Transcripts For CSPAN2 Hearing 20240702

Patients with Rare Diseases. Advocates for medical ethics and a therapeutic industry professionals also testified to provide insight on the fda Clinical Trial process. This hearing before the Senate Special Agent Committee is about two hours. [background noises] [background noises] good morning the Senate Special committee will come to order welcome everybody. Welcome to the committees eighth hearing of the one her 18th congress about Drug Development for rare and serious diseases. As is the tradition of the committee, the aging Committee Ranking member, Ranking Member brought in this case will offer an opening statement. Thank you, senator. Thank the witnesses for coming and for all of the folks from around the country here today. There are over 7000 rare progressive and serious diseases known to man. It is estimated 95 black treatment. Yet in my time et cetera there is not been one Senate Hearing to examine promising therapies for people with rare progressive and serious diseases. The room is packed with people, patients and caregivers that live in this reality every single day. Right here, 350 patient stories from 44 states. This is long overdue. People that watch their bodies deteriorate in real time. Family members who have seen their loved one go from the picture of health to knocking on deaths door. Parents that buried their children before they even started school. I want to recognize and thank each one of you that are here in the audience and let you know i think this is the beginning of a new day for what we are all interested in. Chairman casey a response of the searing our has received these letters, 350 of them, 44 states with a personal experiences i ask by unanimous consent we enter these into the record. Without objection. Thank you. A wide variety of disease groups are represented in these submissions including als, di pg, extremely aggressive pediatric cancer and ultra rare genetic disorder that regularly results in death from Heart Failure before a childs fifth birthday. Importantly none of the diseases that our constituents have contacted us about have any form, any form of fda approval treatment. Not one of them. These diseases are relentless. They are widespread and devastating. Most are considered a death sentence but they are not invincible. Our constituents are not helpless. Patients deserve a promising pathway at the fda. Today im joined by senators gillibrand, wicker, kramer, murkowski, mansion, and warnock and sponsoring the promising pathway act to create a more flexible, accessible and compassionate drug approval system at the fda if there is any indication of the over hour and a half i spent on the senate floor yesterday we are going to be getting a lot more senators on this bill. Promising pathway act will create a rolling realtime drug approval pathway to speed access for individuals with these Rare Diseases. This build this not undermine Patient Safety or fdas Gold Standard for drug approvals in any way. Therapy is developed through the pathway will be rigorously evaluated and continuously studied using real world data. I ask unanimous consent to enter into the record a letter of support for the steering signed by 15 individuals and organizations. Without objection. Promising pathway act as a common sense step to give the fda the flexibility it needs to serve americans with these most trying diseases. Our constituents continue to fight for new treatments, greater access and full lives. To ask my colleagues to join me and unlocking hope for these constituents. I yield back to you at senator casey. Thank you Ranking Member brought in of course you work to put this hearing together. His staff and our staff and im grateful for your work on this. This is a topic thats meaningful to everyone in this room and every member of the committee. We look forward to a robust discussion about this topic today. As Ranking Member braun outlined Rare Diseases are those that affect some 200,000 americans and over 7000 Rare Diseases have been identified. 7000. While each individual rare disease may only affect a small number of people, collectively its estimated some 25 30 million americans are living with the rare disease. We have done a lot of research into Drug Development for these Rare Diseases. In 1983 prior to the passage of the or orphan drug act there were just 38 drugs approved to treat Rare Diseases. In the 40 years since, we have over 111,100 new drugs or new indications for new drugs approved for Rare Diseases. I am proud to work on legislation entitled creating hope act to incentivize the development of drugs for rare pediatric diseases. In particular another legislation to address of the challenges faced by those living with what you might call ultra Rare Diseases which affect even a smaller number of people. My legislation captures what we as legislators are trying to do to give americans living with Rare Diseases hope for the future. But we have made some progress many challenges remain will hear from our Witnesses Today too many People Living with and dying from Rare Diseases still do not have fda approved therapies to treat or mitigate their conditions. I believe every one of these individuals deserves access to an fda approved safe and effective therapy. We must make sure Research Continues in Clinical Trials are designed to allow effectivethers quickly as possible. Rare diseases and the research and Clinical Trials or drugs to treat them are fundamentally different from more common conditions. We will explore some of those differences today and the ways in which they present challenges for Drug Development. Our witnesses and the testimony today. It is important to note my observations on the challenges facing the rear disease communities and the community and the steps we might consider to address these challenges do not necessarily apply to other non rare conditions. But as we will hear today the challenges for Drug Development start from the earliest stages of development. When Patient Populations are small its hard for clinicians and researchers to develop what is known as a quote natural history. For the disease what the trajectory of the disease is, when it is not treated but natural histories are important for developing therapies because if you dont understand how a disease progresses it is hard to measure whether a new therapy is working. Rare diseases often are heterogeneous. Meeting not every patient progress the same way compounding the problem of poorly understood natural histories. Once a promising drug candidate makes it to Clinical Trials there are further challenges drugs intended for common conditions are tested in hundreds of thousands of people. When your entire Patient Population is only a few thousand were a few hundred or a few dozen it is simply not possible to do the same type of Clinical Trials. When you have smaller trials was difficult to demonstrate efficacy. In recent years the fda has taken action to improve how it works with Companies Develop in drugs for rare and serious conditions the agencies have done a lot more work to hear directly from patients affected. More recently the fda has announced new initiatives specifically aimed at supporting Drug Development for Rare Diseases such as support for Clinical Trials advancing Rare Diseases therapeutics. Or the acronym start at the Pilot Program to enable realtime communication between the drug sponsor and the fda on developing issues. Another Important Initiative at the rear disease endpoint advancement Pilot Program to support drug sponsor ability to engage with the fda around the development of socalled endpoints the metrics of efficacy for drugs for Rare Diseases its also done more to hear directly from patients with the patient focused Drug Development. These are meetings that give the fda staff to hear directly from patients other disease affects them. What drug effects are meaningful to them in their daily lives. I support the recent steps we should continue supporting and strengthening their authorities and to do more to facilitate more approvals of safe and effective drugs i look forward to hearing todays recommendation from our witnesses about the steps we can take to lead to more fda treatments of her Rare Diseases next we will move to our witness introductions. I am pleased to return to the first witness the first two witnesses i should say will be sharing their experiences as patients and advocates but in this case they will not be answering questions. Theyll be providing virtually none for our First Virtual witness ill turn to Ranking Member braun. Think it mr. Chairman. My pleasure to introduce ryan a wallick. From the time chris coons and i from the als caucus in the senate which has been an active one, got to know brian well over that time. Really it needs no introduction hes a true changemaker in champion. Brian has a storied career as a Regional Campaign director white House Counsel for president obama. He later became a federal prosecutor in chicago. His life took a turn in november of 2017 when he was diagnosed with als. And given six months to live at the age of 37. Rather than accepting status quo he decided to fight. Along with his wife sandra, he cofounded i am als and nonprofit dedicated to secure als break. Brian is the father of two youg girls, thank you for being with us here today. Think he Ranking Member braun now i will read an introduction for my colleague senator durbin senior senator from illinois. Quote i am so pleased the Agent Committee will be hearing from a constituent this morning and i thank the chairman for affording me the opportunity to share a few words about brian paired with the truly wonderful things about being a nice it senator is the people you had to meet along the way. People like brian is wonderful wife, sandra. Six years ago on the day they shouldve been focused solely on bringing their newborn second daughter home for the first time this young family was confronted with an unimaginable diagnosis. Brian had als a disease for which there is no cure and which as of now is fatal one 100 of the time. Right and center quickly turned turntheir grief into action stag i am als galvanizing the als Community Around advocating for increasing tension research and results for all als patients and their families. And boy have they had success but brian and sandra been the driving force behind getting an act signed into law ensuring congress twice doubled the department of defense als research budget, eliminate the fivemonth waiting period for als patients to get Social Security disability benefits and work with the food and Drug Administration to finally get several new alist treatments on the market for the first time in years. They are not done yet hope the aging committee is is as inspired by brian as i am and always m and i look forward to hearing his recommendation for how we can continue to utilize patient voice to make progress for als families. Unquote that its a statement from senator dick durbin. Our second witness marine bell is from pennsylvania. She was diagnosed with a classic way to make sure princess rate. Good luck to see mia seven days after her birth in 1972. She has experienced many of the challenges of those living with the disease have shes an advocate for those living with this disease and a helpful resource for new patients with their newly diagnosed children. Thank you for sharing your experiences and your story with this alternative Ranking Member braun for two witness introductions. Think it mr. Chairman my pleasure to introduce doctor peggy. She is a brody professor of medicine at the university of virginia hospital. Peggy attended Harvard Medical School completed residency at brigham and Womens Hospital in boston in december of 21 her husband james was diagnosed with als. She has since become a caregiver and an advocate with i am als. Peggy and her husband have two children peggy, thank you for agreeing to testify in james thank you for being here today. Next a witness. As the chief executive officer of salih note therapeutics. Small biotech firm dedicated to treating rare genetic disorders. He has been since 2006. Is a physician with over 20 years of experience in developing biologics drug device combination thank you for being here today. I will turn to senator vance to introduce you the next witness. Think he Ranking Member braun. Thanks to the chairman for hosting this important discussion. Center for ohio on project introduce a great ohio mr. Keith. Cofounder finding cures for the rare pediatric brain cancers that make your other types of cancer shes the president of the pediatric tumor consortium for enhanced wife and 2007 but cancer called the ipg at the age of seven public battle was memorialized the bestselling book which was eventually translated into 22 languages. Has invested more than 30 million and over 130 trials across 17 countries keith helped create an innovative and a registered become a model for other disease registries hes advocating on behalf of a publie Public Policy facilitating his important work by the make it harder. Thanks keith for being with us today. Think it senator vance i will introduce sixth and final witness. He is from philadelphia, Pennsylvania Works in philadelphia but works in delaware county. Vassar assistant medical ethics and apartment medical ethics and health policy. The university of pennsylvania. A lawyer and bioethicist by training the scholarly work focuses on food and Drug Administration of pharmaceutical policy. Access to investigational medicine outside of Clinical Trials. Thank you for sharing your expertise with us today but will start with the first witness Brian Wallick and maureen bell will follow him. You may begin. Chairman casey and Ranking Member thank you for the opportunity. [inaudible] my name is Brian Wallick ive been saving with als for six years. Als has changed every part of me. My leg no longer works. My arms a longer worker. Als has almost taken my voice as well which is why its reading my testimony. Als is a disease that is 106 years old. The paper beat that for 160 years als has killed literally everyone diagnosed with it. Everyone. That is simply unacceptable. To date we hope to reform the fda approach to diseases like als. Under current fda standards it can take 15 years or more for effective drugs to move from preclinical work to approval. In the meantime many people of rapidly progressive terminal including als died and have no viable treatment or option of hope available to them. One of the lessons is there is no such thing as a cold Gold Standard across the fda for how to approve new treatments for rare or fatal diseases. Instead the painful reality is that whether a treatment will be approved or not depends on what fda center it is in and on a specific individual in the fda review assigned to treatment. A second lesson is the existence of the 2019 fda guidance is simply not enough to ensure uniform approval standards of ad new treatments for als. Wheat very, very unfortunate learn this lesson far and away just a few weeks ago during the adcom for neural the question presented did not incorporate the fdas only 2018 guidance about regulatory flexibility. A primary question put before the ad was to the data presented demonstrate substantial evidence of effectiveness for treatment of mild to moderate als. This question did not at all make reference to the 2019 fda guidance that stated quote when making regulatory decisions about how to treat als fda will consider one tolerance for risk to the serious and lifethreatening nature of the condition hen all within the statutory requirements for safety and efficacy. This is exactly legislation the promising pathways is absolutely critical for People Living with als. There is no fda approved for at 95 of us living with als. What is the result of that . The result is treatment for 95 of People Living with als, including brian do not qualify for accelerated approval. The promising pathways act addresses this issue by creating. The promising pathway act is also building the infrastructure to require drug sponsors to move faster when given the fda the authority to remove divisional approval and Additional Data makes clear. We support efforts to make safer promising therapies to more people in the terminal diagnosis pending full fda approval we also support efforts to increase spending on research and the cause of als pending treatment. We do not support this generation, thank you for your contribution to research. Now go home and prepare to die. Academics and vital advocates they have the luxury of debating theoretically what might look like some perfect system People Living with als today whose lives are literally on the line. We do not have that luxury. We are looking to you to provide that with the hope they can live a little bit longer and maybe even be here to see it for als. The key here is approval is provisional it affords early access to promising drugs for people with extremely serious conditions who are willing to take risks and less additional evidence to be collected during a short two year approval windows professional approval can occur only if the drug has been shown to be safe and required patient registry enable much broader Data Collection about efficacy and safety that could even occur in traditional Clinical Trial. This data will help the fda make decisions when it comes to the approval and labeling of new treatment. Moreover drug sponsors want to obtain full approval of any traditionally approved drug other than allowing real oort evidence supple bit an application its ultimate current standard for full drug approval anyway. The als story is exploding and with the measure tried to make faster changes needed to finally get treatment in the community that will allow people such as myself to live longer and potentially be around to see als transform from fatal to chronic. I want to take a moment to recognize the caregivers and the people and with als in his hearing room today. We represent 30,000 americans live with als right now. I hope you or your spouse will take time to hear your stories and why they believe in the need for promising pathways act. I also want to recognize doctor peggy who is before you as a witness. Whos been living and breathing als for the last year end a half. Thank you, thank you for your time for thank you for allowing me too be a part of this discussion. Thank you for understanding how important the pathway back is. I want to thank brian for their testimony. For being with us today. Now will hear from brian bell. My name is marina bell. I live in pennsylvania. I have lived with glock to see me and for my entire life. Shortly after my birth in 1972, i began to show the classic hallmark signs of failure to thrive. This repeated vomiting and weight loss. Seven days later i was diagnosed by an intern as i having classic. I remained in the hospitals for three weeks my mom and dad were given a 32 page booklet entitled a parents guide to a court lactose restricted diet. They were instructed to follow this a booklet as i would need to be on a lactose free, dairy free diet for the rest of my life. That was the early treatment in 1972. I doubt my parents to many more challenges with my head. Along the years to come i havent me follow a dairy free diet. It seems everything is working fine for me at the time but i was getting older and it made me feel very left out when i cannot eat the same foods as my peers. Without modern day advances we have today in nutrition, i cannot tell you how isolating it was for me. There are many social events i could not attend. My mom tried so hard always sending me too parties with the special treats. Not just for me but enough for everyone so i was able to share. Not being able to eat the same cake that everyone else was eating at the Birthday Party was very difficult as a child. I also cannot process information the same way. I always was below average student math list might most difficult subjects. But it still is today i struggle with making chains leaving tips at a restaurant and figuring out percentage. I cannot process it. The circumstances and People Living with were similar to. Justice i was academic go slow in developing physically. I was not having any issues of this. Nearnormal signs of puberty were nothing like Late Development and i still look like i was in grade school physically as opposed to being in high school. This continued and the sense of isolation also continued. I began to have some unusual symptoms such as hot flashes, night sweats and mood swings. After about a year of experiencing these symptoms when having bloodwork i was diagnosed at the age of 18 as having premature ovarian insufficiency which is a direct result of glycemia in female patients this was something that i continue to struggle with today. As a result of this diagnosis i became a what no part in a meeting or socialize like in the other 18yearold would. That was the impact of pli premature ovarian and physician c. This was very difficult in my 20s. I just wanted to be like any other woman at my age socializing and having fun. However i was depressed had a very difficult time making friends and meeting new people. There were nights i cried myself to sleep at a church event in 1999 i met a man named bill who showed interest in me and i started spending time with him. I was very apprehensive about getting involved in a relationship even though i was 26 years old. The fear of falling for someone that telling someone as infertile take a chance on losing the relationship laid on me very heavy. However i finally got the nerve up to tell him. Bill is a pharmacist and his response was priceless. Not caring about my diagnosis and instead advising me too take my calcium because i was such a slacker taking my calcium. What a huge weight that was lifted off my shoulders we recently celebrated our 23rd wedding anniversary. I was told that having this is like looking through a window at everyone at a party and they are eating all kinds of foods i cannot have. I could see them through the window and through the glass but could not break it or join them. The same is true for infertility. I can see it moms i can see childrens and families but i cannot break the glass. This experience but cannot experience what it is truly like to be a mom. All my life i have long to be on the other side of that window. There could finally be a treatment for people like me and even though its too late for me, for younger ones living the way i grew up i spoke at the patient focused Drug Development meeting our Community Never heard from fda after that. They had no questions. No clarifications that made us worry they had not taken the time to learn from our work before reviewing the drug. They understand speech issues dont matter to us the same way as cognition and developmentally do some of us even have more scary symptoms than the ones i have mentioned. Like seizures tremors, cataracts, neurological impairments and intellectual impairments. They understand that if they ask for another trial their diseases often dont have enough patients for another trial. Will they understand that at the if thedrug is approved for someg else our doctor says seen the improvements and our candidates on the right to prescribe it for us too. This drug is already being studied in other Rare Diseases. Government insurance or through my job, Insurance Companies dont treat their diseases like cancer. So that is a whole other hurdle. These days we must fight for approval but also fight insurance two. The foundation is working hard on both things. I hope you can help us all. Im writing about places like fda cms and congress and the other whose lives are impacted by diseases. I do not pretend to understand, but i know even one person can make a difference and i want to help little girls going through isolation, puberty, depression and fear. The inability to understand the process. If all of you can take my story and help them it would mean so much. Thank you. Thank you for your testimony and for sharing your personal experiences we are grateful you will spend this time they hope you can listen to the whole hearing. We will now turn to our next witness. Chairman casie, Ranking Member brown and members of the committee. Thank you so much for the opportunity to present to you today by the testament i gave here is reflective of my own views and not intended to reflect the positions of the university of virginia. Im first and foremost the wife and caregiver to my husband jim we are both sufficient under seven seconds 2021 our lives cracked open. Jim was diagnosed with als. At the time we are both busy scholars our lives are full with meaningful work, community of friends, with this diagnosis our lives were completely upended. What i remember from medical school als physician dreads more than any other. Why . Als is a disease that robs a person trumps everything essential to living our lives to move, to communicate, to eat and drink, and eventually to breathe. The double edge cruelty is that awareness and cognition are left intact. Since living with als can feel each loss and fear at the next when each moment. Als is one 100 fatal. No one has ever survived. The Life Expectancy after diagnosis is three five years. When given this diagnosis patients, here go home, hug your loved ones and get your affairs in order. People worry about giving patients false hope. But i think they dont understand the devastation of having no hope. Simply waiting for the inevitable to the client. Both being physicians we were not naive about als. But having no hope was not an option for our family. Like many als families we got moving we read, we investigated critical trials, we got involved in advocacy. One unacceptable route that we faced as a diseased moves faster than the fda amx oh 35 so drug in a pipeline had excellent safety better evidence for efficacy in a phase 23 trial than anything currently available. As initially denied approval by the fda who wanted an additional confirmatory phase through trial. This drug is a combination of two drugs that have been on the market for many years. One was overthecounter. The only way to obtain a medication was get that one component online. The other component from a Specialty Pharmacy in new jersey. A cost around 1500 to 3000 a month. Most of our friends in the als community could not afford this. Only after fierce advocacy to the fda taken a look at the data and approve it thankfully. Over two years the results of the Clinical Trial were clear what two years means for an als patient for two years ago jim was running races at purdue chief medical officer for a new integrated care network for children across the state of virginia. I start a new program at uva to care for medically complex children. Thriving pediatric practice full of kids and parents who adored him. Today is confined to a will to raise help to eat, cannot roll over in bed, or even scratch an itch. Hes losing his ability to speak it. Inside the body than stealing him jim is is in brilliant and passionate, creative, loving human being. The courage she displays every day is stunning. I am his primary caregiver the nights are the toughest. Every time jim needs to turn over or just as a vent mass, pull up the covers i need to do that for him and hes too somehow communicate that need work not for the support of our amazing grown children, extended family, neighbors and dear friends i am not sure what we would do but als is relentless. What you think our life will be like in six months . One thing i know jim needs to be here hes got a new grandbaby and a wedding to attend. As a physician one of my areas of expertise is reducing errors in medicine. Doctors are naturally focused on getting all the data to make a certain diagnosis before we start treating someone. But we have learned over time that it rapidly progressive lifethreatening illnesses delaying treatment while awaiting that certainty can cost someone their life. So we start treatment while confirmatory data are coming in. I have watched helplessly as my husband lost the ability to use his hands, then his legs, then his voice. In the face of this wonder fatal disease delaying access to a safe promising therapy until confirmatory trial can be achieved is cruel. Jim and i are both old enough to live to the aids crisis. When i started residency there were no treatments the medical wards were filled with aids patients and their loved ones the patients dying no matter what we did. Then patients and their loved ones got activated they fought for more Research Funding. They fought for early access to therapies. I wash it each new therapy one by one turns disease around. The earliest therapies were less effective had more side effects but they say peoples lives. The drugs were added and combined together into cocktails. Like those early hiv activists when the als community are fighting for more Research Funding were fighting for early access to safe and promising therapies. You have the power to change the landscape of a less in this congress. Transforming it to a manageable eventually curable disease. This is not false hope. It is real hope. We need your urgent action and we are counting on you. Thank you very much. Dr. Kagan thanks for auteur testimony thank you for sharing your story on jims as well. Doctor email begin your testimony. Clicks Ranking Member and honorable members of the committee im honored to testify at todays hearing, thank you for inviting me. My testimony today is my personal opinion based on my experience over the years. Im a physician by training, 25 year career almost entirely has been involved evolving treatments for cancer numerological. The last several years for Rare Diseases. None of my work, including that of lifesaving cancer drug has been as meaningful as working with this Amazing Community of families of children and adults. Many of them are in the audience today. While regular challenges across are similar is a much more disproportionate impact on patients with bare diseases. Simpler impact is seen in Small Companies like ours which a large proportion of the work. Our ability to raise money depends on regulatory clarity. If the meeting do not clearly state a path forward or if a Company Receives inconsistent feedback its a difference when having money to carry out a Clinical Trial or giving up on a drug to treat a disease that has no options. Speaking of diseases without options from a pete ws is a rare lifethreatening condition that occurs randomly affects about 1. Children pete ws are often recognized within weeks of birth. The age of three or four years they will start to show more of an interest in food which increases over time until they ultimately developed hallmark symptom. Insatiable desire to eat the brain telling you that you are starving even as you eat. Individuals affected never filled full currently focus on one thing, food and how to get it. Left unsupervised of the potential to literally eat themselves to death. Much like a teenager to debut us a reason he ran away ate an andepistemic ruptured and he pad away. The only remedy for hyperplasia is to restrict access to food. Close kitchens locked refrigeration pantries motion expert or cameras and alarms. Families live in the constant fear of extreme outcomes like visit to the er contravention and in many situations the need to be cared for in an institutionalized setting. And invariably theres a need for constant supervision for life. Numerous drugs have been tried, tested to treat an pws in late stage trials. Each one of them has failed Many Companies have been dissolved. Its a once a day pill based on a known molecule the value is improvement of study from 2080 through 2020 ending a few months of the start of the covid 19 pandemic. The study missed the endpoints. The preet covid data significance in favor of the drug. Up to four years in some patients combating National History of the disease show statistically significant clinically meaningful improvements with the drug. We would ask additional controlled data. We just completed the study which is highly significant meaning for benefit. We need a Regulatory Framework that recognizes the novel complex heartbreaking too. To be of u. S. We cannot continue to apply for all diseases and all drugs. Contacts must payroll. Its amazing to see new options available to people als and the drug. There is also like potts syndrome but it may not have a path forward. Aleatory delays such as a thetreatment back and forth betn the fda have realized Companies Like ours programs will be cut some will shut their doors. Every day come every week, every month, every year, symptoms will worsen preet sometimes a irreversible manner. Patients may die as they wait treatment. Fda is a needs to remain the premier regulatory where it is desirable its a rigorous process. But one that balances the risk of having no treatments treatmee for a desperate population. The pathway act is a significant step in the right direction. Timelimited provision approval will allow patients the ability to life changing treatments. Availability of such treatments to be driven by clinically relevant data only upon a rigorous analysis of data generated from patient registry. In closing i truly appreciate highlighted the significant rare disease communities in particular the pws community pray thank you for your time and look forward to your questions. Dr. Kagan thanks for auteur testimony. You may begin. Thank you. Thank you for the opportunity to inform todays discussion about how best to achieve with a goal we all share but helping patients with a rare serious diseases live better and survive longer. My name is Holly Fernandez lynch im an assistant professor at the university of pennsylvania speaking only on my own behalf. As you heard my scholarship focuses on fda drug approval policy access to medicine prior to updated approval in Clinical Research ethics and oversight. I say to before you as an academic on a panel filled with lived experience in a room filled with lived experiences. Ive not personally living with a rare serious disease but the sad reality is that Rare Diseases are not rare in the aggregate. Any one of us could find ourselves or our loved ones affected at any time. Like many, my family has not been spared from a serious and lifethreatening diseases including parkinsons and childhood cancer. We all have an interest in these important issues but whether we are suffering today may be suffering tomorrow. My key message of the committee is that weakening fda approval standard risks template the essential goals more drugs that work with the deflated goals of simply getting them more drugs. Of course we should tolerate more uncertainty when considering drugs for serious diseases. Thankfully fda has already expansive regulatory flexibility allowing it to just that. The agency is granting accelerated approval for more frequently and broadly that it t has in the past. It is also demonstrated a willingness to approve drugs when trials failed to show benefit on prespecified endpoints. When benefit is supported by just one pivotal study. When trials are very small and when they last concurrent control groups. Unfortunately the flexibility is not always mow the rigorous benefit after drug approval. Which is a concern also raised by the promising pathway act. The proposed bill seeks how long uncertain benefit can stay on the market should always be followed by efforts to collect additional evidence. However, after the promising pathway act will set the bar too low for both provisional approval and confirmation of benefits. I certainly understand why any individual patient might be willing to pursue access to a new drug based on irrelevant early of a positive therapeutic outcome the bill proposed standard. The problem is weak approval standard affect all patients not only those who choose to take a provisionally approved drug. Companies produced evidence about safety and effectiveness because it is a legal requirement for marketing and to profit from their drugs. Fda demands left evidence patients and clinicians will have less evidence. We see this today in the dietary supplement industry. Imagine what you had available to treat your lifethreatening illness with the rows and rows of a product too. None of which were known to work. Weak approval standards can also entrench treatment by making it difficult to study potentially better treatment options. Because of reduced willingness to enroll and challenges interpreting results when new drugs are compared to unproven ones. Promising pathway act proposes to address these challenges by relying on patient registry. Because registry lacked randomization and blinding observed differences and outcomes might be attributable to underlying differences between patients rather than a result of the drug of interest. Instead of weakening already flexible approval standard the stronger path forward is to address scientific bottleneck. Fda and others have already taken important steps in this direction. The agency recently launched a program firmly dubbed operation warp speed for rare disease it will provide realtime advice to companies starting at the earliest stages of Drug Development to speed successful trial manufacturing and other challenges. As a Pilot Program for diseases and als science strategy emphasize improved Scientific Understanding every disease, enhance Clinical Trial infrastructure and innovative trial design to support the developer to better drugs. While the science continues to develop the best way for this committee to improve access to effective rare Disease Treatment is by ensuring Adequate Funding for rare disease research, promoting Clinical Trial accessibility, encouraging use of fda expanded access pathway and clarifying fda has the authority to require and enforce rigorous post market efficacy studies whenever it approve the joke with uncertain benefit. Thank you for your commitment to these important issues and i look forward to your questions. Professor, thanks very much. Our sixth and final witness. Thank you chairman casey Ranking Member braun distinguished members of the committee to discuss the promising pathway acts. Something vital to our efforts to homeland here for cancer. Im of the care starts Foundation President of Pediatric Brain Tumor Consortium most importantly im a father. My daughter elena fought a cancer called the ipd when she was six years old. We had no hope, there were no trials available they told us to go home and make memories. Sadly, she understood this as were fully aware so very last date there is nothing we could do. You see with the ipg each day you see your child lose something. One day it was her ability to bill see out of her left i. The next day it was her ability to speak. Then her ability to walk until one day it became her ability to swallow, to breathe and her heartbeat. Whats particularly cruel about this type of disease it affects children and it is very, very rare in adults. But at the same time many experts believe this is a cancer that can show the most promise of the same time believing this is a cancer they fear most. Universally for this reason it is known as a homerun cure of cancer. We have made our mission to it o focus on these rare cancers Building Tools from scratch such as a registry that spans 129 hospitals, intelligent patient tool strategic research, and even virtual hospitals to try to leverage all of the great guidance and intelligence we can find worldwide to come to bear on one specific patient. And in 17 years since alina lost her fight we have invested in over 30 million in research and support through projects. I understand the perspectives of the researcher. I understand the perspectives of the parents for under 70 perspectives of the registry. I come to you having seen each of these various elements. In addition to talking with patients each and every day when they are in their last weeks. I also come to hear it with hope. I hope for a new way to fight cancer. I believe fdas wellintentioned no one plans for this type of devastating cancer. I believe theres much inherited. Whether by regulation or guidance clarity i argued the system is broken the status quo will not do. For our purpose or effectively only two measures we consider with sgt talk about the ipg expanded access the other is right to trial. Its important to have the expanded access is not alternative or promising pathway act. Kelly from done with the loss of my daughter but calls with over 200 families per year asking for help any help in the last and final days. Expanded access requires four levels of approval. Twentyfour hours for him and to recognize with the new, three days for a doctor to determine the strategy. Two weeks for internal review board to approve a methodology three days for Pharmaceutical Company to respond hand up to 30 days for the fda to effectively approve the entire process. Thats moment longer than our child survives it does not work. In this right to try. Slightly better of the two level processed to patients and families with an end report model it submits to the fda. We think clarity withing transparency, or cornerstones of being able to find a cure. A storm terminal means months or years to live. They assume theyre not intelligent to make decisions for themselves they assume the data and less than ideal situations are worthless they assume every patient is an adult. The assumptions are wrong. The reality is we do not get doctors who understand the assistance we do not get a call back on the weekend and none of these acts were designed for pediatric terminal diseases. The promising pathway act as differential. Offers an alternative to fda mandated unethical practice of trials given the wrong drug to the wrong patients were pediatric terminal diseases. Right now, nearly every therapy designed for pediatric cancer is guided through a threephase adult trial before we can even get to a terminally diagnosed child. Outlier participants and retains it for the use by the fda the Drug Companies and researchers and patients and any thirdparty registry of registrf substance thus improving transparency. Also addressing Insurance Coverage and Financial Burdens in ways that neither previous alternative has. Finally, promising pathway act advances innovative therapies that may be impossible to subject to current trial design. Keep in mind the trials for the rare cancers rarely ever get leading us to give up on good ideas were enrolling children in trials we already know dont work. It is not lost to me the value of a Clinical Trial but what is lost to others is the value of a quick and efficient Clinical Trial. Unfortunately with rare pediatric cancer we have to consider this and sadly in their final days also compassion. I have a pile in front of me of grants. These are grants that we have worked to build, to fund at many different institutions. Theres 46 of them. This is a pile which has hope, it is the dreams of the researchers and frankly it could be the lives of these kids. This is 46 chances to be able to cure cancer and sadly the whole reason why im here today is i believe that these 46 opportunities to be able to cure cancer may never reach bedside unless we get dpa past. I am a big believer in personal initiative but in this case we may be able to go no further unless government gets out of the way. The promising pathway is how we do this. Families are desperate for another chance at seeing their children go to kindergarten, see their child to get a drivers license, to see them graduate from high school, go to college and get married. We want a chance to see them grow up. Rarely do you have a chance or a bill that asks for no money and it isnt really part of what we are asking for. This is the case when you connect to give patients fighting for the power to save their own lives. I lost my daughter but i refuse to believe that we cannot save hours. Youve heard today from some compelling and welleducated witnesses. Im the only one however that has lost everything in the sand was given no options because there wasnt any. There was existing barriers that were either too cumbersome where policies were built around the majority and while some may appear to be small from the aggregate, it is with this type of cancer that experts also believe that we would have the greatest impact to be able to cure it. So what we may ignore may be precisely what may save us. The promising pathway act may be the single biggest piece of legislation that costs nearly nothing but may change everything about how we win the war on cancer. Thank you. Thanks so much for your testimony and for the story of your family and your daughter. I will now turn to the Ranking Member to begin a round of questions. Thank you mr. Chairman. First question is for ryan if youre still with us. We appreciate your testimony and because of your work how youve got so many people engaged in the cause. And kudos to you for that. What was your risk tolerance for a new therapy that is documented, real world evidence showing advocacy and has received provisional approval from the fda . We come back to brian if he is still with us on zoom. Thank you, senator for your question i have no other option for new treatment other than other than the expanded Access Program or provisional approval that other patients may not to be because i know that if i do not try, i know that if i do not try, i will die thank you. Next question. Thank you for sharing your story. Sorry for the loss of your daughter. Will any current drug approval or Access Programs at the fda address real terminal pediatric cases . I dont. Thats the reason im here because there isnt anything that applies to this. The amount of patients that we talk to they are not getting any answers for medicine or Drug Companies or anything of that sort. Its because of two things. One reason is because of time. We dont have that time. We have two weeks and nothing gets done in those two weeks. Ive had so many times ive seen compassionate use has been approved for a patient that usually comes in several days after the patient has already passed. To talk about a difficult call, thats a horrible call to make. Ive also seen where it doesnt address anything having to do with pediatric. We write walls with the ideas of adults and if you look at these guidelines weve put forth, we grant waivers for them not to do it in pediatrics but we never go the opposite way and so because of that we have to wait and hope that it can go through all of the adult trials first before it can ever get to a child so it never gets started so at the end of the day we cant get access to those drugs. The time is not the right amount of time and the children are being ignored in this and it shouldnt be that way. I do have more questions if you want to go ahead and ask another one. Fda has a variety of drug approval pathways and designations in recent years the agency has begun to take steps towards creating a more accessible and flexible system. However millions of americans with of these diseases lack any fda approved treatments. Could you highlight the hold in the fda drug approval and a Clinical Trial system that your husband is falling through . Thank you for that question. I will mention two. One i think weve heard a lot about today and i want to be clear that is important to me and that a problem that i would like to see solved is that patients that are dying dont have timely access to promising safe therapy. To be clear i dont think anyone you heard speak is suggesting a change to the safety standard. At this is about time and access. To confirm safety and establish potential efficacy and then phase three trials. Obviously no one sitting at this table has had for themselves or their loved ones. The time it takes for these confirmatory trials is simply too much for these particular patients with of these particular diseases, so we want access to promising therapies when early evidence has been established and being confirmed all we want as an alternative is a pathway that allows access to therapies at the point where safety and promising evidence and effectiveness have been established. The second point i want to make theres been talk about the accelerated pathway thats really not available to patients with als at this point at least 95 of patients with als because there is no reliable biomarker in the pathway that requires or relies on biomarkers or surrogate endpoints, so thats another hold of for someone like jim that pathway really doesnt apply. Thank you. This question is on bio biotech risks. Mostly Smaller Companies can be billions of dollars and years to submit and the application to the fda Larger Companies generally dont do it. Tell me a little bit about is the market cooling for this due to the fact that we have a process that is stubborn and bureaucratic. The answer is yes. There are parts of the system that are doing well. Patient advocacy is stronger than its ever been before. The funding environment you can see and engage in the Public Companies with about 30 . This may be the third year in a row. It would be the first time thats the case. Number of Companies Going under have been phenomenal. Number of layoffs have been extraordinary. So, yes was the pathway addressed in a way that would be meaningful so we at least keep this in business when you think of why that is the case i think the uncertainty in the Regulatory Environment with Companies Like mine we work on one or two programs and if you dont have the clarity, then its hard to get the funding to do the work it would definitely help. Thank you, Ranking Member. I will next move to my questions and i wanted to note a number of senators have been here and some will be back. After my questions or appearance we will go to senator scott. Weve also had to senator joe legrand and blumenthal here. Let me go to my first maybe two questions. As a predicate, i understand one of the challenges in rare disease Drug Development as isthere are often very few true experts in the disease and this presents difficulties in the drug review process. The fda acknowledged the challenges and indicated they are open to revising some of the policies to ensure a clinical expertise for rare disease therapy. So heres my question. As you work through the Drug Development process, are there areas where greater expertise and Rare Diseases like you mentioned among fda expertise for that syndrome among others, among those reviewers are there instances where that would be helpful for the expertise . Thank you, senator and yes it would be helpful. When youre dealing with the diseases, we dont expect that there would be at the fda because it is a disease. So we would hope that from the very beginning of the process there would be experts at the other end. Thats not been the case. We generally take physician experts with us. The problem and Rare Diseases which is different from other large massmarket type of businesses is that you generally involve all experts in the Clinical Trial otherwise you wouldnt be able to enroll the trials. If you believe them to be conflicted then who would be the expert so this is one not very difficult thing that can be implemented. You can take their opinions with a grain of salt but consider them to be nonconflicted. Thanks very much. I have one more question before turning over to senator scott. How can the fda ensure its consulting with the is these appropriate disease experts while ensuring transparency around potential conflicts of interest during the review . Thank you for the question. This comes up often when the fda is trying to populate the advisory committees of external experts that often called upon to help them understand various issues related to whether or not they should be approving products as well as broad questions about the Drug Development in particular areas. Fda can waive the conflict is in certain circumstances for example where there is a dearth of experts in different areas they often do waive the typical conflict of interest rules. Theres other ways also as managing conflict. So, for example if you include somebody that has ties with industry or has participated in trials you can also invite additional people to provide their broader perspective. So i think that this is something that is already happening. They are already aware of the challenge. And in fact, it is more often academics like myself that are pushing to be more careful about conflicts than they already are. Thank you, professor and i pi moved to senator scott. First i want to thank the chair and the Ranking Member. I want to thank all of the witnesses. I think everybody in the country has been impacted by a rare disease. I built a Hospital Company and the regulatory hurdles. It was a devastating disease all the money that we increase the Research Dollars on cancer and we got all of our Cancer Centers and everybodys doing research to share their data which to accelerate that seemed to have some impact. We put a lot of money into nih and doubled a budget so i think that we have to do it all of your doing to see if there is Something Better we can do. This is how we get things done by people telling their stories. What can congress do despite the delays that you are seeking . First i want to acknowledge as far as the epicenter, the university of florida has the name Jennifer Miller who sees sees thelargest population in te country. Its true the fda already has the authority needed to provide the flexibility and circumstances we are talking about. There is no consistent application of the flexibility. So i dont know what tool it takes, but i think to mandate the consideration of the regulatory flexibility is valuable and to work with experts to define for a given setting with that flexibility should look like is important and to come up with an enforcement mechanism to ensure that is happening is important. So im not sure what it takes but conceptually that is how we would go about it. 24 of my colleagues in the senate and house asked for change at the fda. Requesting the task force to include leaders from all divisions, offices and centers which process the rare disease therapy applications and examine areas of policy procedural inconsistency and shortcomings to see what we can do better. Also the task force to provide recommendations. The fda to disagree with of the task force that they said they are going to share relevant reports. Theres no accountability and that it doesnt work the way its supposed to work. So the more specific you guys are, the greater chance we would get something done. Does anybody know what kind is collected in the Clinical Trials and how does the fda use that . Does anybody have any ideas . Its in a variety of ways. One of the ways as the patient focused Drug Development meeting where they attend and listen to the Patient Populations about the unmet needs et cetera. During trials, trials like ours we collect the patient information based on questionnaires looking at symptoms and signs that are relevant. If they dont have a lot of fans and their evidence. Realworld evidence is something that theyve been discussing, but its been part of a very small number of applications for approval certainly not the only one approved so far. To add onto that its not fda that is gathering the evidence. Its companies that are responsible for conducting the research but through the patient focused Drug Development program at fda, they put out several guidance documents to promote systematic methodologies and gathering patient experienced data to inform the development of Clinical Trials to make sure that they are asking the questions that are important to patients and systematically gathering information so that it can inform regulatory decisions and having the patient representatives on the advisory committees. Thank you chair. Ranking member. I think from the discussion you have heard today that its clear theres a difference between a broad array of the disease is out there and the places where most pharmaceutical companies go and that with everything we are talking about here its just not being addressed. Especially in the case where one with a narrow window of survival and within the paradigm is to meet bureaucratic and not responding in a way to these over along period of time is there any hope that we can get it done within that current structure. It to the comments that we were talking about about whats being collected and then also comes down to the guidance and the idea that it probably could be done. Is that cold compassionate use in the framework . They could take any of these measures and probably try but it doesnt happen. I think that is the reason why it really needs to be there because otherwise without it, theres nothing thats going to make sure that there is any accountability to deliver the right decisions on it. We witnessed time and time again i talked of Drug Companies and they tell me they cant figure it out. They feel what is in the guidelines versus what is in the guidance with the suggestion that they received back is not matching up. Its not going to focus on our realm and on pediatric drugs. We cant have that. These are small Drug Companies but thats where sometimes the best ideas come from and if we take an opportunity to show those ideas, that is a problem. The data isnt a property of one entity or another. There has to be a patient element to this. That is the beauty of the promising pathway act the registries that allow for everybody to be able to communicate that but still to protect the patients privacy at the same time otherwise we are going to get half of the information and be following what we think is the guidance on it and effectively what we are left with is a wild west type of mentality to how we deal with drug trials and we cant keep doing it that way. Thank you mr. Chairman. I very much appreciate holding this hearing and advancing this important idea. For individuals who are experiencing, the promising of new therapy or a cure provides hope in a profoundly dark time. Thats why ive long described federal support for medical research as one of the best investments that our nation can make and why ive introduced legislation to ensure you that that wefully invest in medical breakthroughs. I want to if i can today talk about a slightly different part of what happens in the drug approval process and im concerned about. I want to talk about how we get research from the lab to the pharmacy. One of the key parts of that as many of the people in the room know is Clinical Trials. Once a promising therapy is identified, pharmaceutical manufacturers have to test the drug for safety and effectiveness which involves enrolling patients in Clinical Trials. Patient displays enormous trust in the people running Clinical Trials. This is why all the Research Involving Human subjects in the United States must be approved by institutional review boards. Professor, you lead work on the quality and effectiveness. Can you say a little bit more about what the job actually is . Yes, thank you, senator for the question. Theyve been required to review nearly all funded research and federally regulated research. They prevent problematic research from proceeding and they also help make sure the science is strong. As i understand this, if a Clinical Trial cant answer the questions it sets out to study or does properly communicate the risks of the study to the people who participate in it, then it is the job of the irb to step in and keep patients safe. But rapid consolidation and a private Equity Ownership of irbs has raised serious questions about whether the boards are leaving vulnerable patients exposed to unnecessary risks. While most are affiliated with universities, the irbs that are not associated with any institution known as commercial are reviewing a larger share of drug Clinical Trials and according to a recent gao report despite representing 2 of the review board now review over half of the studies involving investigational new drugs. The gao reported private equity backed irb is and im going to quote our beholden to their clients or equityholders in other words people that put the money up. Professor, what are the risks that of this creates for a Clinical Trial participants . Thank you, senator warren and i very much appreciate that you pushed to examine this issue. I wasnt surprised by the finding that we still lack meaningful measures of quality. This is something thats come up time and time again and the lack of ability to assess the quality meaningfully makes it harder to assess the different types that is a problem that im working on in my own research. One challenge or concern about private Equity Ownership and profit oriented goals in this space is that it creates a primary emphasis on speedy approvals proposed research and keeping the sponsor happy. They have to compete with them. Now of course speed can be a very good and important thing when we are talking about research we want highquality research to move quickly but focusing on speed can also inhibit deep attention to ethical concerns and it can also limit the focus on maximizing scientific quality and approving science that is good enough and kind of meets the floor of regulatory requirements rather than making sure it is maximally valuable. So that is a primary concern here. Appreciate you raising this. I want to make sure we get this right. The gao found that an emphasis on profits can lead the private equity back to rubber stamp rubberstamppreviews of drug clis and focus less on potential harm to research subjects. While hhs and fda are responsible for inspecting the irb to ensure that participants are protected, the number and the frequency of these inspections has been steadily decreasing. So, hhs and fda needed to step up their oversight efforts in this area and that includes clarifying what it means to be working effectively. Something that these agencies have never done despite decades of requests so that Clinical Trial participants have complete confidence in the scientific integrity of the trials that they join and feeling certain that these have been fully vetted. So thats my concern in the space and why i want to say again thank you to the senator for holding this hearing. I look forward to continuing to fight alongside you for patients. We need to do better in this space. Thank you. Thank you, senator warren. Thank you mr. Chairman. And directing my questions. First, let me just say ive got a 6yearold, 3yearold and 1yearold. My heart goes out to you because i know that youve engaged in this fight because you lost a 7yearold daughter and i know a lot of other folks that lost kids and my heart goes out to you as well. The goal is to get to a society where no parent has to bury their own kid because of human illness that is incurable and i know we are working toward that goal. The worry is given the limited Patient Populations because some of the diseases are incredibly rare and because of how differently we treat pediatric illnesses and the medicines to treat pediatric illnesses we are making some mistakes here. I know there is an argument that the right to try legislation, the expanded access that happened in the last administration which was a good thing that that satisfies some of the concerns that you have with the current way in which we give patients access to the drugs. I would like you to explain maybe why thats not right. What are we still not doing correctly in this space . Anytime we tried within our specific classification, theres been a willingness to make it apply to pediatrics. Right to try it seems to be something that may have some adult applications and i cant speak to it because i dont touch those populations but within the pediatric realm everybody is kind of looked at it and said its not going to go for childrens cancers. That is the cornerstone of everything we are talking about because what we tend to do his thing get along the lines of the ideal circumstances. A Clinical Trial and how these can be perfected and how we can do better with it. All of these acts and regulations are dealing with in perfect scenarios. A Clinical Trial requires things such as investment accrual, time, biomarkers and certainly a completion. The issue is while we all i think see the need for Clinical Trials, we are dealing with scenarios dont exist. We cant get it. Im witnessing a trial that we are putting out there with kids in the disease classification and they have an accrual number of 400 patients. Its going to be 80 years and then we will know whether it does or doesnt work and so you cant think of it in those ways. We have to go into this with the idea we dont have the things to do the Clinical Trials sometimes seemed so promising pathways effectively filled that need. Can you explain to me this particular point so very often ive worked with companies and in my private life, my prior life i should say we work with some Biopharmaceutical Companies and Clinical Trials. One of the things that youre trying to do with these Cancer Therapeutics is identify whether the addition to the therapeutic increases the life of the patient. One of the primary points often times but in some of the diseases we are dealing with extending the time from three months of life to nine months of life is not practical because of the time given for the individual patient for a child is so small so the idea you are somehow going to reach a classic adult endpoint sometimes doesnt make any sense does it . Absolutely not. I think that the community is happy with anything. Theyve added months. Right now i would guess looking at the registry data was expanded by three fold and thats a good but we were only talking about maybe six months. Thats not a life by any stretch of the imagination or whatever be in that case. So its just we have to take it and try to as much as we can. I appreciate that. The last comment we understand we have to do better and talking in this context and others we have a Clinical Trial situation, a Clinical Trial infrastructure in this country that in some ways designs for adult diseases and a very common diseases. And if we dont fix the underlining infrastructure dying not because of therapeutics or the capital to invest because the Regulatory Regime doesnt allow us to actually try these things can figure out whether they work. The other thing for the most part we view our kids as not the same level as an adult. Lets take a drug we know works into some of their cancer and give it a try in kids. Okay for that we can do Clinical Trials and put them out there but what happens most often especially right now for the first time we have an ability to craft the drug that focuses on di pg. But now i cant get it out. I cant get it to the bedside because i cant put it in adults. Adults dont normally get this. The reason for bringing these 46 grants is to impress how important it is because i cant. I want to give a sense of the time constraints we are under now. After senator warnock i will turn and then have one quick question and we will conclude. Thank you much chair casey and Ranking Member for holding this important hearing today. I am grateful for your leadership on this issue particularly its great to work with you on legislation ive heard from georgians across the state that have been personally affected by rare and serious diseases from als to many others and despite the differences in these diseases, theres one thing they have in common. Thats why i was proud to cosponsor the promising pathway act. Thats good Public Policy and it would help patients with lifethreatening diseases receive early access to promising treatments. How would the promising pathway act improve access to lifesaving treatment for those that have serious diagnoses and i ask this recognizing that youve been personally impacted by this. Let me thank you for translating the pain and power and being such an important force on this. Your experience how would the promising pathway act help . I think that its a question of time and direction towards pediatrics. Everybody looks at this with a promising pathway. I have something that satisfies the safety requirements and we can try to move it to words giving the conditional approval so we are moving that up and that helps any patient in the terminal diagnosis. With regards to the pediatric side of things, what promising pathways does better than others is it allows it to move faster into the pediatric realm of byte especially in those rare and terminal cases. Thats not all cases. Theres also specific definitions of what is the terminal case that provides clarity to it but short of that, we cannot get it there. The cancers that we are dealing with are absolutely nothing close to ideal. It changes everything. Can you discuss some of the advances that the patient focused Drug Development program had provided . Fda has a formal program called focused Drug Development its worth acknowledging the major stride of the agency made over the past several decades starting with hivaids advocacy pushed to help recognize patients deserve a seat at the table. It refers to a systematic approach to ensure that they experience and meaningfully incorporated into both Drug Development and the fda evaluation of drugs because it recognizes that patients have expertise in the diseases that they are facing. Its important to hear from patients and its stated that it needs to hear from patients about Clinical Trial design and what are the endpoints that are meaningful to them what makes them feasible. I hate to interrupt but im out of time and a little bit. Do you have an example that you could share . Its a variety of documents to help Companies Understand how to systematically collect information that will be meaningful and they also have a program to develop clinical outcome assessments which are also intended to be specific endpoints that are meaningful and in addition to the patient focused Drug Development program, theres been further incorporation of patient voices on the advisory committees. Before my last question the senator from alaska wants to enter in, senator murkowski wants to enter into the record by unanimous consent last question so often you hear folks have to leave the country to get leadingedge treatment. Thats a shame. We should be that leadingedge and have a system that accommodates it. Could you talk about the difference between our system and one that seems to be working better that would be in europe. If thats better we should at least be emulating that. Thank you, senator its a good question and i think its debatable which one is better. I think its true that there are certain. There are delays that are unnecessary and approving drugs early in the process where we dont have the same considerations. The accelerated approval pathway has been existing in the u. S. On two constructs. One you have a known biomarker or surrogate and a second as a clinical benefit that predicts ultimate youth. The challenge with both of these is that neither of them is present in most rare disease situations. Last years approvals six were accelerated. Five for oncology drugs and one was nonmalignant. At the point is that oncology is an area where they are really well understood and others we could not use the pathways. Theyve defined a certain things that they can do on a regulatory site and negotiate a study prior to approval. We dont have the same provisions. I have one more question we have to wrap up. It is certainly understandable for an individual patient to be willing to risk substantial uncertainty for themselves before better evidence becomes available and a via the expanded access however weakened approval standards affect all patients. Can you talk about the balance that i know we all want to strike from the ethical perspective the balance between the needs of the patients when not all have the same needs or the same level of risk tolerance. One of the things ive heard is if patients dont want to take the provisionally approved drug then that is absolutely true but it becomes more complicated because when you lower fda approval standards that tells industry this is the bar that you have to meet. When the bar is lower than industry responds accordingly. What that does is push back to patients and clinicians the need to make decisions without evidence. Thats why the dietary supplement example is salient. That isnt what people that are facing these terrible diseases need. The other challenge is when the standards are low and you allow products on the market that have not demonstrated that they are beneficial. It makes it difficult to approve those studies and then you might also find yourself having to test new interventions against interventions that have not been proven to work and so you cant quite tell if they are benefiting from this new drug words that neither of these are beneficial so they have to account in its Public Health responsibility not only for the interest of patients today but also the broad population of patients which is why im encouraging the committee to draw on what weve heard about challenges to the expanded access pathway. That is the avenue that needs to be improved and provides this balance allowing patients today who have high risk tolerance to take unproven medicines while we continue to gather rigorous evidence. However the patient registries are not going to get us there because they are not randomized, not controlled, they are not going to be able to answer the questions in the way patients need to make all thomas and informed decisions about their treatment. We are going to close statements i have been working on this for most of the five years ive been here in the senate and i come from a world where within the logistics and distribution business sometimes when you want to get from here to there. I think we have had a really good discussion with it today and weve heard most importantly from folks that are suffering through it and one lesson to learn we need to have more of that even on other diseases. Here the urgency is even more compelling. This is a bipartisan effort after much work i think it is going to cascade into something quicker than what most bills take. In the face of such cruel diseases a more compassionate and flexible path has got to be there for patients. Why does europe have such a pathway and we do not . I look forward to working with my colleagues to speed up access for individuals with these diseases while maintaining the Gold Standard of the fda. We can do both at once. This is not a republican or democrat discussion. This is a human discussion. We all have stories that are deeply personal seen firsthand the impact on how these diseases were averaged not only the victims and the families. To turn passion into action, and we are going to do so. Thank you, mr. Chair. Thank you very much. As weve all heard today from patients and Family Members who are desperately awaiting hope, awaiting a treatment we also heard today from patients whove lived their whole lives without any therapy for their condition. We heard from the caregiver perspective spouses, Family Members, father who lost a daughter hearing how hard it is to watch a Family Member suffer with no treatment options. Weve also heard about the challenges the Drug Companies face when working to bring a drug from a rare disease to market. Weve heard about how to balance the unique challenges posed by Rare Diseases with regulatory processes that uphold to the Gold Standard. We must continue the discussion with each other in the senate, with the fda and all the families represented here today. Weve got to substantially improve the process for getting new drugs to patients while maintaining standards of efficacy and safety. I want to thank all the Witnesses Today for their contributions, for the time they spent here and for sharing very personal details about your life. That is not easy to do in a public setting. The hearing record will be kept open until next thursday november 2nd. Thank you all for participating in this hearing. This concludes our hearing. [inaudible conversations] most people dont know much more than that about him. 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