Advancing Future Amyotrophic Lateral Sclerosis Medicines by Incorporating The Patient Voice Into Patient-Centered Holistic Measurement Strategies for Clinical and Real-World Studies: Results from Targeted Literature Reviews

Abstract

Introduction

This analysis sought to understand the patient experience in amyotrophic lateral sclerosis (ALS) and to assess whether commonly used clinical outcome assessments (COAs) reliably and validly capture that experience.

Methods

Two targeted literature reviews were conducted to identify and describe key concepts potentially important to patients (signs, symptoms, impacts), and identify commonly used COAs in ALS. Insights gained were used to map target COAs to concepts identified as potentially relevant to patients and their caregivers. COAs of interest were further examined to evaluate evidence of their validity and reliability within ALS.

Results

Forty-three articles were identified for concept extraction. Signs and symptoms were identified across multiple themes: motor; non-motor; respiratory; cognitive; and behavioral. Patient impacts were identified across multiple themes: physical; functional; emotional; social; and other aspects of well-being. Caregiver impacts were identified across four themes: general; emotional; social; and physical. Of 236 unique COAs identified, 6 were found to provide the greatest coverage of potentially important concepts. Closer examination of these showed some evidence gaps supporting content validity and/or psychometric properties.

Conclusions

Several concepts related to ALS were identified that are relevant to patients in their daily lives. We identified and reviewed COAs commonly used in assessing these concepts, and found gaps in their content validity and/or psychometric properties. These findings suggest the need for further testing/refinement of existing tools, and the opportunity to use other instruments alongside those most frequently used (e.g., ALSFRS-R) to comprehensively capture the patient experience of ALS in future clinical trial and real-world studies.

Supplementary Information

The online version contains supplementary material available at 10.1007/s40120-025-00740-y.

Key Summary Points

Why carry out this study?

Amyotrophic lateral sclerosis (ALS) is the most common type of motor neuron disease, but there are limited data on the ALS patient experience and on whether commonly used clinical outcome assessments (COAs) reliably and validly capture the patient experience.

We sought to: (1) identify and describe key concepts potentially important to patients; (2) identify COAs frequently used in ALS; (3) map the target COAs to the concepts identified as potentially most relevant; and (4) evaluate evidence of the COA's validity and reliability within ALS.

What was learned from the study?

Several concepts related to ALS were identified that are relevant to patients; 236 unique commonly used COAs were identified and reviewed, and gaps were found in their content validity and/or psychometric properties.

These findings suggest the need for further testing and/or refinement of existing tools, along with the opportunity to use other instruments alongside the most frequently used COAs to comprehensively capture the patient experience of ALS.

Introduction

Amyotrophic lateral sclerosis (ALS), the most common type of motor neuron disease, affects ~ 16,000 individuals in the USA, with most developing initial symptoms at the age of 40–70 years and having an expected survival of ~ 2–5 years [1]. While ~ 10% of ALS cases are familial, the other 90% are sporadic. The 2 types are generally similar phenotypically; however, symptoms and disease progression can vary greatly between individuals [1]. ALS can result in a significant impact on the independence and quality of life of patients and their family/friends, who often provide significant care [2]. A survey of informal caregivers (e.g., spouses) found that half felt a high level of burden (measured by the Zarit burden inventory), and ~ 25–50% were likely suffering clinical levels of psychological distress [3].

Current treatment options for ALS are limited, mainly offering only modest benefits in terms of symptoms and functional decline [4, 5]. In 2023, tofersen was the first disease-modifying therapy approved to treat patients with ALS with the superoxide dismutase (SOD1) genetic mutation under the US Food and Drug Administration’s (FDA) accelerated approval pathway. Accelerated approval was based on reduction of plasma neurofilament light, a biomarker of nerve injury and neurodegeneration [6]. The ALS Functional Rating Scale-Revised (ALSFRS-R) score and survival have historically been used in clinical trials to assess ALS treatments [7]. However, ALS is a complex, heterogenous, currently incurable disease, so it is also important to understand the salient concepts (signs, symptoms, and impacts) most important to patients and their caregivers, and to ensure that these are measured in clinical trials and included in patient care, as per the US FDA’s patient-focused drug development (PFDD) guidance [8].

The ALS Association developed a patient- and caregiver-driven initiative to help facilitate robust patient experience and preference studies in ALS [9]. IMPACT ALS was a US-focused PFDD survey that gathered information about the functional impacts of living with ALS as well as the unmet needs related to treating those impacts. The results, ‘The Voice of the Patient’, were submitted to the FDA to guide ALS drug development and to inform regulatory decision-making. The report focused on living with and treatment for ALS, and found that researchers tend to focus on degeneration of motor neurons, whereas patients and caregivers focus on aspects most impactful to health-related quality of life (HRQoL), e.g., fatigue. The survey also highlighted the significant unmet need for effective treatments, particularly disease-modifying treatments.

Clinical outcome assessments (COAs) are integral in gathering information about how patients feel, function, and survive, as well as facilitating PFDD. The ALSFRS-R is the most commonly used and accepted COA in ALS [10]; both the FDA and the European Medicines Agency (EMA) guidance documents for ALS drug development recommend its use, and it has been used to support regulatory approval of ALS therapeutics [7, 11]. Since the initial development of the scale in the 1990s, our understanding of the ALS patient experience has substantially evolved based on qualitative studies [12, 13]. Subsequently, several gaps and limitations of ALSFRS-R have been identified [14]. Some of these gaps may be addressed by using ALSFRS-R alongside other COAs; however, this highlights the need for an overall comprehensive COA measurement strategy.

The FDA’s guidance for industry on developing drugs for the treatment of ALS acknowledges the use of existing outcome measures for ALS as potentially appropriate, but supports the development and use of new COAs capable of measuring clinically meaningful effects in patients [7]. With numerous COAs currently used in ALS, there is a need to review existing instruments and to assess their adequacy whilst considering patients’ needs, wants, and priorities. Our objective was to perform targeted literature reviews to better understand the patient experience of living with ALS, to assess the ability of current COAs to capture that experience, and to identify fit-for-purpose COAs.

Methods

Insights gained from two literature reviews were used to map concepts identified as potentially relevant to patients and their caregivers to COAs that were identified as being used most frequently and/or were of the highest priority in ALS, in order to identify the existing instruments which may best capture patients’ experiences of living with ALS. All COAs identified were reviewed based on their measurement objective, on whether they were ALS-specific, and on their frequency of use. The authors aligned on an initial shortlist of COAs for further review, and selected instruments were then examined in terms of existing evidence of their content validity and psychometric properties.

Identification of Concepts

Objectives

The objectives of the first literature review were to identify the signs, symptoms, and functional impacts (concepts) of potential relevance to patients with ALS, as well as to understand the caregiver experience, including key impacts on daily life and broader HRQoL. Signs are objective evidence of disease that can be observed by others, while symptoms are experienced by the patient [15]. Signs and symptoms are concepts that are more proximal to the disease experience than the resulting impacts of the disease on the patient or caregiver, including physical, mental, social, and emotional functioning and well-being [16, 17].

Search Strategy

A targeted search of peer-reviewed literature was conducted in PubMed, the Cochrane library, and Embase between December 2021 and February 2022, limited to the previous 10 years, English language, human participants, and papers with abstracts (Supplementary Table 1).

Inclusion/Exclusion Criteria

To ensure high quality, results from peer-reviewed, empirical literature were reviewed by title, then abstract, and finally full text, using the inclusion/exclusion criteria (Supplementary Table 2). To identify relevant literature, populations, interventions, comparators, outcomes, and study designs (PICOS) of interest were identified and used as a guide for the eligibility of the search results reviewed. In brief, articles were included for closer examination if they met the following: adult (aged ≥ 18 years) patients with ALS, including those with the SOD1 mutation (because disease-modifying treatment is now available for this ALS subtype), or their caregiver; qualitative (prioritized over other study types because they directly report the patient or caregiver experience of ALS), non-interventional, observational studies or reviews; and included data on disease-related symptoms and/or impacts and HRQoL. Articles were excluded at each stage if they did not meet the pre-specified inclusion/exclusion criteria. To be considered for concept extraction in the study, articles had to meet all pre-specified inclusion criteria and none of the pre-specified exclusion criteria. Moreover, PICOS of interest were identified and used as a guide to ensure relevant and high-quality articles were identified.

Data Extraction

ALS-specific concepts mentioned within articles were extracted. Concepts were reviewed across articles and standardized for consistency, e.g., the standardized concept of “difficulty breathing” was extracted for an article that mentioned “breathing getting worse” or “shortness of breath.” Concepts were organized into broader themes of signs, symptoms, or impacts based on how they were described in the articles and author discussion. For each concept in each article, the following information was noted (if available): whether the concept was reported by the patient, caregiver, or clinician; frequency (i.e., the number of patients or caregivers experiencing that concept in the study sample); and any direct quotes from patients or caregivers related to the concept. For each article, names of COAs used, if applicable, were extracted alongside a summary of the study’s methods, objective(s), and sample.

Identification of COAs

Objectives

The objectives of this literature review were to identify COAs used in ALS and to closely examine select COAs for evidence of their conceptual coverage, content validity, and psychometric properties.

Search Strategy

Articles utilizing COAs were extracted from the concept literature review, with additional targeted literature searches of PubMed, Embase, and the Cochrane library conducted between December 2021 and February 2022 (Supplementary Table 3). The following were also searched: ClinicalTrials.gov database for ALS clinical trials in the last 10 years; the PROLABELS™ database for regulatory-approved labels for ALS treatments in the last 10 years that included COAs; IQVIA’s Health Technology Assessment (HTA) Accelerator database for their assessment of treatments for ALS that included feedback on COAs from HTA bodies; and the PROQOLID™ database for COAs by therapeutic area.

Inclusion/Exclusion Criteria

The search strategy included only those articles that described any use of a COA. Articles were reviewed by title then abstract. COAs reported in the abstracts of any articles were extracted. The same PICOS of interest from the concept literature review were used (Supplementary Table 2).

Data Extraction

A list of COAs from most to least reported was established. ALS-related instruments found in PROQOLID were listed and their content briefly described. For instruments identified from PROLABELS, the following were extracted: the name and acronym of the instrument; the disease and population; the product for which the instrument supported a claim; the health authority granting the claim; and the year, endpoint position of the instrument, and labeling information. For instruments identified from IQVIA’s HTA Accelerator, the following were extracted: the submitting company; the drug reviewed; the reviewing HTA body; the HTA body’s decision regarding reimbursement recommendation; any COAs included as part of the decision; and any comments related to the COAs made by the HTA body.

COAs identified were reviewed to develop a shortlist of target COAs for concept mapping and evaluation based on their frequency of mention in abstracts and priority (i.e., disease-specific and assessing identified concepts) (Table 1).

Table 1.

Preliminary shortlist of ALS COAs

Instrument	Category	Reporter	Objective	Rationale for further assessment
ALSFRS-R	Disease-specific	Clinician	To monitor the progression of disability in patients with ALS. The scale measures physical function in carrying out activities of daily living	Specific to ALS Total score used in primary endpoint for FDA-approved label indicated for ALS Most used COA in clinical trials (17)
ALS-CBS	Disease-specific	Clinician/observer	To measure cognition and behavior patterns in patients with ALS	Specific to ALS Cognitive assessment used in clinical trials (2) Frequently mentioned across all data sources (18)
ALSSQOL-R	Disease-specific HRQoL	Patient	To measure HRQoL in patients with ALS	Specific to ALS Commonly used HRQoL measure in clinical trials (5) Frequently mentioned across all data sources (13)
ECAS	Disease-specific	Clinician/observer	To measure changes in cognition and behavior	Specific to ALS Used in clinical trials (2) Frequently mentioned across all data sources (35)
ALSAQ-40	Disease-specific HRQoL	Patient	To assess HRQoL in patients with ALS	Specific to ALS Most used ALS-specific HRQoL measure identified Frequently mentioned across all data sources (28)
ALS-FTD-Q	Disease-specific	Observer	To screen for behavioral disturbances in ALS	Specific to ALS Frequently mentioned across all data sources (9)
DALS-15	Disease-specific	Patient	To detect and quantify dyspnea	Specific to ALS Frequently mentioned across all data sources (6)
SI-ALS	Disease-specific	Patient	A self-reported measurement of spasticity	Specific to ALS (newly developed instrument) Frequency of mentions across all data sources (2)
mHADS	Disease-specific	Patient	To assess symptoms of anxiety and depression in MND	More specific to MND than the generic HADS
ROADS	Disease-specific	Patient	To assess the degree to which ALS affects daily and social activities	Specific to ALS (newly developed instrument) Frequency of mentions across all data sources (4)
CNS-LS	General	Patient	To provide a quantitative measure of the perceived frequency of pseudobulbar affect episodes	Pseudobulbar affect identified in patients with ALS Frequently mentioned across all data sources (8)
SWAL-QOL	General HRQoL	Patient	To measure the quality of life and quality of care for patients with oropharyngeal dysphagia	Frequently mentioned across all data sources (7)

Numbers in parentheses indicate the frequency of use of COAs in clinical trials or all data sources

ALS amyotrophic lateral sclerosis, ALSAQ-40 ALS Assessment Questionnaire–40, ALS-CBS ALS Cognitive Behavioral Screen, ALSFRS-R ALS Functional Rating Scale-Revised, ALS-FTD-Q ALS Frontotemporal Dementia-Questionnaire, ALSSQOL-R ALS Specific Quality of Life-Revised, COA clinical outcome assessment, CNS-LS Center for Neurologic Study-Lability Scale, DALS-15 Dyspnea ALS Scale 15 items, ECAS Edinburgh Cognitive and Behavioural ALS Screen, FDA Food and Drug Administration, HADS Hospital and Anxiety Depression Scale, HRQoL health-related quality of life, mHADS Hospital Anxiety and Depression Scale for MND, MND motor neuron disease, ROADS Rasch-Built Overall ALS Disability Scale, SI-ALS Spasticity Index-ALS, SWAL-QOL Swallowing Quality of Life

Mapping of COAs to Patient-Relevant Concepts

The shortlist of COAs identified was mapped against the signs, symptoms, and impacts of ALS identified as potentially important to patients. The content of each instrument shortlisted was reviewed to identify the concept(s) they assessed and then mapped against the signs, symptoms, and impacts identified from the concept literature review to indicate which concepts fully aligned with those measured in the COA, which were partially covered (i.e., appeared related but not exactly the same), and which were not covered.

Closer Examination of Select COAs

COAs that provided the best conceptual coverage were further examined by leveraging evidence from additional literature searches regarding their development and evidence of content validity and psychometric properties within ALS (Supplementary Methods), using criteria that are in line with the COSMIN study design checklist for patient-reported outcomes measurement instruments [18], and with the PFDD draft guidance on selecting, developing, or modifying fit-for-purpose COAs [19]. The content validity of the COAs was evaluated based on the overall strength of evidence for adequacy across three general criteria: (1) patient or caregiver input; (2) development process; and (3) target indication, where each was considered either adequate or inadequate. An inadequate rating indicated that no information was found or that the researchers did not consider evidence for the criterion of content validity to be adequate. For each COA, the overall content validity rating was assessed as follows: strong = developed for ALS and involved patients or caregivers in its item generation and debriefing of final measure, along with a review of literature or existing measures and expert input; medium = developed for or later confirmed as relevant for the target indication, with input from patients or their caregivers for either item generation or debriefing of the final measure, plus the development process included a review of the literature, existing measures, or expert input; and weak = not developed or confirmed in the target indication, or the development process was unclear with no input from patients or caregivers, clinicians, or existing literature/measures.

Overall psychometric evidence was rated by the number of psychometric properties out of eight that were assessed as adequate: (1) internal consistency; (2) test–retest and inter-rater reliability; (3) convergent validity; (4) divergent validity; (5) known-groups validity; (6) ability to detect change; (7) interpretation of change; and (8) structural validity (see Supplementary Methods for criteria for the adequacy of each extracted property). “Adequate” indicated sufficient evidence for the psychometric property and “inadequate” indicated that either no information was found or there was not adequate evidence. Ratings were assigned as strong = 7 or 8 psychometric properties assessed as adequate; medium = 4–6; and weak = 0–3.

Ethical Approval

This study was non-interventional, comprising comprehensive literature reviews using secondary data; no patients were involved. Therefore clinical research ethics committee or independent review board approval was not required.

Results

Identification of Concepts and Themes

Of 1290 articles identified from the literature review, 105 were reviewed in full, 43 of which were identified as high quality and therefore most relevant for concept extraction (Fig. 1). Of the 43 articles, 33 involved or reviewed qualitative research with patients or their caregivers and sought to understand the experience of living with ALS or the impact of specific symptoms, and 10 were non-qualitative articles that employed questionnaires or reviewed such studies to assess the experience of symptoms or impacts.

Fig. 1.

PRISMA diagram for ALS concept extraction. ALS amyotrophic lateral sclerosis, CAM complementary and alternative medicine, PRISMA Preferred Reporting Items for Systematic Reviews and Meta-Analyses

Patient Experience of Living with ALS

Overall, the experience (signs and symptoms) of ALS reported by the reviewed articles was heterogeneous in nature but could be grouped into five key themes: motor; non-motor; respiratory; cognitive; and behavioral. Motor signs and symptoms included spasms or cramps, muscle weakness in upper and lower extremities and facial muscles, muscle stiffness, and difficulty walking. Non-motor symptoms included physical pain, fatigue, excessive sweating, drooling, constipation, weight loss, altered taste/smell, dizziness, fainting, changes in sleep quality, and frequent urination. Respiratory problems included difficulty breathing and cough. Cognitive symptoms included memory impairment and concentration issues, and behavioral symptoms included hallucinations, delusions, and inappropriate episodes of crying or laughing. Most articles reviewed did not report prevalence data for signs or symptoms, and some of those that did report prevalence data had inclusion or exclusion criteria that would have potentially inflated these data (e.g., an article on spasticity in ALS that only included patients with ALS experiencing spasticity). However, prevalence of symptom domains has been described elsewhere [19–22]. Example patient quotes from the literature are summarized in Table 2 [23–29].

Table 2.

Patient and caregiver quotes on the experience of living with ALS

Sign/symptom	Patient quotes
Motor: muscle stiffness	My fingers stiffen up. My body seems to be frozen. The feeling is hard to express in words. I feel like I’m a robot rusting slowly and destroyed by illness and pain [23]
Non-motor: pain	What I have in my neck is more like a continuous dull pain that I have all the time [24]
Respiratory	And that was the main thing I was aware that since there was an issue over my breathing, that was likely to get worse, so it wasn’t just a question of “I don’t really need any help now” it was the knowledge that it was likely to continue to deteriorate, and if it would help me with sleeping and not having to get up so often… [29]
Cognitive	You see MND [ALS] is the worst neurological condition one could get. This for me has taken away so much. It’s going in the direction of taking all my faculties, my independence, my speech, my mobility, concentration, eating…everything I was doing is now gone [25]
Behavioral	No quotes available from sources reviewed

Caregiver quotes
You have to keep track of the breathing all the time, you hear the alarm from the ventilator and we have a sound monitor too, if the tube slips out or something like that [26]
…sometimes overnight it changes, so you never know what’s going to happen [27]
We did try to go away for a holiday break…and the hotel couldn’t handle it. They couldn’t prepare the food in the way that was necessary, so we had to come home and maybe only stayed 1 night [28]

Quotes are intended to be illustrative and are not necessarily representative of reviewed patient experience data that informed the identification of the concept domains

The impacts on patients with ALS were also heterogeneous and could be grouped into five themes: physical; functional; emotional; social; and other aspects of well-being.

Experiences of Caring for Patients with ALS

Caregivers were impacted by their role in caring for a patient with ALS [30, 31], and described the broader impact of the disease on family life [32]. Themes for caregivers were grouped as general, emotional, social, and physical, and included concepts such as impact on work and sex life, loss of privacy, insecurity, depression, and loss of freedom. Example caregiver quotes identified in the literature are summarized in Table 2.

Identification of COAs

A total of 236 unique COAs were identified (Fig. 2). The ALSFRS-R was the most utilized (n = 467), and the only COA included in labeling for regulatory-approved ALS treatments; all 17 clinical trials identified from clinicaltrials.gov used the ALSFRS-R. A total of 39 other COAs were used 6–64 times across all sources reviewed, and 12 COAs were initially shortlisted for concept mapping (Table 1).

Fig. 2.

COA frequency of usage and usage by type. *Measures mentioned 6 or more times across data sources included in this figure for a total of 40 COAs. AES; ALSAQ-40-R; ALS-CBS; ALSFRS; ALSFRS-VAS; ALSFRS-R; ALS-FTD-Q; ALSSQOL; ALSSQOL-R; ALSSS; BDI; CBI; ClinRO; CNS-LS; COA, clinical outcome assessment; DALS-15; ECAS; EQ-5D; EQ-5D-5L; EQ-VAS; ESS; FAB; FBI; FSS; FVC; HADS; HHD; MiND-B; MIP; MoCA; MMSE; MMT; MQOL; MRC; Norris Scale; ObsRO; PerfRO; PRO; PSQI; SF-36; SNIP; SVC; SWAL-QOL; WHOQOL-BREF; ZBI

Mapping of COAs to Patient-Relevant Concepts

Concepts identified from the concept literature review were mapped to the 12 shortlisted COAs (Table 3). Only a few COAs directly assessed motor symptoms. The Spasticity Index-ALS (SI-ALS) specifically measured spasticity, muscle stiffness, spasms, and cramps, while other measures, e.g., the ALSFRS-R, focused on the impacts of motor symptoms (e.g., difficulty walking) rather than assessing symptoms directly. The ALS Specific Quality of Life–Revised (ALSSQOL-R) and Swallowing Quality of Life (SWAL-QOL) covered the most non-motor symptoms, the Edinburgh Cognitive and Behavioural ALS Screen (ECAS) covered the most cognitive and behavioral symptoms, and the ALSFRS-R, the ALS Assessment Questionnaire-40 (ALSAQ-40), and the ALSSQOL-R covered the most impacts.

Table 3.

Mapping of signs and symptoms relevant to patients with ALS to COAs

Sign/symptom	ALSFRS-R	ROADS	ALSSQOL-R	ALSAQ-40	SWAL-QoL	DALS-15	SI-ALS	CNS-LS	ALS-CBS	ECAS	ALS-FTD-Q	mHADS
Motor
Spasticity							✓
Spasticity upper extremities								✓
Spasticity lower extremities								✓
Muscle stiffness							✓
Muscle stiffness in hand joints
Spasms							✓
Twitching
Cramps							✓
Muscle weakness			✓
Muscle weakness upper extremities
Muscle weakness lower extremities
Muscle weakness in facial muscles
Difficulty walking	✓	✓		✓			~
Loss of eye movement									✓
Double vision										✓
Poor voice quality	~	~	~
Slurred speech	~	~	~	✓
Difficulty swallowing	✓	✓		✓*	✓
Non-motor
Physical pain			✓	~
Fatigue			✓	~	✓	~			✓
Excessive sweating
Drooling	✓		✓		✓
Constipation			✓
Weight loss
Altered taste/smell
Dizziness
Fainting
Changes in sleep quality			✓		✓		~
Frequent urination			✓
Respiratory
Difficulty breathing	✓					✓
Cough					✓	✓
Secretions			✓		✓
Cognitive
Memory impairment										✓	✓
Attention/concentration issues									✓	✓	✓
Behavioral
Hallucinations										✓	✓
Delusions										✓
Inappropriate episodes of crying or laughter								✓	✓

✓ concept is covered; ~ concept has partial coverage; * concept partially covered by the ALSAQ-5

ALS amyotrophic lateral sclerosis, ALSAQ-5 ALS Assessment Questionnaire–5, ALSAQ-40 ALS Assessment Questionnaire–40, ALS-CBS ALS Cognitive Behavioral Screen, ALSFRS-R ALS Functional Rating Scale-Revised, ALS-FTD-Q ALS Frontotemporal Dementia-Questionnaire, ALSSQOL-R ALS Specific Quality of Life-Revised, CNS-LS Center for Neurologic Study-Lability Scale, COA clinical outcome assessment, DALS-15 Dyspnea ALS Scale 15 items, ECAS Edinburgh Cognitive and Behavioural ALS Screen, HADS Hospital and Anxiety Depression Scale, mHADS Hospital Anxiety and Depression Scale for MND, MND motor neuron disease, ROADS Rasch-Built Overall ALS Disability Scale, SI-ALS Spasticity Index-ALS, SWAL-QOL Swallowing Quality of Life

Ten symptoms identified as potentially important to patients were not covered by any of the 12 shortlisted COAs. These were the motor symptoms of muscle stiffness in hand joints (muscle stiffness in general was covered), twitching, and muscle weakness in specific areas of the body (general muscle weakness was covered), and the non-motor symptoms of excessive sweating, weight loss, altered taste/smell, dizziness, and fainting. Ten impacts identified as potentially important to patients were not covered by any of the shortlisted COAs (Table 4). These were: physical—excessive daytime sleepiness; functional—impact on life at work; emotional—bitterness, guilt, feelings of insecurity, suicidal ideation (depression was covered), disorientation as an emotion, feeling overwhelmed, grief, and worry about the caregiver/family (worry in general was covered).

Table 4.

Mapping of impacts relevant to patients with ALS to COAs

Impacts	ALSFRS-R	ROADS	ALSSQOL-R	ALSAQ-40	SWAL-QoL	DALS-15	SI-ALS	CNS-LS	ALS-CBS	ECAS	ALS-FTD-Q	mHADS
Physical
Decreased mobility	✓	✓	✓	✓*			~
Difficulty sleeping	~		✓		✓	~	~
Excessive daytime sleepiness
Difficulty eating/drinking	✓	✓	✓	✓	✓
Aspiration/choking	✓				✓
Decreased appetite					✓
Functional
Difficulty with self-care/ADLs	✓	✓		✓		~
Modification of diet/textures	✓				✓				✓	✓
Difficulty writing	✓	✓		✓
Loss of independence	✓	✓	✓	✓
Impact on work life
Emotional
Anxiety									✓			✓
Anger				✓					✓		✓
Agitation/frustration				~	~				✓			✓
Depression			✓	✓	~	~			✓			✓
Apathy									✓	✓	✓
Apathy—lack of motivation			✓							✓
Apathy—lack of interest									✓	✓	✓	✓
Bitterness
Feeling sad or down			✓	✓	~				✓			✓
Desperation/hopelessness			✓	✓*
Helplessness			✓
Guilt
Shame											✓
Embarrassed				✓			~
Feelings of insecurity
Uncertainty			✓
Suicidal ideation
Panic												✓
Stress									✓			✓
Disorientation (emotion)
Lack of pleasure												✓
Feeling overwhelmed
Feelings of loneliness/isolation			✓	✓		~
Feeling like a burden to others				✓
Grief
Worry			✓	✓					✓			✓
Worry about caregiver/family
Worry about not being able to breathe						✓
Fear			✓		~	~						✓
Loss of self			✓
Social
Impact on social life			✓		~					✓
Impact on relationships/family life			✓		~					✓
Impact on communication		~	✓	✓*
Impact on leisure activities			~	~	~	~
Difficulty traveling/driving		✓
Other
Impact on overall physical and mental health			~
Impact on sexual life			✓								✓
Impact on religion			✓
Impact on finances										✓

✓ concept is covered; ~ concept has partial coverage; * concept partially covered by the ALSAQ-5

ADL activity of daily living, ALS amyotrophic lateral sclerosis, ALSAQ-5 ALS Assessment Questionnaire-5, ALSAQ-40 ALS Assessment Questionnaire-40, ALS-CBS ALS Cognitive Behavioral Screen, ALSFRS-R ALS Functional Rating Scale-Revised, ALS-FTD-Q ALS Frontotemporal Dementia-Questionnaire, ALSSQOL-R ALS Specific Quality of Life-Revised, CNS-LS Center for Neurologic Study-Lability Scale, COA clinical outcome assessment, DALS-15 Dyspnea ALS Scale 15 items, ECAS Edinburgh Cognitive and Behavioural ALS Screen, HADS Hospital and Anxiety Depression Scale, mHADS Hospital Anxiety and Depression Scale for MND, MND motor neuron disease, ROADS Rasch-Built Overall ALS Disability Scale, SI-ALS Spasticity Index-ALS, SWAL-QOL Swallowing Quality of Life

Of the 12 shortlisted COAs, 6 were identified as providing the greatest coverage of the themes and concepts identified as potentially most relevant to the ALS patient experience and underwent further review: ALSFRS-R [10]; Rasch-Built Overall ALS Disability Scale (ROADS) [33]; ALSSQOL-R [34]; ALSAQ-40 [35]; SI-ALS [36]; and SWAL-QOL [37].

Closer Examination of Content Validity and Psychometric Properties

Upon closer examination, there were gaps in the evidence supporting the content validity for all 6 shortlisted instruments (Table 5) [10, 33, 34, 36–38]. Five were developed specifically for ALS; the sixth, SWAL-QOL, was developed for oropharyngeal dysphagia. The ROADS, ALSSQOL-R, ALSAQ-40, and SI-ALS included input from patients with ALS during their development, but only SI-ALS was clearly debriefed with patients with ALS.

Table 5.

Content validity of shortlisted COAs with the most conceptual coverage

Criteria	ALSFRS-R [10, 38]	ROADS[33]	ALSSQOL-R [34]	ALSAQ-40 [35]	SI-ALS [36]	SWAL-QOL [37]
Overall strength of evidence	Weak	Medium	Medium	Medium	Strong	Weak
Patient or caregiver input	Inadequate evidence Not available	Medium evidence Patients provided input on initial item bank to ensure comprehensiveness No information found on whether final measure was debriefed with patients	Medium evidence Qualitative interviews with patients with ALS informed the original ALSSQOL OI No information found on whether final measure was debriefed with patients	Medium evidence Exploratory in-depth patient interviews (n = 18 patients with ALS/MND of different ages and phases of disease) to generate an initial 78-item questionnaire, reduced following a pilot study Face validity assessed by 2 patients, 1 regional care advisor, and 2 neurologists, but no information found on whether final measure was debriefed with patients	Adequate evidence Semi-structured concept elicitation interviews with patients with ALS of varying age, spasticity level, and disease duration Draft scale debriefed with patients (n = 17 with ALS)	Inadequate evidence Thirteen focus groups of patients (n = 52) and caregivers (n = 15) with a variety of reasons for dysphagia, including neurologic disorders, but inclusion of patients with ALS not specified
Development process	Medium evidence Original ALSFRS (1991) created from review of existing measures ALSFRS-R (1999): 3 new items added to the original	Adequate evidence Developed in 2020 to overcome limitations of the ALSFRS-R Literature review included existing ALS-specific scales Literature review and expert panel informed preliminary questionnaire	Adequate evidence Original ALSSQOL (2006): Developed based on review of existing measures and qualitative interviews with patients with ALS Revised ALSSQOL-R (2011): Developed based on reducing items in the ALSSQOL	Adequate evidence Developed in 2000 following patient interviews to generate initial items and pilot testing to reduce the number of items	Adequate evidence Developed in 2018 based on interviews with patients and a panel of clinicians The 71-item draft scale was endorsed by panel of clinicians and mailed to patients (with clinically confirmed ALS) along with other scales to further reduce the number of items (n = 465 patients with ALS)	Medium evidence Published in 2000 Literature review conducted informing content of focus groups A 185-item version pilot was tested to reduce to 93 items, which were further reduced
Target indication	Adequate evidence ALS	Adequate evidence ALS	Adequate evidence ALS	Adequate evidence ALS or MND	Adequate evidence ALS	Inadequate evidence Patients with oropharyngeal dysphagia

Strong = developed for ALS and involved patients or their caregivers in its item generation and debriefing of final measure, along with a review of literature or existing measures and expert input; medium = developed for or later confirmed as relevant for the target indication, with input from patients or their caregivers for either item generation or debriefing of the final measure, plus the development process included a review of the literature, existing measures, or expert input; weak = not developed or confirmed in the target indication, or the development process was unclear with no input from patients or their caregivers, clinicians or existing literature/measures. Adequate = sufficient evidence for aspect of content validity; inadequate = no information found or inadequate evidence for aspect of content validity

ALS amyotrophic lateral sclerosis, ALSAQ-40 ALS Assessment Questionnaire–40, ALSFRS-R ALS Functional Rating Scale-Revised, ALSSQOL-R ALS Specific Quality of Life-Revised, COA clinical outcome assessment, MND motor neuron disease, ROADS Rasch-Built Overall ALS Disability Scale, SI-ALS Spasticity Index-ALS, SWAL-QOL Swallowing Quality of Life

Psychometric evidence for all 6 measures was also mixed (Table 6) [10, 33–55]. None met the criteria for strong evidence, and three were considered to have weak evidence.

Table 6.

Psychometric properties of shortlisted COAs with the most conceptual coverage

Criteria	ALSFRS-R	ROADS	ALSSQOL-R	ALSAQ-40	SI-ALS	SWAL-QOL
Overall strength of evidence	Medium	Weak	Weak	Medium	Weak	Medium
Internal consistency	Adequate evidence Cronbach’s α total and domain: 0.71–0.92 (n = 59 patients with MND; n = 485 patients with ALS) [38, 39] Original ALSFRS Cronbach’s α: > 0.6 for individual items; 0.811–0.815 for total (n = 75 patients with ALS) [40]	Inadequate evidence NA for the English version PSI = 0.94 (n = 254 patients with ALS; Chinese translation) [41]	Adequate evidence Cronbach’s α total and domain: 0.71–0.92 (n = 389 patients with ALS) [34] Cronbach’s α of original ALSSQOL Total score = 0.75 (n = 342 patients with ALS) [42]	Adequate evidence Cronbach’s α for each domain: 0.92–0.97 (n = 35 patients with ALS/MND) [35]	Adequate evidence Cronbach’s α = 0.87 (n = 287 patients with ALS) [36]	Adequate evidence Cronbach’s α for each domain: 0.59–0.91 (n = 386 patients with dysphagia) [37]
Test–retest and inter-rater reliability	Adequate evidence Test–retest: ICC ≥ 0.917 for all domains and total (n = 170 patients with MND; 14–21 days apart); [38] Pearson correlation > 0.88 for all items and Cohen’s κ 0.59–0.82 (n = 75 patients with ALS; 7 days apart) [40] Inter-rater: ICC = 0.93 (n = 9 patients with ALS; n = 30 raters) [43]	Adequate evidence ICC = 0.97 (n = 67 patients with ALS, 2–7 days apart) [33]	Inadequate evidence No information found for the English version Pearson correlation = 0.80, ICC = 0.89 (n = 30 patients with ALS, 4-week retest, Korean translation) [44]	Inadequate evidence No information found for the English version 85% agreement between evaluations (30 days) based on Wilcoxon test [n = 20 patients with ALS, Portuguese (Brazil) translation] [45]	Adequate evidence Concordance correlation coefficient among those who were stable was 0.793 (95% CI: 0.632–0.889); retest questionnaire 2 weeks apart (n = NA) [36]	Inadequate evidence ICC for each domain ranged from 0.59 to 0.91 Pearson correlation coefficient for each domain ranged from 0.60 to 0.91 (n = 37 patients with dysphagia; 2 weeks apart) [37]
Convergent validity	Adequate evidence Pearson correlation between ALSFRS-R total and FVC% = 0.41; SIP = –0.72 [10] Pearson correlation between ALSFRS-R domain/total scores and ALSFRS total ≥ 0.61, excluding the ALSFRS-R respiratory domain (n = 387 placebo-treated patients with ALS) [10]	Adequate evidence Correlation between ROADS and ALSFRS-R = 0.82; between ROADS and vital capacity percentage = 0.57 (n = 243 patients with ALS) [33] Correlation between ROADS and ALSFRS-RSE = 0.90 at baseline; Cohen’s kappa between measures was 71% and 74% at 3 and 6 months, respectively (p < 0.001; n = 176 patients with ALS) [46]	Adequate evidence Pearson correlation between ALSSQOL-R total and WHOQOL-physical health = 0.54; WHOQOL-psychological = 0.68; WHOQOL-social relationships = 0.58; WHOQOL-environment = 0.46 (n = 176 patients with ALS) Criterion validity: Pearson correlation between ALSSQOL-R total and MQOL-SIS = 0.58 (n = 385 patients with ALS) [34]	Adequate evidence Spearman correlation coefficients between ALSAQ-40 scales and related SF-36 domains were 0.55–0.65; and between ALSAQ-40 scales and related ALSFRS domains were 0.2–0.95 (n = 173 patients with MND) [35]	Adequate evidence Correlation between the Leeds Spasticity scale and the SI-ALS was 0.61; 80% agreement in the presence and absence of spasticity between the 2 scales. (n = 287 patients with ALS) [36] Significant gradient was observed across NRS with anchors of “no spasticity” and “worst possible spasticity” (F = 23.4; p < 0.001). About 92% of participants who reported spasticity on the NRS completed the SI-ALS. (n = 287 patients with ALS) [36]	Inadequate evidence Correlations between SWAL-QOL domains and related MOS domains > 0.30; [37] Spearman correlation between SWAL-QOL total and ALSFRS-R bulbar function = 0.46 (n = 81 patients with ALS) [47]
Divergent validity	Inadequate evidence NA	Inadequate evidence NA	Adequate evidence ALSSQOL-R total weak correlation with manual muscle testing as measured by composite MRC = 0.094; and with ALSFRS-R = 0.22 (n = 385 patients with ALS) [34]	Inadequate evidence NA	Inadequate evidence NA	Adequate evidence Average correlation between overall quality of care and the SWAL-QOL was 0.18 (n = 81 patients with ALS) [37]
Known groups validity	Inadequate evidence NA	Inadequate evidence NA	Inadequate evidence NA	Adequate evidence Kruskal–Wallis test of difference between groups self-reported as (1) poor/fair; (2) good; or (3) very good/excellent; difference in groups for ALSAQ-40 eating and drinking (p < 0.01), physical mobility (p < 0.02), and emotional functioning (p < 0.001); communication and ADLs/independence followed trend (n = 75 patients with ALS)	Inadequate evidence NA	Adequate evidence Differences detected in some domains between “normal” swallowers and those with dysphagia as well as between those who are and are not fed with a tube (p < 0.001; n = 386 patients with dysphagia and n = 40 “normal” swallowers); [37] differences in SWAL-QOL total in patients with ALS between swallowers, penetrators, and aspirators as determined by VFSS (p < 0.001; n = 81 patients with ALS) [47]
Ability to detect change	Adequate evidence Pearson correlation of changes in measures to month 9 between ALSFRS-R and FVC% (0.58), SIP (–0.58), and ALSFRS (0.97) (n = 387 placebo-treated patients with ALS) [10]	Inadequate evidence Mean change from baseline at 3 and 6 months was – 1.0 per month, with mixed models for categorical time being significant for detecting a functional decline at 3, 6, and 12 months (p = not specified) [46]	Inadequate evidence NA	Adequate evidence Patients (n = 75 with ALS) grouped by health worsened (55.3%), stayed the same (40.8%), or improved (2.6%) at follow-up.. For the worsened group, eating and drinking and ADLs/independence showed statistically significant change (p-values not provided); communication and physical mobility showed non-statistically significant change in hypothesized direction and no statistically significant differences were found on any dimensions for patients reporting no change Patients on mastinib + riluzole (n = 99) vs. placebo + riluzole (n = 102) showed significantly lower deterioration in ALSAQ-40 score with a between-group difference of 29% (LSM change of 19.42 vs. 27.18; p = 0.008) [48]	Inadequate evidence NA	Inadequate evidence Improvements (p = NS) detected in SWAL-QOL and most pronounced 1–4 days after treatment (pharyngeal electrical stimulation in addition to standard logopedic therapy) (n = 20 pts with ALS assessed at baseline, 1 day, 4 days, 3 weeks, and 3 months) [49]
Interpretation of change	Inadequate evidence Change of 20–25% or greater in slope of ALSFRS-R clinically meaningful (survey of n = 42 ALS clinicians) [50] Attempt to establish meaningful change from the patient/caregiver perspective unsuccessful (n = 81 dyads of patients with ALS and their caregivers) [51]	Inadequate evidence Rasch-built scales are linearly weighted, meaning that a 1-point change is a consistent measurable unit across the scale [33]	Inadequate evidence NA	Inadequate evidence Minimal meaningful change on a 0–100 scale estimated at 6.59 in physical mobility, 6.72 ADLs/independence, 8.66 for eating and drinking, 5.57 for communication, 6.97 for emotional functioning, and 4.61 for ALS index total based on distribution-based methods using 1 SEM where SEM = SD of score × √(1-reliability) (n = 764 patients with MND) MID for worsening calculated as 3.35 in physical mobility, 5.67 in ADL/independence, 6.4 in eating and drinking, 6.67 in communication, 2.67 for emotional functioning based on the mean change score for patients (n = 764) reporting a little change [52]	Inadequate evidence The SDC was 7.5, which represents 12.5% of the total scale width. The SDC was calculated as 1.96 × √2 × SEM, where 1.96 derives from the 95% CI, and SEM = SD all testing scores × √ (1-ICC). (n = 287 patients with ALS) [36]	Inadequate evidence No ALS-specific information found
Structural validity	Inadequate evidence Support mixed for a 4-factor domain structure and total score [39, 40, 53]	Inadequate evidence Variance explained by measured construct = 58.2% (> 50% was considered sufficient for unidimensionality) [33]	Inadequate evidence Six-factor structure supported by confirmatory factor analysis: Χ2 = (2985.91/974) = 3.06, p = 0.000; CFI = 0.766; and RMSEA = 0.069, 90% CI: 0.066–0.072 (n = 389 patients with ALS) [34] Correlations between ALSSQOL-R individual items and factors were 0.429–0.903; and correlations between factors were − 0.074 to 0.591 (n = 389 patients with ALS) [34]	Adequate evidence Item to scale correlations from 0.63 to 0.95 (n = 173 patients with MND) [35]	Inadequate evidence Developed using a Rasch model; initial fit of 71-item draft was poor; the iterative phase of item reduction led to a 20-item version with satisfactory fit (< 5% of independent t tests found significant; 95% CI: 1.9–7.8) [36]	Adequate evidence Factor analysis confirmed 2-factor solution: dysphagic-specific QoL (eigenvalue = 5.58; factor loadings 0.54–0.83); generic QoL (eigenvalue = 1.02; factor loadings 0.81–0.83) [37]
Other psychometric properties	Predictive validity: patients with baseline ALSFRS-R total score below the median of 38 had a 4.4-fold increase in the risk of death or tracheostomy (HR = 4.38, 95% CI: 2.79–6.86, p < 0.001; n = 267 patients with ALS) [54] Ten of 12 items have displayed ceiling effects (≥ 25% indicating “normal” function) at baseline (n = 888 patients with ALS from pooled clinical trial data who completed the ALSFRS-R) [51]	Rasch analyses and clinician experts’ review of items’ face validity resulted in final a 28-item measure [33] Difference between empirical variance and Rasch modeled variance = 0.1% [33] No items demonstrated significant DIF on the basis of age; 2 items (read a newspaper or book and watch television) demonstrated DIF on the basis of sex and were removed [33] Predictive validity: change from baseline to 6 months was significantly predictive of mortality at 12 months (HR = 1.9, z score = − 4.2, p < 0.001) [46]	NA	Potential floor effect in the eating and drinking scale, with a 25.4% scoring minimum in a development study and a 25th percentile of 0 in another study (n = 296 patients with MND) [55]	No DIF observed for age, sex, marital status, onset type, or year of data collection [36]	Floor effects ranged from 2.4% (fear) to 19.1% (eating duration); ceiling effects ranged from 4.2% (fatigue) to 42.2% (patient satisfaction) [37]

Strong = 7 or 8; medium = 4–6; weak = 0–3 number of psychometric properties assessed as adequate. Adequate = sufficient evidence for psychometric property; inadequate = no information found or inadequate evidence for psychometric property (see Supplementary Information for specific criteria for adequacy of extracted psychometric properties)

ADL activity of daily living, ALS amyotrophic lateral sclerosis, ALSAQ-5 ALS Assessment Questionnaire–5, ALSAQ-40 ALS Assessment Questionnaire–40, ALS-CBS ALS Cognitive Behavioral Screen, ALSFRS-R ALS Functional Rating Scale-Revised, ALS-FTD-Q ALS Frontotemporal Dementia-Questionnaire, ALSSQOL-R ALS Specific Quality of Life-Revised, CFI comparative fit index, CI confidence interval, COA clinical outcome assessment, DIF differential item functioning, FVC forced vital capacity, HR hazard ratio, ICC intraclass correlation coefficient, LSM least squares mean, MID minimal important difference, MND motor neuron disease, MOS medical outcome study, MQOL-SIS McGill Quality of Life Questionnaire–Single Item Score, MRC Medical Research Council, NA not available, NRS numeric rating scale, NS not significant, PSI Person Separation Index, QoL quality of life, RMSEA root mean square error of approximation, ROADS Rasch-Built Overall ALS Disability Scale, SD standard deviation, SDC smallest detectable change, SEM standard error of measure, SF-36 The 36-Item Short Form Health Survey, SI-ALS Spasticity Index-ALS, SIP sickness impact profile, SWAL-QOL Swallowing Quality of Life, VFSS videofluoroscopic swallow study WHOQOL World Health Organization Quality of Life

Discussion

ALS remains a highly morbid and ultimately fatal disease, with significant patient and caregiver burden [56]. It is therefore imperative that studies of new ALS treatments assess the signs, symptoms, and impacts most important to patients, as well as looking at survival. This study provided useful insights into patients’ experience of living with ALS, including identification of potential key concepts, and a greater understanding of the COAs used to measure these concepts.

Analysis of the available literature identified many signs and symptoms that may have a significant impact on patients’ HRQoL. Furthermore, patients reported that the disease not only had physical and functional impacts but also emotional, social, and other impacts on well-being, many of which have not historically been prioritized for assessment during ALS clinical research. The current literature also describes how caregivers' experience impacts on their emotional, social, and physical well-being.

We identified over 200 unique COAs used to assess ALS. A COA is considered fit for purpose if there is strong evidence that supports its score reflecting the concepts of interest within the specified context of use [19]. We therefore mapped select COAs to the concepts identified as being potentially most relevant to patients and caregivers, and identified six that provided the greatest coverage. These instruments are generally recommended in ALS because of their comprehensiveness and specificity. However, all instruments were associated with some gaps with regards to content validity and/or psychometric properties [10, 33–37]. Therefore, a holistic patient-centered measurement strategy may be required to fully capture the patient voice in ALS, e.g., the use of multiple COAs.

The ALSFRS-R was used and/or referenced considerably more frequently than other COAs. This is expected, given that it is recommended by medical agencies (e.g., the FDA and the EMA [7, 11]) in their guidelines on investigating ALS treatments; it is also the only COA used in labels, and is considered the ‘gold standard’ measure of functional disability and disease progression in ALS [7, 14]. Using our assessment criteria, we determined that the ALSFRS-R had weak content validity, as no patients or caregivers were included in its development, and no information was found on subsequent qualitative research showing that the relevance of the concepts assessed by the ALSFRS-R aligned with the experiences of patients themselves. Moreover, it did not assess many symptoms and impacts which are potentially most important to patients. Therefore, primary research with patients living with ALS and their caregivers is strongly recommended to better understand the concepts of interest and to support the selection of COAs that map these concepts in a clinical trial.

Hartmaier et al. also conducted a literature review assessing the most commonly used COAs in ALS [14], recognizing that there are gaps in the current COAs and stressing the importance of monitoring ALS HRQoL and cognitive screens to assess the potential of new ALS therapies more comprehensively. This was also highlighted by Zizzi et al. in their qualitative analysis, which concluded that identifying and understanding the most prevalent and important symptoms to patients could provide potential targets for future ALS treatments [12]. Our study was conducted before the publication of this analysis, so unfortunately important information and data regarding the frequency and importance of symptoms and impacts were not included. However, both our findings and those of others show the heterogeneity of this disease, the many impacts that symptoms have on the day-to-day lives of patients with ALS and their caregivers, and the limitations of single COAs to provide a truly holistic patient-centered management strategy.

Some limitations should be noted. Our findings were based on secondary research, and thus further research, especially primary qualitative research with patients, caregivers, and clinician experts, is recommended. Such primary research could further refine our findings and explore the patient experience with ALS based on open-ended questions to observe what spontaneously emerges as important to patients, as well as to identify anything else from a patient perspective not captured by available secondary research. Although different types of ALS appear to be phenotypically similar, ALS is a heterogenous disease. The literature searches we conducted were limited to sporadic ALS and SOD1 ALS. Additional research on other specific types of ALS could explore potential nuances in the patient experience either conceptually or in terms of manifestations.

Conclusion

In conclusion, this study identified themes and concepts of ALS that may be of importance to patients and their caregivers. Furthermore, it identified and reviewed current COAs commonly used in assessing these concepts, and found opportunities to improve their content validity and psychometric properties. Once the concepts most important to patients have been confirmed, further studies are needed to explore how best to measure and implement them in clinical and real-world trials. The empirical evidence from these literature reviews, coupled with evidence from additional qualitative research, could then be used to support advancing future ALS research.

Supplementary Information

Below is the link to the electronic supplementary material.

Author Contributions

Diana Rofail, Michael Chladek, Betsy Williams, Nick Patel, William B. Nowell, Stella Karantzoulis, and Oren Levy contributed to the study conception and design. The first draft of the manuscript was written by Diana Rofail and Michael Chladek, Betsy Williams, Nick Patel, William B. Nowell, Stella Karantzoulis, and Oren Levy commented on subsequent versions of the manuscript. Diana Rofail, Michael Chladek, Betsy Williams, Nick Patel, William B. Nowell, Stella Karantzoulis, and Oren Levy read, edited, and approved the final manuscript.

Funding

This study was sponsored by Regeneron Pharmaceuticals, Inc. and Alnylam Pharmaceuticals. The journal’s Rapid Service Fee was funded by Regeneron Pharmaceuticals, Inc.

Data Availability

Qualified researchers may request access to study documents (including the clinical study report, study protocol with any amendments, blank case report form, and statistical analysis plan) that support the methods and findings reported in this manuscript. Requests should be submitted to https://vivli.org/.

Declarations

Conflict of Interest

Diana Rofail, Nick Patel, William B. Nowell, and Oren Levy are full-time employees of Regeneron Pharmaceuticals, Inc., and hold stock in Regeneron Pharmaceuticals, Inc. Michael Chladek, Betsy Williams, and Stella Karantzoulis are employees of IQVIA.

Ethical Approval

This study was non-interventional, comprising of comprehensive literature reviews using secondary data; no patients were involved in this study. Therefore clinical research ethics committee or independent review board approval was not required.