which I am sure folks know1549is the big investor conference in our industry, I heard more1550opportunities about Chinese therapeutics and companies than1551ever before, and I don't think that is an accident.1552    Ten, twenty years ago, we might have thought the science1553wasn't good. We might have distrusted the quality and the1554safety. I can tell you that the innovation there and the1555science is equally as good as ours.1556    We still have an advantage, but if we are not careful, we1557are going to lose that advantage, and at the end of the day,1558the American patients suffer, the American economy suffers, and1559I am convinced that that is a real threat, in addition to the1560most important piece, which is making sure drugs get to1561patients faster.1562    The Chairman. Dr. O'Neill, in progressive rare diseases,1563how should regulators account for the fact that clinical1564decline is often irreversible? Should the harm of waiting be1565weighed alongside uncertainty in the data? If so, how?1566    Dr. O'Neill. Thank you. Yes, to call back to Dr.1567Schmahmann's points around this and about exposure to not being1568on drug, the risks of not treating this disease are known. You1569know, these are not in question.1570    We know these children will be permanently, severely brain1571injured for the rest of their lives. There are critical, time-1572sensitive neurodevelopmental windows in childhood when it is1573important to intervene to be able to receive the maximum1574benefit. There is a continuum of this, but earlier is always1575better.1576    What we are still hearing as recommended to sponsors is1577that observational, or no treatment, or placebo controlled1578trials are being recommended for these pediatric conditions.1579This is very, very troubling when we know that they will become1580brain injured. We have also seen--you know, when parents ask me1581about this, I have to kind of step back and think, oh my1582goodness, I know what a perfect science experiment looks like.1583    Yes, that is the perfect science experience, but these are1584children. You cannot do good medicine unless you are putting1585the patients first and following the ethics of medicine and we1586have heard changes around the use of animals in preclinical1587studies. Just last April, the FDA published its roadmap to1588reducing animal testing in pre-clinic studies, and this says, I1589quote, "due to the limitations of animal testing as well as1590ethical concerns about animal testing, there have been1591increased focus within the scientific community on new approach1592methodologies."1593    We are concerned about the ethics of animal testing more1594than we are concerned about the ethics of allowing children to1595be brain injured in clinical trials, and I think we all need a1596gut check on that.1597    The Chairman. Would any of you like to talk about what1598patients and caregivers tell you about their willingness to1599accept uncertainty or incomplete data when the alternative is1600no treatment at all?1601    Dr. Schmahmann. I think it starts off with safety. Nobody1602likes side effects, and patients do want to know that the1603medications are safe, or the approaches are safe. Given that1604piece, if we can make a comment about safety, the degree to1605which the medication works or not is often something that1606patients, I think, are willing to take on.1607    We can certainly hear from the others about that and the1608other rare diseases. In our space, knowing that the medications1609we have available are safe, and have been shown in other1610circumstances, patients are not just willing, they are--we are1611getting emails every day from people around the world, what1612trials do you have for me that I can use to try and slow down1613the process of my disease?1614    Ms. Kennedy. Yes. I really appreciate that question, and I1615think my response would be that for each subpopulation within1616each condition, within each targeted therapy, that1617consideration would be very different, which is why Congress1618authorized the use of the benefit-risk framework within the1619consideration of regulatory review. That is one of the things1620that we are concerned about is not being applied.1621    We don't know how it is being used. One of the things that1622we are asking for today is more questioning around how are1623these tools being utilized, because every community for every1624clinical trial within every subpopulation of that community1625will approach that threshold for risk tolerance differently.1626    That is a super important question, Senator, and we are1627just not sure that that is being questioned the way it was1628intended for the tailorization that is required for rare1629disease therapeutic development.1630    The Chairman. Mr. Campbell, can I ask you a separate1631question? How important is transparency from the FDA in1632maintaining trust with rare disease communities? What happens1633when explanations for delay are unclear or incomplete?1634    Mr. Campbell. You know, I feel like as sponsors,1635manufacturers, we have a great duty to our patients. I think1636somebody--one of the Senators asked me why I am in this1637business. I will tell you, you know, it is for the patients,1638but when you have a chance to develop a therapy for people1639living with a rare disease, it sort of gets in your blood. You1640also, then you bear a great responsibility.1641    I feel, I think, like sponsors are at the front lines, in1642front of the agency trying our best to get those drugs over the1643finish line. If we fail to do that for any reason, we owe it to1644the patients, to the community, to the caregivers to give them1645an explanation. When there is no good explanation or when the1646explanation is a crack on the floor, you know, that is just not1647good enough.1648    I think I really do believe that sponsors bear some of that1649responsibility. I think it works best when we truly work1650together. Congress has the tools. The FDA has proven itself1651over time to be very effective in working with sponsors. I1652shared our story, which was an incredible, innovative1653regulatory science, medical science that helped thousands of1654patients.1655    If you don't have that transparency, and if you do not have1656that consistency then, you know, we all lose, and I really1657believe that we are at the center of that. It pains me, you1658know, to hear these stories.1659    We are not in that position today as Amicus, but we owe a1660responsibility to these people who are giving their lives to1661participate in clinical studies who have so much hope, we owe1662them clarity and we all do. Everybody who is involved in that,1663including the regulators.1664    The Chairman. Ranking Member Gillibrand, you want to say1665anything before we close?1666    Senator Gillibrand. I would like the audience members who1667have pictures of their loved ones to stand please so we can see1668their loved one. Thank you for coming to represent them. Thank1669you all. I want to just thank our guest who is in the corner1670who has been so well behaved this entire time. I am very proud1671of her for being such a good girl. Just thank you all for being1672here today. This has been an extremely powerful hearing. We1673have gotten some amazing testimony, and I am very hopeful that1674we will find better solutions so that we can all work together1675to get these cures that our loved ones so desperately need.1676Thank you all.1677    The Chairman. I want to thank everybody for being here. I1678want to thank the Ranking Member for this. We have been doing1679this for a little over a year, and we have been able to do a1680lot of things together.1681    What we heard today was not abstract policy theory. We1682heard from Mr. Campbell that 95 percent of rare diseases still1683have no approved treatment. At the current pace, it could take1684more than a century to meaningful close that gap. We heard Dr.1685Schmahmann about a multi-year data set supported by real-world1686evidence and natural history comparisons, showing meaningful1687showing of disease progression, yet still unable to clear the1688regulatory bar.1689    We heard from Ms. Kennedy that at least 23 rare disease1690therapies received complete response letters in the past year,1691even as advisory committee meetings declined, raising concern1692about whether the flexibility Congress authorized is being1693applied consistently. We are reminded that for some patients,1694success is not an abstract endpoint, but the ability holds one1695breath long enough to survive another moment.1696    I recently spoke with Commissioner Makary. It was clear1697that the FDA's framework was built for common diseases, not1698rare to ones. He is implementing reforms like the plausible1699mechanism pathway, greater flexibility for gene therapies, and1700strengthening the rare disease innovation hub. We look forward1701to working with him to ensure those changes are applied1702consistently and urgently for patients. He inherited a broken1703system, and the FDA cannot be fixed overnight.1704    That said, he has made significant progress, and I am1705completely encouraged by the reforms President Trump has1706empowered Commissioner Makary to make at the FDA, and I know he1707cares deeply about getting results and making sure the United1708States remains the world's leader for innovation and treatment1709of rare diseases.1710    Taking together the testimony presented before our1711Committee today makes one thing clear, the question is not1712whether to protect safety, it is whether the system is moving1713with the urgency Congress intended and patients require. The1714Committee will continue exercising oversight to ensure that1715flexibility enacted into law becomes reality in practice.1716    I look forward to continuing work with our members. If any1717Senator has additional questions for the witnesses or1718statements to be added, the hearing record will be open until1719next Wednesday at 5:00 p.m. Thanks everybody for being here.1720    [Whereupon, at 11:05 a.m., the hearing was adjourned.]1721=======================================================================17221723                                APPENDIX17241725=======================================================================17261727                      Prepared Witness Statements17281729=======================================================================1730[GRAPHIC NOT AVAILABLE IN TIFF FORMAT]17311732=======================================================================17331734                        Questions for the Record17351736=======================================================================17371738                 U.S. Senate Special Committee on Aging17391740 "From Regulator to Roadblock: How FDA Bureaucracy Stifles Innovation"17411742                           February 26, 202617431744                        Questions for the Record17451746                             Annie Kennedy17471748                        Senator Raphael Warnock17491750    Question:17511752    Over the past few decades, the FDA has adopted strategies1753to accelerate the development of treatments for ultra-rare1754diseases. These strategies have included the Support for1755Clinical Trials Advancing Rare Disease Therapeutics Pilot1756Program, Rare Disease Evidence Principles, and the Plausible1757Mechanism of Action Framework. However, there are many rare1758diseases that still need treatments.1759    What would be the advantages of the FDA extending the above1760strategies to other rare diseases? How can Congress ensure the1761FDA balances acceleration and thoroughness in its review of1762potential rare disease treatments?17631764    Response:17651766    We have been following closely the recent agency1767announcements, including the Rare Disease Evidence Principals1768(RDEP) initiative, the Plausible Mechanism Framework, the1769establishment of the Rare Disease Innovation Hub in 2024, and1770the implementation of new guidance documents and regulatory1771science pilot initiatives contained in PDUFA VII (10/1/2022 -17729/30/2027).1773    The application of these programs and policies can shape1774the prospects of rare disease therapy development for a given1775community, drive investment into one area and out of another,1776and determine how patient advocacy organizations allocate1777precious resources. For a variety of reasons the ways in which1778available guidances, programs, and pathways can be applied to1779different subpopulations of rare diseases differ. Multiple1780factors have led to some rare disease communities having1781greater success in leveraging FDA's regulatory flexibility1782including population size, therapeutic modality, disease1783characterization, extent of diagnostic delays, age of onset,1784and others.1785    We are encouraged by the intent signaled by FDA's most1786recent initiatives, RDEP and the Plausible Mechanism Framework,1787however, more information is needed to understand how the1788Agency plans to operationalize these new approaches for1789products in today's pipeline and beyond, and which1790subpopulations of rare diseases stand to benefit initially, and1791over the longer term.1792    We encourage additional dialogue and input from the1793community into these new initiatives as even the best ideas1794need the benefit of robust dialogue and operational details for1795them to have the intended effect.1796    Specific to the RDEP announcement - this announcement1797appears to be responsive to calls for more predictability in1798the regulatory process, but more details will be needed before1799we have a detailed reaction. Many rare disease communities may1800not realize the program's benefits due to its narrow focus;1801however, it can provide valuable insights for expansion if1802appropriate metrics and evaluation methods are incorporated1803from the outset.1804    We are eager to hear more details on how RDEP will be1805operationalized, as well as a better understanding of how1806RDEP's requirements for pre-specifying the trial requirements1807will be handled, given the nature of many rare disease trial1808designs.1809    Regarding the Plausible Mechanism Framework, we are1810encouraged by the release of the draft Guidance, and what it1811represents for the eligible communities for whom traditional1812approaches to clinical trials and regulatory requirements are1813fundamentally at odds with the reality of their conditions. We1814are grateful to the FDA for taking on this challenge of1815ensuring no disease is too rare to deserve treatment. And we1816are incredible grateful to the many families and experts who1817applied their personal expertise to yield transformational1818change.1819    We also recognize that for many in our rare disease1820community, the Plausible Mechanism Framework will not apply,1821and we urge FDA leadership to continue pursuing solutions that1822will ensure the tools and policies that Congress has created1823over decades, are deployed in a predictable and consistent1824manner that can unleash scientific innovation and speed safe1825and effective therapies to patients across the more than 10,0001826rare diseases. The EveryLife Foundation team is in the process1827of closely reviewing the recently released draft Guidance.1828    Regarding the Rare Disease Innovation Hub and opportunities1829yielding from PDUFA VII Pilot Programs, we are hopeful that the1830opportunities stemming from these PDUFA VII investments will be1831applied more broadly across rare disease product development.1832The Rare Disease Innovation Hub is well positioned to be a1833catalyst of progress by spearheading the dissemination of data,1834case studies, and other learnings resulting from these pilots1835and experiences with the application of regulatory flexibility1836tools more broadly.1837    Since 1983, Congress has created incentives and policies1838that recognize the inherent complexities in developing1839treatments for rare diseases. Congress has explicitly given the1840FDA authority to uphold the highest standards of regulatory1841safety and rigor, while applying tailored approaches (i.e.1842"regulatory flexibility"). Such approaches include:18431844      
Establishment of the accelerated approval pathway1845      
Consideration of the totality of evidence in the1846regulatory review1847      
Inclusion of Patient Experience Data (PED) in clinical1848trial design & regulatory processes1849      
Utilization of innovative clinical trial designs and1850real-world evidence (RWE)18511852    Nearly 1,400 orphan-designated therapies are changing the1853lives of patients and families, but 95% of rare diseases remain1854without an FDA-approved treatment.1855    Congress must continually ensure that FDA review statutes1856keep pace with the science and are designed to work across the1857spectrum of rare diseases, from n-1 to just under 200,000, and1858from pediatric to adult populations. Congress should look to1859address gaps more regularly, ideally more often than the1860typical practice of moving regulatory legislation alongside the1861five-year PDUFA reauthorization window allows. Congress should1862regularly engage in dialogue with the Agency leadership and1863rare disease stakeholders, seek comprehensive metrics to1864understand how the Agency is applying regulatory flexibility,1865and ensure the Agency has adequate resources, such as funding1866for the Rare Disease Innovation Hub, to optimize their ability1867to apply tailored approaches to rare disease product1868evaluation.18691870    Question:18711872    As part of his sweeping reductions-in-force (RIFs) of1873Department of Health and Human Services (HHS) employees, HHS1874Secretary Robert F. Kennedy dismissed 3,500 Federal Drug1875Administration (FDA) employees in April 2025. The RIFs targeted1876employees across the agency, including advisory committee1877staff.1878    You mentioned that the FDA held far fewer advisory1879committee meetings in 2025 relative to 2024 and that this1880drastic drop meant fewer opportunities for experts and patients1881to share information to inform the FDA's decision-making. What1882are the ramifications of last year's RIFs at the FDA for the1883development and treatment of illnesses that do not yet have a1884cure?18851886    Response:18871888    Significant leaders the rare disease community has built1889relationships with over the years have either resigned or been1890laid off in the last 12 months, resulting in the loss of1891powerful allies and institutional knowledge that have generated1892the progress the rare disease community has seen over the last1893decade. However, thousands of committed public servants remain,1894and the EveryLife Foundation, together with our community, is1895committed to policies that will support and enhance the1896Agency's rare disease capacity and expertise.1897    Rare disease product reviews occur in every division and1898product Center at the FDA. With the appropriate resources, the1899Rare Disease Innovation Hub is poised to enhance its role as1900the FDA's coordinating office to optimize rare disease1901expertise, processes, and engagement with stakeholders across1902all therapeutic areas, including drugs, cell and gene1903therapies, and medical devices. Given the departure of1904experienced staff, the importance of a robust Rare Disease1905Innovation Hub is magnified. The Hub's first full year of1906operations has laid the foundation for meeting this moment of1907opportunity if institutional support and resources are1908enhanced.19091910    Question:19111912    How can Congress conduct oversight over the FDA to ensure1913the agency continues to hold advisory committee meetings and1914review rare disease treatments?19151916    Response:19171918    We are concerned about the dramatic decline in1919opportunities to leverage external scientific, clinical, and1920patient-community insights to inform deliberations on complex1921rare-disease product reviews. While not every product1922application requires an advisory committee, where relevant,1923their use was one of the few ways the Agency discussed its1924approach to the review in public and heard from clinicians who1925treat patients and run trials, and from the patients and1926families who took part. This additional insight affords review1927teams with another data point to consider among the totality of1928evidence they must balance when determining how to apply the1929regulatory flexibility tools that Congress has authorized.19301931    As I encouraged Congress in my testimony, Congress should1932conduct outreach to the Agency to understand its approach to1933the following:19341935      
The application of the accelerated approval pathway to1936rare disease therapies;1937      
Improving the predictability and consistency of the1938application of regulatory flexibility; and1939      
Resuming the use of Advisory Committee Meetings to1940receive external expertise on product reviews and key policy1941topics.19421943    Based on this engagement and the Agency's responses, we1944encourage Congress to identify opportunities for additional1945public dialogue with the Agency and rare disease stakeholders1946to identify a path forward that will ensure sustainable,1947transparent, and predictable processes for leveraging external1948expertise in relevant product reviews and to inform overall1949rare disease regulatory science approaches moving forward.19501951                 U.S. Senate Special Committee on Aging19521953 "From Regulator to Roadblock: How FDA Bureaucracy Stifles Innovation"19541955                           February 26, 202619561957                        Questions for the Record19581959                            Bradley Campbell19601961                        Senator Raphael Warnock19621963    Question:19641965    Approximately one in ten Georgians live with a rare1966disease. Many of these individuals, including older adults, do1967not have access to life-saving treatments due to incomplete1968scientific knowledge of their disease and limited funding.1969Families seeking treatments that were reviewed under a priority1970voucher program are also experiencing delays due to the1971prolonged FDA approval process.1972    How can Congress reduce regulatory barriers to expedite the1973FDA's approval process for rare disease treatments while1974maintaining the safety and quality of these treatments?19751976    Response:19771978    Senator Warnock, thank you for this thoughtful question. As1979noted in my testimony, I believe there are low-hanging fruit1980that we can seize while still maintaining FDA's "gold standard"1981for safety and efficacy:19821983      
Speeding up approval of early phase clinical trials1984      
Harnessing innovative endpoints based on biomarkers1985      
Expanding the use of real-world evidence1986      
Streamlining manufacturing inspections19871988    In cases where there is residual uncertainty about the1989durability or extent of patient benefit for promising1990therapies, real-world data should be collected post-approval1991via the Accelerated Approval pathway.\1\ If that data does not1992bear out patient benefit, the agency should consider1993withdrawing that treatment in consultation with the patient1994community. When it comes to rare diseases, patients and their1995families are the true experts, and their voices need to be1996respected as such.1997---------------------------------------------------------------------------1998    \1\ Examples of rare-disease therapies that entered the market via1999FDA Accelerated Approval and later converted to full approval include2000sparsentan for primary IgA nephropathy, agalsidase beta for Fabry2001disease, and delandistrogene moxeparvovec-rokl for Duchenne muscular2002dystrophy.2003---------------------------------------------------------------------------2004    FDA already has Congressionally granted authority to do2005everything I listed above. The challenge is simply doing them2006consistently. This is where Congressional oversight is vital.20072008    Question:20092010    How do bipartisan initiatives like the FDA Pediatric2011Priority Review Voucher program, which I was glad to see2012reauthorized recently, help incentivize innovation for rare2013disease treatments?20142015    Response:20162017    Senator Warnock, we are deeply grateful to Congress for2018reauthorizing the FDA's Pediatric Priority Review Voucher (PRV)2019program.2020    Small and mid-size biotech companies are the driving force2021behind U.S. drug development for all diseases, but particularly2022for rare diseases. These companies are often pre-commercial,2023meaning they are years-to-decades from sustainable2024profitability.2025    When a company with a PRV voucher receives FDA approval,2026the sponsor can sell that voucher, sometimes for hundreds of2027millions of dollars. That funding is a critical lifeline for2028continued operations when the alternative is bankruptcy.2029    Rare pediatric diseases that have benefited from PRVs2030include pediatric neuroblastoma, the most common cancer in2031infants; spinal muscular atrophy (SMA), the most common genetic2032cause of infant mortality; and epidermolysis bullosa, which2033causes fragile, blistering skin.2034    There we no treatments for any of these diseases before2035Congress created the PRV program in 2012.2036    The PRV program has no cost to taxpayers, but when2037investors are considering whether to fund an early-stage rare2038disease company, having a PRV designation can be decisive.2039=======================================================================20402041                       Statements for the Record20422043=======================================================================2044[GRAPHICS NOT AVAILABLE IN TIFF FORMAT]20452046                          [all]