Amyotrophic Lateral Sclerosis: Accelerating Treatments and Improving Quality of Life

Proceedings of a Workshop—in Brief

INTRODUCTION

Amyotrophic lateral sclerosis (ALS) is a rapidly progressive, invariably fatal neurological disease. Individuals affected by ALS include those living with ALS, their caregivers, and presymptomatic individuals at risk for developing ALS. No treatments stop or reverse the disease, although Food and Drug Administration (FDA)-approved formulations may extend life by several months. As part of its charge to identify and recommend key actions for the public, private, and nonprofit sectors to undertake in order to make ALS a livable disease within a decade, the National Academy of Sciences, Engineering, and Medicine’s Committee on ALS: Accelerating Treatments and Improving Quality of Life convened three public workshops¹ on August 10, August 23, and September 1. Topics discussed included access to high-quality, evidence-based ALS care, the lived experience of ALS, and ALS research and therapeutic development. These public workshops were designed to assist the committee in gathering the evidence required to inform their findings, conclusions, and recommendations. The committee’s full report, including their recommendations, will be available in Summer 2024.

This Proceedings of a Workshop—in Brief summarizes the presentations, discussions, and the broad range of views and ideas the speakers, panelists, and workshop participants expressed at the three workshops and should not be seen as a consensus of the workshop participants, the committee, or the National Academies of Sciences, Engineering, and Medicine.

INSURANCE COVERAGE FOR ALS CARE

Medicare and Medicaid

Terri Postma of Centers for Medicare and Medicaid Services (CMS) noted that Medicare covers certain disabilities, including ALS, for people over age 65, while Medicaid pays for health care costs for people with limited means and resources. Medicaid may cover services that Medicare does not cover, including nursing home care, personal care, and home and community-based services. Each state defines its own eligibility standards for Medicaid coverage, including the type, duration, and scope of covered services, as well as payment rates.

Medicare coverage, said Postma, is limited to items and services that are reasonable and necessary for the diagnosis or treatment of an illness or injury. Medicare makes coverage determinations through

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evidence-based processes, including opportunities for public input. National coverage determinations require a formal nomination process. Occasionally, the Medicare Evidence Development and Coverage Advisory Committee (MEDCAC) also provides input to a coverage determination. Absent a national coverage determination, a local Medicare contractor can make a local coverage determination for its region. When these differ across regions, CMS can make a national coverage determination that brings those local coverage determinations into alignment.

Kathleen Holt (Center for Medicare Advocacy) said Medicare contractors regularly misunderstand or misapply coverage determinations. Many, for example, believe patients need to show improvement for Medicare coverage, but Medicare is available to maintain a condition or slow progression. Another “myth,” said Holt, is that Medicare does not cover long-term care, but there is no time limit on receiving at-home aide care for up to five hours daily for individuals receiving a skilled service at home at least once every 60 days.

People with ALS are outliers in the massive, standardized Medicare program, said Holt, because they have unique health care needs. One obstacle ALS patients face is the difficulty or inability to enroll in Medigap supplemental plans in 46 states, leaving patients access solely to private Medicare Advantage plans that do not maintain adequate provider networks and aggressively deny access or significantly limit services. In addition, Medicare provider payments incentivize short-term, post-acute care needs and rarely support services for comprehensive, multidisciplinary care or ongoing complex care needs.

Holt said Congress and CMS can improve Medicare access for ALS patients by passing federally protected Medigap coverage; reminding CMS that ALS patients are Medicare beneficiaries; changing CMS’s mindset from serving the Medicare population in the aggregate to developing specific plans, programs, and administrative policies that better recognize higher-acuity patients with long-term needs; amending the Social Security Act to remove statutory barriers to additional outlier payments for home health providers; and enforcing greater accountability from private Medicare Advantage plans to provide necessary coverage.

In addition, Holt said, states should expand access to Medicare Savings Programs, which help low-income individuals pay for Medicare costs by eliminating asset tests and increasing qualifying income levels.

Home Health Care for Veterans with ALS

Renee Golden of Maxim Healthcare Services said VA medical centers (VAMCs) have started using expanded care, or private duty nursing, when the veteran’s care needs exceed the VA’s skilled home health care bundles. As of December 2022, 51 percent of VAMCs have adopted this level of care. According to Golden, there were 116 expanded care referrals per month during the first half of 2022 and 171 per month in the fourth quarter of 2022.

One barrier to access is the 65 percent rule, which limits the amount the VA can spend on home-based community care to 65 percent of its total budget. Golden suggested the committee recommend that legislators track the use of expanded care per VAMC, change the 65 percent rule to 100 percent or more of a facility’s budget, and for the VA to continue to make progress in balancing the amount spent on home and community-based care.

Private Insurance

Lisa Latts (Optum Health) said when selecting a private health insurance plan, individuals with ALS should consider medical care and services subject to traditional copays, deductibles, co-insurance, and restrictions for drug coverage, behavioral health coverage, and durable medical equipment.

Latts said to improve care, quality of life, and outcomes for ALS patients, it would help having centers of excellence and certified ALS care facilities scattered around the country where individuals could access high-quality care in person or virtually and have that care translated back to their local care setting. Care coordination and specialty care management are important to consider for improving outcomes, and access to telehealth should expand given the number of homebound patients and those for whom travel is difficult.

Access to new FDA-approved ALS drugs, though not universal across all private health insurance plans, is available, but copays can be prohibitively expensive. Finding ways for patients to meet copays will be important going forward, as will collecting real-world evidence for outcomes with new ALS drugs in a value-based reimbursement environment. Latts also noted the need to increase and simplify enrollment in clinical trials and to enable caregivers to be certified as home health aides.

NAVIGATING ALS CARE AND PAYMENT

Lived Experience Perspective

Bruce Rosenblum, diagnosed with ALS in 2017, has progressed from fully functional to quadriplegia. Three challenges he has faced include: obtaining prior authorization for FDA-approved medications, overly restrictive coverage for durable medical equipment, and lack of financial support for caregivers. For example, since his neurologist prescribed newly approved Radicava in 2022, prior authorization has been denied four times, including through an external review conducted by a neurologist specializing in multiple sclerosis. Rosenblum was denied access to Radicava because he did not meet the inclusion criteria that the drug used during its initial clinical trial phase. This restriction is not included in FDA’s approval or in current clinical practice guidelines. A fellow ALS patient with the same insurance plan received a denial for Relyvrio, another new drug. That patient’s insurance plan told him that a less expensive drug, riluzole, was the plan’s formulary alternative, even though it is not a pharmacological alternative.

While Rosenblum’s insurance mostly covered his powered wheelchair, it did not cover a seat lift function necessary for patient safety, so he paid to add that essential feature. Insurance has been unwilling to cover needed bathroom equipment, a fully electric hospital bed, or an electric lift, so he paid $5,000 for an electric bed and low air loss mattress. An ALS nonprofit has loaned him a sit-to-stand lift, enabling him to stand regularly to prevent painful contractures and saving him the out-of-pocket expense of needing two caregivers to help with transfers, which a manual lift requires.

Insurance coverage for caregiving is inadequate, said Rosenblum. The five hours of professional caregiving he pays for exceeds 50 percent of his take-home pay. After paying for all the uncovered costs of ALS, he and his wife have had to draw on their retirement savings for non-medical living expenses.

To make ALS a more livable disease, Rosenblum proposed CMS and the rest of the insurance industry should adopt the American Medical Association’s February 2023 proposal² to change prior authorization so patients can gain timely access to treatments; insurance companies should acknowledge the heterogeneous presentation and rapid progression timeline of ALS and adopt faster, more flexible policies for prior authorization of durable medical equipment; and the nation needs to provide broader, consistent financial support for family members who serve as caregivers.

Challenges Accessing ALS Care

Colleen Hoarty (University of Nebraska Medical Center) said that Medicaid waiver programs, long-term care insurance, and grants from ALS nonprofits can provide funds for home care. For adults aged 60 and older, Area Agencies on Aging can provide for a minimal amount of care. Nebraska has a state respite program that provides $100 to $200 to cover a few hours of care a month. This situation creates disparities in care, said Hoarty, with middle-income families struggling the most to afford outside care.

Hoarty suggested advocating for Medicare benefits that would help pay for the ongoing, day-to-day care ALS patients need; for states to create Medicaid waivers specifically for people with ALS; allow for higher income limits to qualify for Medicaid; and to create special funding pools to help pay for care. With more people choosing Medicare Advantage plans over traditional Medicare, she recommended requiring all Medicare Advantage plans to cover services for people with ALS in a similar manner.

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Hoarty said true palliative programs assisting with in-home care are limited, and since Medicare only pays for hospice care or treatment focused on the hospice diagnosis, many patients with ALS and their families choose not to elect hospice coverage until the end of life because they do not want to give up the option of meeting with their ALS multidisciplinary care team or discontinue their ALS medication. Hoarty also advocated for palliative care to be a Medicare benefit, which should come with ongoing in-home assistance from nurses, home health aides, or palliative care teams. The modification of the Medicare hospice billing structure would also help families with ALS receive the support of both hospice services and ALS-specific multidisciplinary care.

Melanie Lendnal (ALS Association) said poor health insurance literacy is a barrier to access and cause of disparities, as is the insufficient number of multidisciplinary clinics for people living with ALS; multidisciplinary care, the gold standard for ALS, increases both the quality and quantity of life. President Biden’s Executive Order 13985 for populations disproportionately affected by health inequities, such as individuals with rare and rapidly progressing terminal diseases, addressed such needs but requires further expansion. Prior authorization, said Lendnal, is another barrier to care, and denial of prior authorization has profound consequences beyond medical ones for patients and their families, including worry and stress, challenges for caregivers, and financial hardship. Denial of noninvasive ventilators by Medicare Advantage plans is alarming, said Lendnal, because requiring an ALS patient to first fail on a device intended for chronic obstructive pulmonary disease causes patients to end up in a hospital, die prematurely, or spend over $20,000 to purchase the appropriate ventilator on their own.

People with ALS, said Lendnal, need immediate access to medically necessary care prescribed by their physician. They also need research investments to expand treatments and cures and support for family and paid caregivers who help keep people with ALS from requiring more expensive health care.

Practical Considerations for Improving Care for Persons with ALS and Their Families

Joanne Lynn (Eldercare consultant) said ALS differs from other fatal, chronic diseases because it mostly affects people in the prime of life who have no other serious health problems. ALS is similar to other fatal, chronic diseases because it is progressively disabling, and it is challenging to predict when decline and death will occur. Patients and families want normalcy, and they want to rely on local long-term services and supports, which are often inadequate. Lynn suggested that policy solutions to the challenges ALS patients and their families face could serve as a model for other fatal, chronic diseases or as an opportunity to address the shortcomings of the nation’s long-term care infrastructure and payment system.

Lynn suggested the committee should be thoughtful and deliberate about the relationship of ALS to long-term care—whether it should be treated differently than other conditions requiring long-term care—be conversant and forthright about dying and the decisions patients and families face as the disease advances, and confront the costs of ALS and the inadequacy of supports for caregivers. Lynn suggested recommendations the committee might make: develop a set of quality metrics, with the caveat that measuring quality by survival time may not be useful, given that patients may end their life early rather than hang on for the last few months of life; involve the Agency for Healthcare Research and Quality, not only the National Institutes of Health (NIH), in ALS-related health services research; involve the Administration for Community Living and Area Agencies on Aging in local demonstrations of chronic care that can improve the efficiency and efficacy of local programs; and lead a public discussion to plan and redesign long-term care, particularly regarding financing via a national catastrophic long-term care insurance plan and the organization of service delivery.

PERSPECTIVE ON NEEDS AND OPPORTUNITIES IN THE ALS MULTIDISCIPLINARY CARE MODEL

Lori Banker-Horner (ALS Association) said the goal of the ALS Association’s certified treatment center of excellence program is to ensure that every individual with ALS has access to and uses multidisciplinary clinics. Through an annual audit process, the ALS Association

ensures these centers of excellence continue to meet the criteria for certification and to learn about new challenges, barriers, models, and innovations. Through its partnership with the VA, the clinic network also serves veterans with ALS and raises awareness of the services the VA provides veterans with ALS. The ALS Association has 79 certified Treatment Centers of Excellence, 18 Recognized Treatment Centers, and 125 affiliated clinics that serve more than 12,000 people living with ALS every year.

Nora Capocci of the Muscular Dystrophy Association (MDA) said every care center in MDA’s network has a multidisciplinary care team with a physician, typically a neurologist, a physical therapist, a care coordinator, and social worker as core members. The network also works with a wide range of specialists to meet individuals’ particular needs. MDA/ALS-specific care centers must meet the American Academy of Neurology (AAN) practice parameters, participate in ALS-related research, and share information about the national registry with the patient community. All care center clients also have access to free genetic testing. Within the MDA care center network, 48 sites meet these criteria, though other sites in the network see ALS patients. In 2022, 115 care centers saw nearly 13,000 ALS patients, with some 70 centers participating in ALS-specific clinical trials.

Capocci said MDA encourages its care centers to participate in MDA’s Neuromuscular Observational Research (MOVR) data hub, a unified national patient data hub for neuromuscular diseases. MOVR collects comprehensive clinical data and accurate genetic diagnostic information from individual MDA clinical centers. Today, over 60 care centers are active in MOVR, with ALS being one of the most represented diseases in the database. In 2022, some 2,000 individuals with ALS participated in MOVR.

Capocci’s recommendations include: expand Medicare coverage to include multidisciplinary care and allowing team members beyond the treating medical doctor and nurse practitioner to bill for the services they provide; conduct further studies on the benefits of multidisciplinary care, telehealth, and home and community-based services; expand access to home and community-based services; expand access and coverage for medical devices; and improve health insurance options.

ALS MULTIDISCIPLINARY CARE—PROVIDER PERSPECTIVES

Terry Heiman-Patterson (Temple University) said multidisciplinary care prolongs survival, promotes independence, reduces complications, and improves quality of life for people with ALS. The multidisciplinary care team comprises the clinical staff and people outside the clinic—family, friends, specialty physicians, home care companies, and community organizations. Virtually all ALS centers provide physical, occupational, speech and language, and respiratory therapy, as well as nutrition support and a nurse coordinator. Only 25 percent of the clinics provide palliative care, but Heiman-Patterson believes that is because many clinicians feel they are already delivering palliative care through symptom management.

In a survey, Heiman-Patterson said ALS patients receiving care in a multidisciplinary clinic reported a higher quality of life and increased attention to AAN care parameters. They also reported their clinics addressed respiratory and speech therapy more frequently, screening for speech and swallowing, screening for cognition difficulties, developing and updating care plans, and offering help with end-of-life planning. Given the choice, Heiman-Patterson said, 88 percent of those living with ALS would be extremely likely to choose care in a multidisciplinary clinic.

Challenges to multidisciplinary care, said Heiman-Patterson, include a need to expand the use of telemedicine to accommodate patients who cannot travel to a clinic, accommodating the three hours or more required for a full multidisciplinary clinic visit, and having the space to see every individual who needs a full visit. Other challenges include accessing resources and durable medical equipment and the cost of providing multidisciplinary care. Her center incurs expenses of nearly $500,000 per year, or approximately $1,000 per patient visit, while reimbursement is at most $250 per visit. Over 90 percent of ALS clinics, said Heiman-

Patterson rely on philanthropy for support and only 16 percent break even.

Respiratory Care for People with ALS

John Hansen-Flaschen (University of Pennsylvania) said respiratory care for people with ALS is “abysmal,” and he asked the committee to consider two recommendations. The first is to promote developing a new subspeciality devoted to chronic respiratory failure, which would enable a co-principal care model involving a neurologist and pulmonologist, each with their areas of special expertise and with some sharing of palliative and end-of-life care. While many clinics currently have respiratory therapists, these therapists require close supervision by a physician.

Hansen-Flaschen would also like the committee to recommend promoting policies for respiratory supportive care of ALS that would enable insurance coverage for respiratory assist devices well before a person begins experiencing diaphragm muscle weakness. Current CMS policies are out of sync, said Hansen-Flaschen, with European and American evidence-based recommendations calling for earlier use of respiratory care, which produces better outcomes. Moreover, CMS’s policy for ventilators prohibits using them to deliver continuous or intermittent positive airway pressure. An expert panel made detailed, evidence-based recommendations to CMS and other insurers to optimize respiratory care.³ The best solution, said Hansen-Flaschen, is to have Congress create a national health insurance program for chronic neuromuscular respiratory failure modeled after the end-stage kidney disease program.

UNDERSTANDING LIVING WITH ALS

Four individuals living with ALS spoke about their experiences. Desi Kessler said her symptoms began in October 2013 during the third trimester of her pregnancy, with a diagnosis coming six months later. Though her condition has been stable since 2017, the beginning was difficult because she also experienced postpartum depression. She credits wanting to be present as a mother spurring her to get treatment for her depression. She discovered a group called Her ALS Story, which is a community of women diagnosed with ALS before age 35. “You cannot imagine what it is like to find a group of women who know what you are experiencing,” said Kessler. “It is liberating.”

Kessler’s daughter made her realize that she has a choice to make every day: whether to feel sorry for herself and live expecting doom or to live in the present and make happy memories. She chose the latter, and though she has bad days and feels sorry for herself occasionally, she acknowledges those feelings and then moves on.

Kessler requires a home health aide for 12 hours a day, her mother serving as a key member of her care team. She uses a communication device to manage her daughter’s schedule and run her household. She is also an ALS advocate, attending fundraisers and speaking at local schools to raise awareness about ALS. She knows she is lucky to have a huge support system that keeps her going and believes that with some perspective and the proper tools, anyone can live a fulfilling life with ALS.

Paul Seifert’s experience with ALS began in 2020, but his diagnosis, in January 2023, at age 61 came as a shock because a prior neurologist had told him he did not have ALS. However, genetic testing showed he had a mutation of the C9orf72 gene, which meant he had to tell his three children that there was a 50/50 chance he had passed the gene on to them. For Seifert, his diagnosis meant that every hope and expectation he and his partner had were gone and that he may not see his daughter get married or meet his grandchildren. Uncertainty about the future is challenging, he added.

Asia Jami said she was diagnosed with ALS on December 1, 2016, and continued working until she retired in 2022. When first diagnosed, she was embarrassed and ashamed and sought counseling to help her process how to tell her family and friends. Despite the devastating diagnosis, Jami continued to travel the world. She also created #AsiaDay when she does everything her heart desires. “I

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am living my life with zero regrets,” said Jami. “I hope a little Black girl sees me with my disability and knows whatever she wants out of life is hers.”

Jim Clingman, joined at the workshop by his wife and primary caregiver Sylvia, was diagnosed at the end of August 2013, four years after symptoms first appeared and after having an unnecessary laminectomy on the assumption that a pinched nerve in his back was causing the weakness in his legs. While living well with ALS may sound counterintuitive, he tries to do the best he can, which means constantly trying to be comfortable and have the resources to accommodate his myriad needs. Going forward, his mission is to raise more awareness and trigger more advocacy to result in increased funding for ALS research, more clinical trials, more drugs, and everything needed to live well, no matter how long he has left to live.

Discussion

Seifert said everyone’s journey is different as is their idea of what living well means. For him, living well means fighting the disease, going to ballgames, and having dinner with friends, though doing so is difficult. Medicare and Medicaid policies add to the difficulties ALS patients face.

Clingman said the phrase “living well” may be problematic because it might connote to some people that living with ALS is not so bad. Not everyone has the resources he has, and without those resources, he believes it is virtually impossible to live well. He lives well by helping others, such as by writing about ALS regularly. He added that just because people living with ALS might seem “helpless,” it does not mean they are useless.

Before connecting with the VA, Clingman’s private insurance provided little aside from paying for muscle function tests, and he had to help pay for his powered wheelchair. He would like to see the VA share its knowledge about ALS with other providers and insurers so all patients would benefit. His wife, Sylvia Clingman added that having the full VA care team available as her husband’s disease progresses has been invaluable; even as a nurse, she has had to learn what his needs are and will be as the disease starts to ravish his body.

When asked to provide advice to someone newly diagnosed with ALS, Seifert said he would tell them to get involved in advocacy, get treatment early, and start checking off items on their bucket list. Clingman agreed that getting diagnosed and getting treatment early is critical because the longer it takes to diagnose, the more time wasted trying to live well with it, which takes planning and realization.

Sylvia Clingman noted her husband could not get into clinical trials because his symptoms had been developing for four years before he was diagnosed, which meant he did not meet trial inclusion criteria. Getting diagnosed early allows the patient and family time to make decisions about the future. It is important, she said, to find a group of people, including family and friends, to rally around the family and help with an overwhelming situation.

Jami said she would tell someone newly diagnosed to listen to their body and to not do anything they do not want to do. For example, it is their choice to have a tracheostomy and a feeding tube. She would also advise that the individual record and bank their voice⁴ as soon as possible.

Kessler’s advice would be to find a good clinic and community, ask for help, and obtain the tools to live their best life. She would also tell a newly diagnosed individual that while it is scary, they can get through it and find meaning while living with ALS.

THE COST OF CARE

Four individuals living with ALS discussed the financial costs of living with ALS. Ron Faretra, a 27-year Air Force veteran diagnosed in 2016, receives his care from the VA hospital in Charleston, SC. In his opinion, the VA has provided excellent care.

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Kristin Rankin was diagnosed in 2016 and now uses a speech device to communicate. She noted she is not representative of most people living with ALS because she has lived longer than expected and has continued working part-time. She thinks of costs as falling into several buckets. The first bucket includes the costs of moving to a more accessible home, completing home modifications, and purchasing a wheelchair-accessible van that allows her to participate in activities outside the home. The second bucket is for out-of-pocket expenses for caregiving. The third bucket includes the loss of both hers and her husband’s income; he stopped working fulltime to care for her and their three children. She receives a disability check, but it does not total the earnings she and her husband forgo. The fourth bucket includes the copays for medical care and medications, plus the price for dietary supplements that might slow disease progression. Her fifth bucket, not relevant for everyone with ALS, includes the out-of-pocket expenses for traveling from Chicago to Massachusetts to participate in a clinical trial for a promising stem cell treatment. She is fortunate to have the resources to handle these costs and that her job comes with disability benefits and good health insurance. Nonetheless, she and her husband have been spending their savings, and she worries that caring for her could bankrupt her family.

Julian Rodriguez, diagnosed in May 2020, discussed the difficulties with comfort he experienced. For example, his insurance-provided chair is not the most comfortable or accessible. After fighting with the insurance company, he made adjustments that allow him to use his chair with a computer. He noticed that the doctors and companies are more accustomed to dealing with older patients, so they question why he needs his chair to allow him to use a mouse and computer. Similarly, finding pillows and chairs that allow him to be comfortable has been a trial-and-error process for which insurance companies will not pay. Rodriquez pays out-of-pocket for his home-based physical therapy sessions, which alleviate his pain and provide an emotional support system; getting insurance to pay for these sessions is too much of a hassle. Insurance companies expect to see improvement in a patient’s health as a result of receiving a particular service, such as physical therapy, so it is difficult for individuals with ALS to negotiate their need for services that help them maintain functions but not necessarily show improvement.

Jean Swidler is a presymptomatic carrier of an ALS gene and was a caregiver for her mother who died from ALS. She said it is important to consider what the specter of a shortened life costs a person and their family and how it might affect potential employers. Regarding financial expenses, she said her parents spent more than $100,000 on costs related to caring for her mother even though she lived only 16 months after her diagnosis.

Insurance Challenges

Rankin said most insurers do not cover lift mechanisms for wheelchairs. Faretra said the walker and wheelchair the VA provided him are far superior to the walker that Medicare, Medicaid, and most private insurance provide. “What the VA does for its patients should be the standard,” said Faretra. Vehicles are another problem; a used wheelchair van can cost around $50,000 with no insurance reimbursement. He noted that South Carolina recently allocated $500,000 to help ALS patients with their copays and caregivers. He called for a federal program that standardizes the equipment insurers must provide.

Swidler said her mother had a good experience thanks to having suitable health insurance. She received the newest ALS drug as soon as FDA approved it and a power wheelchair with all the needed capabilities. She acknowledged the help her family received from a local ALS nonprofit to pay for other expenses, including a wheelchair-accessible van. Swidler added that few insurance plans will cover the cost of in vitro fertilization with preimplantation genetic testing, which ensures a genetic carrier would not pass the mutation to their children.

Time is Valuable

Rodriguez said dealing with financial issues has been frustrating, difficult, and time-consuming. Time is the most important currency he has, but he wastes much of it getting the necessary equipment or adjustments to his chair. Even then, if it takes two months to get a new armrest for his chair, his body might change and make the new armrest unsuitable. Faretra agreed that time is

a valuable commodity, particularly given the uncertain future for those living with ALS.

An issue for Rankin is that she takes so much longer to do normal activities of daily living, such as going to the bathroom. Receiving a suprapubic catheter has been a huge time-saver, but it has drawbacks such as urinary tract infections. “I found this to be a common pattern with ALS where a solution for one problem results in another problem, and you feel like you are always troubleshooting something new,” said Rankin.

EXPLORING THE CAREGIVER EXPERIENCE

Four caretakers of individuals living with ALS discussed their experiences. Vanessa Jackson cared for her daughter, who was diagnosed at age 22 after experiencing symptoms for over two years. When the family received the diagnosis, the neurologist informed them via phone with no support. Katrina Boyd lost her partner a mere 76 days after her diagnosis and now works with six ALS organizations advocating for veterans, cures, and diversity and inclusion issues.

Siobhan Pandya lost her husband and father of their two young children nearly a decade after his diagnosis. Maintaining quality of life was important to him so he could spend time with their children and be able to donate his organs after his death. Upon receiving his diagnosis, the couple decided to bring in a caregiver so she could continue working fulltime to alleviate some of the financial pressure. Pandya said she would advise any caregiver to build a toolkit for dealing with the disease that includes having the mindset to fight the disease and live life to the fullest, lining up support, gaining medical knowledge, and building a network of relationships with different support groups.

Ashley Lee cares for her father, who was diagnosed in 2009 and now has a tracheostomy, a ventilator, and a feeding tube.⁵ As a veteran, her father received “excellent” care from the VA, which helped him maintain his quality of life. At times his symptoms would plateau, and it almost felt as though her father was living with a disability rather than a fatal disease, but then a new loss of function would begin. Never having outside help to rely on, Lee has been unemployed and worries that the large employment gap will hamper her moving forward when her father eventually dies.

Quality of Life

For Pandya and her husband, quality of life meant maintaining some normality within the household, such as doing activities with their children and sticking to a routine as much as possible. They also sought counseling for the children so they could navigate their feelings about their dad’s illness.

Jackson’s experience differed in that her daughter died 13 months after receiving her diagnosis. To her daughter, quality of life meant trying to accept what was happening and make decisions for herself, which included refusing a feeding tube and tracheostomy when she developed pneumonia. Jackson’s advice to caretakers is to be respectful of the choices and wishes of the person with ALS. Sylvia Clingman and Boyd seconded that idea. Boyd added that she and her partner had been caring for others during their entire relationship, so she knew how to be a compassionate caregiver. One important thing she did was to let her partner know that she did not need to stay alive for her sake.

Respite Care

Jackson’s state of residency, Connecticut, would pay for aides, but she had to locate and hire them herself. Since none were professionally trained to care for people with ALS, she never used an aide. Her only breaks came when her daughter’s boyfriend would take over care and when her sister would come over to cook for her daughter. It was important to Jackson to shield her daughter from seeing any evidence that she was feeling tired or broken. Mental health care for caregivers is critical, she added.

One thing to deal with, said Pandya, is the anger that invariably arises from not having the appropriate support, particularly from insurance companies who do not understand what it means to have ALS. She noted there is no training when a loved one is diagnosed, which means all training is learned through experience. Clingman added that it is important to accept having

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ALS is not just the patient’s journey but the caregiver’s as well. She has taken advantage of respite care twice, though even respite facilities do not know how to care for an ALS patient. “It is difficult to take care of yourself when you are trying to get someone to help you take care of your patient with ALS,” said Clingman.

Lee said it was a struggle to get her father to not worry about her and her daughter. For her, taking a break seemed like missing an opportunity to spend more time with him. Though she took advantage of the VA-provided respite care, she stopped using it when her father lost his ability to speak and use a call button. Today, her 18-year-old daughter is her greatest aide.

SUPPORTING AND DEVELOPING ALS RESEARCH

The National ALS Registry

Paul Mehta (National ALS Registry, Centers for Disease Control and Prevention) said the National ALS Registry includes a biorepository, funds external research, and partners with ALS organizations to inform people with ALS and their caretakers about the registry. Data from the registry are either self-reported or obtained from CMS, Veterans Health Administration, and Veterans Benefits Administration. The registry works with academic and industry researchers to augment clinical trials through the research notification mechanism that contacts people in the registry about suitable clinical trials and epidemiological studies. More work needs to be done to recruit minoritized patients into the registry.

Mehta offered three recommendations to improve the pace and success of ALS research: use existing research platforms to recruit persons with ALS into clinical studies and better understand national epidemiological trends; identify possible risk factors and etiologies for ALS to reduce the public health burden and make the disease livable by 2030; and coordinate with other federal agencies on funding opportunity announcements, including possible joint proposals, and share resources.

Congressionally Directed Medical Research Programs (CDMRP)

Sarah Fontaine (Department of Defense ALS Research Program) said the ALS CDMRP’s mission is to fund impactful research and develop an ALS drug development pipeline. She listed six therapeutic development challenges and opportunities:

• Determine therapeutic specificity for ALS’s subtypes to better inform treatment responsiveness;
• Identify and analyze biomarkers during therapeutic development to diagnosis, improve subtype definitions, and determine optical therapies;
• Centralize data sharing to ensure both positive and negative outcomes are widely communicated;
• Develop alternative, non-pharmacological options that can positively affect patients’ lives;
• Collaborate with patients and the ALS community on clinical trial design to ensure accessible, efficient, and humane clinical trials; and
• Conduct biomarker-driven trials with outcomes tied to measurable results that inform treatment response to de-risk, improve, and accelerate later-stage, larger clinical trials.

ALS DRUG DEVELOPMENT

Academic Research and the ALS Drug Development Pipeline

Justin Ichida (University of Southern California Keck School of Medicine) said genetics studies can provide more information about the genetics of disease progression and risk, which could boost efforts to identify targets that slow the disease. His work has identified 11 compounds that improve survival of most motor neuron cell lines, and he has developed an antisense oligonucleotide inhibitor of PIK5 that a biotechnology company hopes to have in clinical trials in 2024. He advocated for more flexibility and innovative thinking about outcome measures and surrogate endpoints for ALS clinical trials. He also shared his experiences with the Harrington Discovery Institute, whose Therapeutics Development Center team helped him identify candidates and refine his methods. Harrington, Ichida said, made a “huge difference” in the process of going from a target to a therapeutic that the private sector might be interested in licensing and, eventually, bring to market.

FDA and NIH Public-Private Partnership (PPP)—A Critical Path for Rare Neurodegenerative Diseases

Collin Hovinga (Critical Path Institute) said his organization is establishing a PPP with FDA and NIH,

persons with lived experience and advocates, academic researchers, and industry researchers to work on ALS and other neurodegenerative diseases. Consistent input and engagement with patients, caregivers, and advocates is critical to the success of this model. Collaboration among academic and industry researchers will help define scientific evidence and identify gaps in drug development.

Hovinga said his organization identified four focus areas: an ALS-focused data warehouse and portal with standards and mechanisms to enable data use for regulatory submissions; biomarker and endpoint development; clinical outcome assessments for different stages of the disease; and ALS disease staging and progression models and clinical trial simulation tools to aid clinical trial design. He called for the use of digital health technologies to better follow patients. The goal of establishing the data warehouse is to use existing data to guide interventions, funding opportunities, and investment strategies. Integrating regulatory considerations and input from persons with lived experience early and often into research, Hovinga shared, may help advance drug development. The Critical Path for Rare Neurodegenerative Disease program can collaborate on ALS drug development by generating drug development tools to address unmet needs and advise on regulatory strategies for noncompetitive, federally funded research projects. The ALS field, said Hovinga, needs a portfolio manager to connect the many promising ALS research projects, both domestically and internationally.

ALS Therapy Development Institute (TDI)

Fernando Vieira (ALS TDI) said his nonprofit organization conducts fundamental and preclinical research to discover targets, therapeutics, and biomarkers using cell and animal models of ALS for drug screening and lead optimization. After identifying lead drug candidates, ALS TDI then partners with contract research organizations (CROs) and for-profit enterprises to take the lead therapeutics through IND (investigational new drug)-enabling studies and clinical trials, respectively. Translating findings from cell-based and animal models of genetic ALS to broader population of sporadic ALS patients is a challenge, Vieira shared. Another challenge is that identified targets are often not druggable; for example, RNA binding proteins and splicing errors rely on new therapeutic modalities such as gene editing. Delivering drugs into the human central nervous system is a third challenge.

To address the substantial cost and time to conduct IND-enabling studies, Vieira said his organization outsources that work to a contract research organization. With positive preclinical data, two challenges remain: finding a clinical partner to take the drug candidate through clinical trials and identifying the right population of ALS patients to participate in clinical trials.

Vieira offered recommendations to address these challenges: establish a concerted funding mechanism to characterize and validate disease models relevant for the biological processes that occur during different disease progression in sporadic ALS; establish precompetitive core resources for omics data analysis; and dedicate more resources to the CDMRP program to fund the preclinical studies needed for an investigational new drug application.

Discussants

Some panelists did not give full presentations but were invited to participate in group discussions. Michael Benatar (University of Miami) emphasized the importance of committing to fidelity in the research process, recognizing the myriad ways research can go wrong, and being acutely aware of biases and blind spots. A diversity of views and scientific approaches is essential to progress, and he wants researchers to be modest in their conclusions, recognize the limitations of their work, and ensure that the field is making decisions based on the best science—not on politics. Vieira also cautioned against developing monolithic platforms that constrain protocol variation.

Neil Thakur (ALS Association) said increased spending generated by the Ice Bucket Challenge boosted productivity, identified new genes and treatments, and engaged more researchers in the ALS field. He expressed concern that people living with ALS who participate in long-term research will not benefit from that research

and called for developing a research portfolio that balances the timing of clinical benefit so as not to pit one generation of ALS patients against another.

Thakur said proven interventions increase the length of life and improve quality of life, but getting these interventions to those who would benefit has been problematic. Research is needed to develop more efficient approaches for delivering effective interventions, but this type of research is underfunded. Thakur highlighted the need to consider prevention as a clinical outcome and design interventions for people with a genetic risk but who have not yet developed ALS.

Discussion

Vieira said investing in target identification is challenging given the heterogeneous nature of the ALS population. He recommended focusing on stratifying the population, which will require expertise in data analysis, and then searching for targets within each stratified subset. Benatar suggested that enhanced methodological rigor, independent replication in the same model, and reproducibility in a different model would increase confidence in preclinical findings and should be a prerequisite to translation into human trials.

Hovinga said foundational elements needing support include an open-access registry with biospecimens, an ALS-focused computing center for data analysis, and a common platform for clinical trials that would enable multiple simultaneous clinical studies. Vieira supported connecting these resources to create a pipeline for drug development. Hovinga said common data standards and data analysis tools are available. Data sharing, however, is hard because many investigators hold onto their data, and many informed consents do not include data sharing. Benatar and Hovinga said the neurofilament light chain biomarker, while imperfect, should be incorporated as a response biomarker in every drug development plan.

Benatar noted the need to focus on people at genetic risk and other risk factors as they are identified for early therapeutic intervention. The challenge, said Thakur, is the lack of presymptomatic carriers in registries and a lack of curation of this type of research.

DESIGNING CLINICAL TRIALS IN ALS

James Berry (Massachusetts General Hospital) said the HEALEY ALS adaptive platform trial enables parallel testing of multiple investigation drugs against a placebo. This approach is changing the pace at which researchers can test compounds in a randomized, controlled trial design. What dismays Berry is that every program at his institution is supported largely by philanthropy, a source of funding unavailable to most ALS centers, and he called for a continued expansion of federal funding for ALS research. He recommended that CMS should fund multidisciplinary care team members because successful multidisciplinary ALS clinics are essential for recruiting diverse patient populations and conducting clinical trials. CMS could follow its model for funding multidisciplinary care teams at specialized kidney clinics. Berry recommended: expand the field of ALS through increased funding for consortia and researchers at all career stages; support the development of novel endpoints and biomarkers to improve early diagnosis, predict treatment response, and monitor disease progression; increase the use of digital tools to collect data from people in their homes and clinics; develop a roadmap for incorporating novel endpoints and biomarkers into clinical trials; and support innovation in ALS trials execution and reporting and for regulators to partner with ALS investigators to find new approaches to clinical trial design.

Robert Hebron (I AM ALS Clinical Trials Team), father of an ALS patient, said there is a critical need for a more efficient clinical trial process that quickly produces greater certainty in evaluating drug and treatment efficacy. Also needed is a best practice infrastructure that can disseminate findings to all researchers, physicians, and drug and treatment developers. He noted the National Institute of Neurological Disorders and Stroke is soliciting proposals for a national ALS coordinating center. With the proper infrastructure, anyone diagnosed could contribute observational data immediately and throughout disease progression. Hebron mentioned the need to identify biomarkers for diagnosing ALS and tracking disease progression and survival that can serve as clinical trial surrogate endpoints; the need to

understand the genetic and environmental risk factors that define sporadic ALS; and developing more reliable disease progression predictive algorithms for use in clinical trial designs.

LESSONS LEARNED FROM OTHER DISEASES

Measuring Population Health—Cystic Fibrosis (CF)

Albert Faro (Cystic Fibrosis Foundation) said that more than 130 CF Foundation-accredited centers must provide interdisciplinary care, contribute to the patient registry, practice continuous improvement, and deliver care informed by CF Foundation clinical care guidelines. The CF Foundation patient registry includes 84 percent of individuals in the United States with CF, each providing longitudinal data.

Faro said the registry has helped researchers understand disease progression and trajectory, provided a framework for clinical research, contributed to post-market surveillance, and promoted quality improvement and evidence-based clinical decision-making. Registry-based studies describe long-term trends in population-level outcomes such as the prevalence of infections, the effect of social determinants of health, and changes in survival. His recommendations were to: support the development of high-quality specialized care centers, preferably at academic institutions, to train the next generation of ALS providers and promote research; establish a patient registry for data from both care centers and patients; define best practices through guidelines and actively disseminate and promote implementation; implement training sites for quality improvement work; and use the care network to build a research infrastructure to accelerate drug development.

Patient-Reported Outcomes and Preferences

Norah Crossnohere (The Ohio State University College of Medicine) said having data on patient experience can improve patient-centered outcomes. Patient-centered benefit-risk assessment, for example, informs how regulators consider new products, and routine collection of patient-reported symptoms can improve quality of life and extend survival. Patient-reported experiences can improve physician-patient communication. After describing three studies using patient-reported data, Crossnohere made the following recommendations: use available standardized experimental approaches to measure preferences and priorities of patient communities and inform research and care; establish patient-reported outcome systems for routine care to improve communication; and facilitate treatment consistent with patient preferences and values.

Integrating Research and Clinical Care— Pediatric Oncology

William Woods (Emory University School of Medicine) said the Children’s Oncology Group (COG) funds an operations center, a data and statistics center that consolidates data from all COG sites, and some research. Woods estimated that $10 million would do the same for ALS given the smaller number of patients with ALS. COG runs clinical trials that accept all arrivals, producing a record of diverse, equitable, and inclusive treatments for all children. The culture that developed from this approach has generated two generations of clinicians taught that patients can participate in clinical trials and that all patients are eligible for a clinical trial. Some lessons learned by Woods are that collaboration is critical, as is deciding on common protocols, have physicians and investigators lead the programs, and acquire some government support.

DISCLAIMER This Proceedings of a Workshop—in Brief has been prepared by Rebecca English, Lyle Carrera, Ashley Bologna, and Joe Alper as a factual summary of what occurred at the meeting. The statements made are those of the rapporteurs or individual workshop participants and do not necessarily represent the views of all workshop participants; the planning committee; or the National Academies of Sciences, Engineering, and Medicine.

*The National Academies of Sciences, Engineering, and Medicine’s planning committees are solely responsible for organizing the workshop, identifying topics, and choosing speakers. The responsibility for the published Proceedings of a Workshop—in Brief rests with the institution.

REVIEWERS To ensure that it meets institutional standards for quality and objectivity, this Proceedings of a Workshop—in Brief was reviewed by Ronald Faretra, Chief Master Sergeant, United States Air Force (retired), person living with ALS and Melanie Lendnal, Esq., Senior Vice President, Policy and Advocacy, The ALS Association. Leslie Sim, Senior Report Review Officer, Health and Medicine Division, National Academies of Sciences, Engineering, and Medicine served as the review coordinator.

STAFF Rebecca English, Senior Program Officer; Lyle Carrera, Research Associate; and Ashley Bologna, Senior Program Assistant.

SPONSORS This workshop was supported by the National Institute of Neurological Disorders and Stroke, National Institutes of Health, contract number HHSN263201800029I, task order 75N98022F00011.

For additional information regarding the workshop, visit https://www.nationalacademies.org/our-work/amyotrophic-lateral-sclerosis-accelerating-treatments-and-improving-quality-of-life#sectionPastEvents.

SUGGESTED CITATION National Academies of Sciences, Engineering, and Medicine. 2023. Amyotrophic lateral sclerosis: Accelerating treatments and improving quality of life: Proceedings of a workshop—in brief. Washington, DC: The National Academies Press. https://doi.org/10.17226/27395.