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Edaravone in the Treatment of Amyotrophic Lateral Sclerosis: Efficacy and Access to Therapy - A Roundtable Discussion
Benjamin Rix Brooks, MD; James A. Jorgenson, MS, RPh, FASHP; Barbara J. Newhouse, MS, BSW; Jeremy M. Shefner, MD, PhD; and Wendy Agnese, PharmD
Edaravone in the Treatment of Amyotrophic Lateral Sclerosis: Efficacy and Access to Therapy - A Roundtable Discussion Appendix
Benjamin Rix Brooks, MD; James A. Jorgenson, MS, RPh, FASHP; Barbara J. Newhouse, MS, BSW; Jeremy M. Shefner, MD, PhD; and Wendy Agnese, PharmD

Edaravone in the Treatment of Amyotrophic Lateral Sclerosis: Efficacy and Access to Therapy - A Roundtable Discussion

Benjamin Rix Brooks, MD; James A. Jorgenson, MS, RPh, FASHP; Barbara J. Newhouse, MS, BSW; Jeremy M. Shefner, MD, PhD; and Wendy Agnese, PharmD
Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neuromuscular disease affecting approximately 5 out of every 100,000 individuals living in the United States. ALS is associated with 50% mortality within 30 months of initial symptom onset. The rarity of the disease, along with the significant inter- and intra-patient variability in clinical course and a lack of reliable biomarkers, have rendered the development of effective agents to treat ALS a challenge. Because oxidative stress is considered a contributing factor to ALS onset and progression, drugs that eliminate free radicals may protect motor neurons from damage potentially caused by free-radical and oxidative stress. Edaravone is an antioxidant free-radical scavenger approved by the FDA in 2017 for the treatment of ALS. A review of the edaravone clinical development program offers a clearer view of the clinical utility of this agent. Broader treatment success is also influenced by factors such as limited patient access and the restrictive payer environment. Cooperation within the healthcare community, among clinicians, patient advocacy groups, pharmaceutical companies, and managed care payers, must occur to advance ALS management and treatment and improve patient access. Moreover, collaborative discussions are useful in identifying potential solutions to problems currently surrounding patient access.
Am J Manag Care. 2018;24:-S0

Objectives of the Roundtable Discussion

Mitsubishi Tanabe Pharma America and The American Journal of Managed Care® hosted a roundtable discussion to initiate a conversation among key health care stakeholders about the challenges and barriers to real-world management of amyotrophic lateral sclerosis (ALS), including patient access to treatment. Acknowledging their diverse perspectives, the participants highlighted the objectives, responsibilities, and challenges encountered in their respective roles, and discussed potential ways in which stakeholders can collaborate to improve appropriate patient access. As part of the conversation, participants discussed the recent edaravone clinical trials, interpretation of data, and how the data reflect and possibly inform the management of ALS in a broader, real-world setting.


Roundtable participants represented key health care stakeholders important to the appropriate use of agents used to treat ALS and patient access. Key stakeholders included clinicians who specialize in ALS treatment, Dr Benjamin Brooks and Dr Jeremy Shefner; an advocate for patients with ALS, Ms Barbara Newhouse; a consultant to healthcare payers and health systems, Mr James Jorgenson; and 2 managed care payers, who did not participate in the development of this publication.

ALS Experts

Most ALS experts are neurologists and lead multidisciplinary teams, which collectively care for patients with ALS. They see, firsthand, the impact of this relentless and progressive disease, for which to date there is no cure. These expert clinicians are skilled at evaluating study outcomes and the clinical utility and relevance of these outcomes for their patients. As clinicians, they “have to look at individual patients and see where they might benefit from this treatment as we go forward,” Dr Brooks observed. A common frustration of clinicians is the denial of coverage of ALS agents, such as edaravone, by payers when the clinician believes the patient may benefit from the agent.  Dr Shefner stated that decisions regarding insurance coverage are the main barrier to patient access to edaravone.

ALS Advocates

Patient advocacy organizations, such as The ALS Association (ALSA), are often the public voice for patients and their families. They are particularly active and impactful in the rare diseases sphere; without their influence, such diseases would otherwise not get the attention or resources allocated to more prevalent diseases. ALSA’s mission is “to discover treatments and a cure for ALS, and to serve, advocate for, and empower people affected by ALS to live their lives to the fullest.” The association’s primary focus is improving patients’ quality of life and providing support that patients and their families need to cope with ALS. Knowing the extensive impact ALS has on a patient’s quality of life, ALSA advocates zealously for unrestricted access to any therapy that may provide relief to a patient. “When you are facing a life-threatening disease…a 2.5-point difference [on the ALS Functional Rating Scale; ALSFRS] can make a huge difference in the life of somebody with ALS. It can make the difference between them perhaps living a bit longer and being able to be with their families,” Ms Newhouse stressed. Appendix I provides a full discussion of the development of the ALSFRS, and studies examining the significance of point changes in its scoring metric.

Managed Care and Payers

Payers are tasked with the arduous responsibility of balancing economic and clinical dynamics for all disease states and afflictions, which impact their “covered lives population.” The managed care participants explained the payer’s perspective:

There is substantial pressure on payers to contain the cost of healthcare, and payers must make population-level decisions that are based upon population financial dynamics as much as clinical dynamics. As a rare disease with few treatment options, ALS is not frequently evaluated or discussed by those outside of the ALS community. Payers are not always familiar with scoring metrics used in clinical trials. A managed care participant elaborated, “When [payers] are dealing with these unfamiliar scales … they want to know if it relates to something that [patients] actually relate to and can notice a difference.” Thus, a common challenge for payers is applying study data to a real-world population. As Mr Jorgenson noted, there is an unmet need for clinical models that can accurately extrapolate study data to a given population, providing payers with a more realistic expectation of a drug’s impact on patients with ALS.

Background of ALS

ALS is a relentlessly progressive and fatal neuromuscular disease that is associated with 50% mortality within 30 months of initial symptom onset, and a lifespan of 3 to 5 years from the time of disease onset.1,2 However, the disease course may vary depending on the patient and can be difficult to predict.3 ALS is a rare disease that affects approximately 5 of every 100,000 individuals living in the United States,4,5 totaling an estimated 30,000 individuals.5,6

ALS involves the progressive degeneration of nerve cells of the brain and spinal cord, leading to loss of voluntary muscle function.7 It is characterized predominantly by upper motor neuron (UMN) and lower motor neuron (LMN) symptoms of degeneration.1

Patients with initial UMN symptoms typically present with difficulty walking due to muscle spasticity, while LMN symptoms initially manifest as muscle weakness, cramps, and muscle twitches.1 Approximately 70% of patients with ALS present with limb-onset disease, 25% with bulbar-onset (eg, speech and swallowing difficulties), and 5% with initial truncal or respiratory involvement (eg, orthopnea, dyspnea), which will ultimately spread to other body regions.1

Diagnosis is complex and often delayed, coming 12 months on average after symptom onset.8,9 This delay often precludes patients from benefiting from treatment that can be initiated in earlier stages of ALS, and it disqualifies patients from clinical trial consideration because, through no fault of their own, they exceeded the window of disease duration often required by study inclusion criteria.9

Due to the complexity of diagnosis, criteria have been developed to provide a uniform means of diagnosis.11 The revised El-Escorial Criteria (rEEC), also known as Airlie House, are commonly used by clinicians and clinical investigators to categorize patients as having “definite,” “probable,” “possible,” or “suspected” ALS.11 Although the rEEC provide a level of certainty for diagnosis, they do not provide guidance regarding disease severity or progression.3 Beyond the rEEC, there are no specific biomarkers of disease onset or progression that have been identified to date that clinicians, clinical investigators, or regulatory agencies can use to define the point a patient has reached in the continuum of their disease.3

Because no cure currently exists for ALS, the mainstay of treatment is symptom management and palliative care.12 When the American Academy of Neurology (AAN) ALS guidelines were developed in 2009, the only disease-modifying agent approved for ALS treatment was riluzole.13 Riluzole was approved in 1995 after clinical trials showed that it modestly slowed ALS progression. Twenty-two years passed before another agent was approved by the FDA for the treatment of ALS.5,13,14

The AAN’s guidelines recommend multidisciplinary care, because study results have demonstrated that patients treated with multidisciplinary models have had longer survival, better quality of life, and greater access to therapies.12 However, a study conducted by the AAN found that many evidence-based treatment recommendations were underutilized.15 Consequently, an ALS quality measurement set was developed to provide expert guidance and best practices for managing ALS patient care (Table 1).15 At the time those quality measures were published in 2014, riluzole was the only agent approved by the FDA for treatment of ALS; therefore, beyond recommending disease-modifying treatment, the measures focused mostly on patient referrals to multidisciplinary care clinics, appropriate screenings, and supportive symptom care.13,15

While multidisciplinary care has been shown to improve quality of life and overall survival in patients with ALS, these individuals will become unable to work as they increasingly lose functional ability to perform activities of daily living (ADL), such as driving.1,16 Therefore, under the Social Security Administration’s (SSA) Compassionate Allowance Program, patients with ALS can apply for disability benefits.17 Patients will be covered starting 5 months after they have become disabled in accordance with the SSA definition of disability.18 However, for patients with ALS, a 5-month waiting period may be difficult and burdensome to endure. Under Public Law 106-554, the 24-month waiting period for Medicare coverage for disabled individuals with ALS is waived.19

Given the evidence that former military personnel have an increased risk of ALS,20 the Department of Veterans Affairs has recognized the increased prevalence of ALS in veterans and has classified ALS as a disease presumed to have been caused by military service. Veterans who are diagnosed with ALS and meet the criteria of continuously serving for 90 days or more will be qualified for “presumptive” disability benefits.21

Challenges and Advancements in ALS Study Design and Research

Historically, many challenges have precluded the development of efficient ALS clinical trials and effective ALS treatment.22 From 1971 to 2013, 52 agents have been evaluated in ALS trials, with only 1 disease-modifying agent receiving FDA approval.1,5,22,23

The most significant challenges to developing effective ALS agents are the disease’s rarity, the large inter- and intra-patient variability in clinical course, and the lack of reliable biomarkers and surrogate markers.3,7,16,23 The heterogeneity of ALS’ clinical course coupled with its low prevalence makes it difficult to obtain adequate sample sizes for clinical studies.16 Evaluating a treatment agent’s efficacy in slowing the progression of ALS is further complicated by its inherent heterogeneous and progressive nature and the lack of surrogate markers to accurately measure treatment response.24 It is thus difficult to design a trial that can accurately correlate a patient’s response to the study drug.

ALS investigators have utilized several novel trial designs, including strategies to minimize sample size requirements and limit the study duration.24 For example, use of homogenous subpopulations in clinical trials can increase statistical power and decrease a trial’s duration.3

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