Defining the clinical benefits of disease-modifying therapy in people living with spinal muscular atrophy who require permanent ventilation: a UK-based modified Delphi consensus process

Summary

Background

Spinal muscular atrophy (SMA) is a rare inherited neuromuscular disorder that may require permanent ventilation (PV) in severe cases. Although disease-modifying therapies (DMTs) have transformed outcomes for many, prior to this research, access in the UK was restricted for patients receiving PV (SMA-PV). This study aimed to develop consensus recommendations on DMT use and to define clinical benefit in SMA-PV.

Methods

A multidisciplinary UK-based expert panel conducted a modified Delphi consensus process between 08 April and 09 June 2025. Draft statements informed by published evidence and expert insights were anonymously voted on for up to three rounds, with consensus defined as ≥75% agreement. Statements not achieving consensus were revised and re-evaluated. Input from a non-voting patient advisory panel (PAP) was also considered. The study was not prospectively registered.

Findings

Excluding the Chair, 18 participants evaluated 22 statements across seven thematic areas specific to SMA-PV: DMT access; treatment initiation; treatment monitoring; defining clinical benefit; functional outcomes; quality of life (QoL); and future research priorities. All 22 statements achieved consensus after two voting rounds (100% participation; agreement range 89–100%). Two statements were revised and re-voted in round 2: one after narrowly missing consensus (72% agreement) and the other to incorporate PAP feedback despite achieving 100% agreement in round 1. The panel agreed that PV alone should not preclude access to DMTs and that trial access with personalised treatment goals may be appropriate. The panel also emphasised broader definitions of clinical benefit, including subtle changes in function and QoL, alongside sensitive assessment approaches and harmonised outcome measurement.

Interpretation

These consensus-based recommendations support careful reconsideration of treatment exclusions for patients with SMA-PV and more inclusive, patient-centred approaches to evaluating treatment benefit.

Funding

Roche Products Ltd.

Research in context.

Evidence before this study

Access to disease-modifying therapies (DMTs) for patients with spinal muscular atrophy (SMA) who require permanent ventilation (PV) (SMA-PV) is limited because evidence relevant to this subpopulation is sparse. We conducted a targeted literature review of articles indexed in MEDLINE and Embase from database inception to October 2024 using terms for SMA (‘spinal muscular atrophy’, ‘5q SMA’, and ‘Kugelberg-Welander disease’) and PV (‘permanent ventilation’, ‘long-term ventilation’, ‘ventilatory dependence’, and ‘respiratory support’). Grey literature was also reviewed. Overall, 91 relevant articles were identified. PV is commonly used as an endpoint in SMA trials; however, patients with SMA-PV at baseline are typically excluded, and post-ventilation outcome data are limited to small observational studies. Standard SMA outcome measures are often not feasible or sufficiently sensitive in patients with SMA-PV, further limiting assessment of treatment benefit. Consequently, there is no established consensus or published guidance on how treatment benefit should be defined, assessed, or monitored in SMA-PV.

Added value of this study

A UK-based modified Delphi process with 19 multidisciplinary experts, including a non-voting Chair and 18 voting participants (3 steering committee members and 15 Delphi panellists), produced 22 consensus statements on DMT use in SMA-PV, spanning access, initiation, monitoring, and continuation. Informed by available evidence and expert clinical judgement, with advisory input from patients and caregivers, the recommendations identify feasible outcome domains beyond conventional SMA measures, including functional, respiratory, and quality-of-life changes.

Implications of all the available evidence

These recommendations support consideration of broader outcome domains when evaluating treatment benefit in SMA-PV, rather than reliance on standard SMA measures alone. Although developed in a UK clinical context, the assessment challenges and resulting recommendations are relevant to healthcare systems requiring demonstrable clinical benefit to inform treatment decisions.

Introduction

Spinal muscular atrophy (SMA) is a rare inherited neuromuscular disorder affecting an estimated 1·14–1·78 individuals per 100,000.^1,2 In most cases, it is caused by mutations in the SMN1 gene, resulting in reduced expression of survival motor neuron (SMN) protein.^1,3 This leads to progressive muscle weakness and atrophy.³ Disease severity is determined predominantly by age at onset and number of copies of the SMN2 gene, which can partially compensate for SMN1 loss by producing a limited amount of functional SMN protein.¹ SMA types range from SMA Type 0 (most severe, with one SMN2 copy and prenatal onset) to Type 4 (least severe, with 4–6 SMN2 copies and adult onset).^1,4, 5, 6

Owing to progressive muscle weakness, individuals with SMA experience varying degrees of motor function loss, affecting their mobility and daily activities.^1,4,5 Critically, respiratory function is also compromised by weakened respiratory muscles, leading to impaired secretion clearance, respiratory insufficiency, recurrent infections, and eventual ventilatory failure.^7,8 Musculoskeletal complications, including scoliosis and chest wall deformities, may also develop and further compromise respiratory function, increasing the complexity of clinical management.^9,10 The respiratory burden is further compounded by bulbar muscle weakness and impaired cough,⁷ often requiring ventilation support in more severe SMA types.¹¹ Ventilation may be non-invasive¹² or invasive (via tracheostomy),⁴ with ‘permanent’ defined as invasive ventilation or ≥16 h of non-invasive ventilation per day for ≥21 consecutive days.⁷

Currently, three disease-modifying therapies (DMTs) are approved for patients with SMA: risdiplam,¹³ nusinersen,¹⁴ and onasemnogene abeparvovec.¹⁵ These therapies increase the amount of functional SMN protein through different mechanisms, and are approved in the UK and internationally with varying indications according to SMA type and SMN2 copy number.13, 14, 15, 16, 17, 18, 19 DMTs are approved for individuals requiring permanent ventilation (PV) (SMA-PV) who meet the label criteria; however, prior to this research, access in the UK was restricted because of the recently concluded managed access agreements from the National Institute for Health and Care Excellence (NICE), which excluded patients with SMA-PV from DMT eligibility.16, 17, 18 Consequently, disease management for SMA-PV was limited to supportive or palliative care and compassionate use programmes.

A cyclical challenge exists between treatment access and evidence availability: limited clinical evidence restricts access, and restricted access limits real-world evidence generation. Clinical trials often focus on motor function endpoints and rarely include patients with SMA-PV at baseline.20, 21, 22, 23 Although some trials use time to PV as an endpoint, follow-up data after ventilation are sparse.^20,23,24 As a result, the potential clinical benefit of DMTs in SMA-PV remains unclear.

There is a pressing need for clinical guidance on treating and monitoring patients with SMA-PV, particularly to inform access decisions. In the absence of robust trial data, the Delphi consensus method offers a validated approach for generating expert recommendations.25, 26, 27 We conducted a modified Delphi process to develop evidence-informed expert consensus recommendations for DMT use in SMA-PV and to define clinical benefit in this population. These recommendations aim to inform clinicians, researchers, and decision-makers in the UK and beyond.

Methods

Overview

A modified Delphi consensus process was conducted, informed by a targeted literature review and clinical expertise. Draft statements were generated and voted on by a UK-based expert panel over up to three rounds until consensus was reached. Fig. 1 provides an overview of the consensus process. Although the protocol was not formally registered, all methodological details are reported in accordance with the ACCORD (ACcurate COnsensus Reporting Document) guideline (Supplementary Table S1).²⁸

Fig. 1.

The modified Delphi consensus process.^aNon-voting PAP members had the opportunity to review each statement and provide anonymised feedback for consideration by the steering committee. This activity was run in parallel to the consensus process. PAP, patient advisory panel; TLR, targeted literature review.

Delphi consensus participants

The roles and responsibilities of the modified Delphi consensus participants are outlined in Table 1. Briefly, 19 experts participated in the consensus process, comprising a non-voting Chair, three additional voting steering committee members, and 15 voting Delphi panel members. Participants represented a range of specialities involved in SMA care, including paediatric and adult neurology, neuromuscular medicine, respiratory medicine, and physiotherapy (Table 2). The Delphi panel was recruited from a pool of 18 experts identified by the steering committee and invited by the Chair via email; three invitees did not respond (recruitment response rate: 83% [15/18]). Participation was voluntary and non-incentivised.

Table 1.

Summary of roles in the Delphi consensus process.

Delphi consensus role (n)	Responsibility
Chair (1)	• Makes the final decisions on: ○ the design of the Delphi consensus process, including selection of Delphi panel members and the agreement threshold to be used in voting rounds ○ the content of the proto-statement questionnaire ○ the structure of consensus statements ○ revisions made to statements that do not reach consensus •Does not vote in the Delphi consensus voting rounds •Formally endorses final statements at the end of the Delphi consensus process
Steering committee (4, including the Chair)	•Supports the Chair in deciding the design of the Delphi consensus process, the content of the proto-statement questionnaire, and the structure of the consensus statements •Discusses statements that do not achieve consensus and proposes revisions •Votes in the Delphi consensus voting rounds (except the Chair)
Delphi panel (18, including 3 steering committee members)	•Completes proto-statement questionnaire •Votes in the Delphi consensus voting rounds
Patient advisory panel (5)	•Provides feedback on consensus statements from a patient/caregiver perspective to the steering committee for consideration after each voting round •Does not vote in the Delphi consensus voting rounds •Support dissemination of consensus statements to patient groups

Table 2.

Participants of the UK SMA-PV modified Delphi consensus process.

Name	Affiliation	Speciality	Years of relevant experience
Steering committee
Mariacristina Scoto (Chair)	Great Ormond Street Hospital for Children NHS Foundation Trust, The Dubowitz Neuromuscular Centre, NIHR Great Ormond Street Hospital Biomedical Research Centre, Great Ormond Street Institute of Child Health, University College London, London, United Kingdom	Neurology	15
Chiara Marini-Bettolo	The John Walton Muscular Dystrophy Research Centre, Translational and Clinical Research Institute, Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom	Neurology	16
Elaine Chan	Great Ormond Street Hospital for Children NHS Foundation Trust, The Dubowitz Neuromuscular Centre, NIHR Great Ormond Street Hospital Biomedical Research Centre, Great Ormond Street Institute of Child Health, University College London, London, United Kingdom	Respiratory Medicine	19
Anita K. Simonds	Royal Brompton Hospital, Guys and St Thomas' NHS Foundation Trust, London, United Kingdom	Respiratory Medicine	29
Delphi panel
Giovanni Baranello	Great Ormond Street Hospital for Children NHS Foundation Trust, The Dubowitz Neuromuscular Centre, NIHR Great Ormond Street Hospital Biomedical Research Centre, Great Ormond Street Institute of Child Health, University College London, London, United Kingdom	Neurology	20
Anne-Marie Childs	Leeds Teaching Hospitals NHS Trust, Leeds, United Kingdom	Neurology	26
Lisa Edel	Great Ormond Street Hospital for Children NHS Foundation Trust, The Dubowitz Neuromuscular Centre, NIHR Great Ormond Street Hospital Biomedical Research Centre, Great Ormond Street Institute of Child Health, University College London, London, United Kingdom	Physiotherapy	10
Christopher Edwards	Leeds Teaching Hospitals NHS Trust, Leeds, United Kingdom	Respiratory Medicine	12
Marjorie A. Illingworth	University Hospital Southampton NHS Foundation Trust, Southampton, United Kingdom	Neurology	12
Richa Kulshrestha	The Robert Jones and Agnes Hunt Orthopaedic Hospital, Oswestry, United Kingdom	Neurology	14
Min T. Ong	Sheffield Children's NHS Foundation Trust, Sheffield, United Kingdom	Neurology	8
Rishi Pabary	Royal Brompton Hospital, Guys and St Thomas' NHS Foundation Trust, London, United Kingdom	Respiratory Medicine	25
Matt Parton	Centre for Neuromuscular Diseases, National Hospital for Neurology & Neurosurgery, University College London Hospitals NHS Foundation Trust, London, United Kingdom	Neurology	19
Sithara Ramdas	Oxford Children's Hospital, Oxford, United Kingdom	Neurology	10
Saam Sedehizadeh	Nottingham University Hospitals NHS Trust, Nottingham, United Kingdom	Neurology	10
Hui-leng Tan	Royal Brompton Hospital, Guys and St Thomas' NHS Foundation Trust, London, United Kingdom	Respiratory Medicine	14
Stuart Wilkinson	Royal Manchester Children's Hospital, Manchester, United Kingdom	Respiratory Medicine	13
Tracey Willis	The Robert Jones and Agnes Hunt Orthopaedic Hospital, Oswestry, United Kingdom; Chester University Medical School, Chester, United Kingdom	Neurology	18
Elizabeth Wraige	Guy's and St Thomas' NHS Foundation Trust, London, United Kingdom	Neurology	23

NHS, National Health Service; NIHR, National Institute for Health and Care Research; SMA-PV, spinal muscular atrophy with permanent ventilation.

Patient advisory panel

Adults with SMA-PV (n = 3), caregivers of children with SMA-PV (n = 2), and a patient advocacy group representative (n = 1) were invited to participate alongside the consensus process as part of a patient advisory panel (PAP). Given the rarity of SMA-PV and the limited pool of eligible participants, the PAP was designed to capture a range of perspectives relevant to the SMA-PV community. A plain language summary outlining the process and its aims was provided alongside the invitation to ensure informed consent (Table 1). Five of the six invitees agreed to participate (recruitment response rate: 83% [5/6]).

Targeted literature review

Searches of MEDLINE and Embase were conducted from database inception to October 2024 using search strings that included terms for SMA combined with terms for PV (Supplementary Table S2). Grey literature was also reviewed. Findings from the literature review informed the development of the proto-statement questionnaire and draft consensus statements. All relevant articles, alongside a summary of the evidence, were shared with the Delphi panel and PAP as supporting material for the consensus process.

Proto-statement questionnaire and generation of statements

A bespoke free-text questionnaire was developed in Google Forms and shared individually to the Chair and members of the Delphi panel to elicit their expert insights (Supplementary Material). To preserve anonymity, each participant was assigned a unique identifier for use during questionnaire completion. Their anonymised responses were compiled in Microsoft Excel and reviewed by the steering committee. These insights, along with the findings of the targeted literature review, informed the generation of draft statements for the consensus process. The questionnaire was not piloted, and no modifications were made to enhance accessibility.

Voting rounds

The voting process allowed for a maximum of three voting rounds (Fig. 2). Participation in at least one of the first two voting rounds was mandatory. Consistent with the proto-statement questionnaire, voting was conducted individually, anonymously, and remotely via Google Forms, and responses were compiled and analysed in Microsoft Excel.

Fig. 2.

Overview of the modified Delphi voting process.

Formal Delphi consensus voting

In each voting round, Delphi participants indicated their level of agreement on each statement using a 6-point Likert scale: ‘Strongly agree’, ‘Agree’, ‘Somewhat agree’, ‘Somewhat disagree’, ‘Disagree’, or ‘Strongly disagree’. In rounds 1 and 2, participants could provide free-text feedback on statements they disagreed with (i.e., if they selected ‘Somewhat disagree’, ‘Disagree’, or ‘Strongly disagree’), allowing them to explain their reasoning and suggest revisions. After each round, the percentage agreement (defined as the proportion of responses selecting ‘Strongly agree’, ‘Agree’, or ‘Somewhat agree’) was calculated for each statement and compared with a predefined consensus threshold of ≥75%. Statements meeting this threshold were considered final and excluded from subsequent rounds. Those falling below the threshold were revised by the steering committee according to the feedback and included in the next voting round. In round 3, any revised statement that failed to reach consensus would be removed, with no further opportunity for revision or voting. The Chair resolved any instances of conflicting feedback during statement revision.

Informal PAP review and feedback

PAP members did not participate in voting and did not contribute to the determination of consensus. Unlike Delphi panel members, PAP members were not provided with Likert-scale voting options and were invited to provide optional free-text feedback on each draft statement during each voting round from the patient, caregiver, or patient advocacy perspective. PAP feedback was reviewed by the steering committee at the end of each voting round and could be used to inform statement revisions where considered clinically relevant and appropriate.

Ethics

Institutional Review Board approval was not required for this modified Delphi consensus process as it did not involve the collection or analysis of patient-level data. The study was informed by published literature and the opinions of participants. Participation was voluntary, and all participants provided informed consent for the collection, processing and reporting of their responses for research and publication purposes.

Role of the funding source

This study was funded by Roche Products Ltd. The modified Delphi consensus process was designed and conducted independently by the Delphi participants, who retained full control of and responsibility for the study methodology, development and refinement of the consensus statements, and final recommendations. Roche Products Ltd. had no role in the development, drafting, voting, analysis, or interpretation of the consensus statements.

In line with pharmacovigilance obligations, Roche Products Ltd. reviewed the consensus materials and the manuscript solely to verify factual accuracy and adverse event reporting requirements. This review did not involve changes to the consensus statements or influence the interpretation of results.

Given that the original research concept was initiated by Roche Products Ltd., a member of the Roche study team is included as an author. This authorship reflects the origin of the research concept and did not involve participation in the consensus process or influence over its outcomes.

Results

Targeted literature review

The targeted literature review identified 91 articles relevant to the topic of interest, including clinical trial data, observational data from real-world studies, case reports, and qualitative survey data from expert neurologists with experience in treating patients with SMA-PV (Supplementary Table S3). Overall, the review identified a lack of clinical trials specifically evaluating DMTs in patients with SMA-PV. However, available real-world evidence suggested potential treatment benefits, including improvements or stabilisation of motor and respiratory outcomes, while also highlighting limitations of conventional outcome measures in capturing subtle treatment effects. Evidence relating specifically to management of patients with SMA-PV receiving DMTs was limited, although broader guidance for SMA management was available.

Delphi consensus process

The modified Delphi consensus process ran from 08 April to 09 June 2025 and was completed after two voting rounds. All 18 voting Delphi participants engaged in both voting rounds, with each round taking approximately 2 weeks.

Twenty-two draft statements across seven key themes entered the process. After round 1, 21 statements (96%) achieved consensus. The one statement that did not meet the predefined consensus threshold (Statement 3; 72% agreement) was revised by the steering committee for round two. In addition, one statement that had reached consensus in round 1 (Statement 7; 100% agreement) was revised for round 2 in response to PAP feedback. Because both revised statements achieved consensus in round 2, there was no need for a third round of voting.

PAP involvement

All five PAP members fulfilled their responsibilities to review each draft statement and provide their feedback from the patient and caregiver perspectives during each voting round. Overall, feedback was broadly supportive of the statements and emphasised the importance of equitable access to DMTs, individualised decision-making, patient and caregiver involvement, and the role of quality of life (QoL) in treatment evaluation and ongoing care. Aside from Statement 7, no additional requests for modifications to the draft statements were raised.

Final consensus statements

Overview

Overall, 22 statements are included in the final list of consensus statements: these are presented by theme in Table 3 and discussed in detail below, alongside relevant supporting literature where appropriate. The distribution of individual Likert responses is provided in Supplementary Table S4.

Table 3.

Consensus statements for the use of DMTs in patients with SMA-PV.

Statement		Agreement, n/N (%)a,b
Overarching statements regarding DMT use in patients with SMA-PV
1	Access to SMN2-targeted therapy should be modified to incorporate a trial period of at least six months to determine treatment benefit in patients with SMA-PV, irrespective of prior experience with SMN1 replacement therapy	17/18 (94)
2	PV alone should not preclude the use of DMTs in patients with SMA-PV	18/18 (100)
3	Ideally, access to DMTs for patients with SMA-PV should not be limited by treatment cost alone. However, decisions regarding ongoing access should be based on a resource–benefit analysis conducted in consultation with an expert clinical panel	17/18 (94)c
Considerations before initiating DMTs in patients with SMA-PV
4	Candidacy for DMT in patients with SMA-PV should be determined in accordance with local/regional guidelines and in consultation with an expert clinical panel. Patient age and disease stage; extent of disease progression (i.e., the degree of motor, respiratory, or bulbar dysfunction); concurrent illness; mode of ventilatory support; level of ventilator dependency; potential to wean from PV; DMT route of administration; and anticipated long-term clinical outcomes should all be considered	18/18 (100)
5	The decision to initiate DMTs in patients with SMA-PV should be agreed with the patient, where possible, or their caregivers. Additionally, it is important to agree on realistic, individualised treatment goals with predefined timepoints to guide future treatment decisions, including palliative or supportive care	18/18 (100)
6	To optimise clinical outcomes in patients with SMA-PV, respiratory (e.g., ventilatory support, secretion management, and antimicrobial prophylaxis) nutritional (e.g., weight management, gastronomy, and supplementation), and orthopaedic supportive care should be prioritised, and comorbidities that may be associated with respiratory deterioration (e.g., aspiration or gastroesophageal reflux disease) should be managed	18/18 (100)
Considerations following treatment with SMN1 replacement therapy or during SMN2-targeted therapy in patients with SMA-PV
7	Following SMN1 replacement therapy or during SMN2-targeted therapy, patients with SMA-PV should continue to be managed in accordance with international standards of care, with an emphasis on optimising respiratory, bulbar, and musculoskeletal function, in order to maintain the highest perceived QoL possible	18/18 (100)d
8	Following SMN1 replacement therapy or during SMN2-targeted therapy, patients with SMA-PV should be reviewed biannually by the MDT. For adult patients, reviews may be reduced to a minimum of once a year if respiratory and bulbar functions have stabilised	18/18 (100)
9	The decision to continue SMN2-targeted therapy in patients with SMA-PV should be made on an individualised basis within the MDT and in consultation with an expert clinical panel, where needed. Factors may include any reportable evidence of stabilisation or improvement in respiratory, bulbar, or motor function, or ventilation needs; lack of treatment-related side effects; reduction in hospitalisations; patient and/or caregiver-perceived QoL; and patient or caregiver consent for continued treatment	17/18 (94)
10	Supportive or palliative care should continue to be offered to patients with SMA-PV when SMN2-targeted therapy is discontinued, as there are no other approved treatments available and the use of off-label treatment is not recommended. Discussions regarding this change should be conducted sensitively and in careful consideration of the patient's or caregivers' preference	18/18 (100)
11	Candidacy for switching SMN2-targeted therapy should be determined on an individualised basis, by the MDT and in consultation with an expert clinical panel. If approved, a trial period of at least six months should be initiated after switching treatment	16/18 (89)
Defining clinical benefit in patients with SMA-PV treated with DMTs
12	The clinical benefit associated with DMT use in patients with SMA-PV should be determined through practical, validated clinical outcomes, observations and patient- and caregiver-reported outcomes	18/18 (100)
13	Patient- and caregiver-perceived changes in functional ability, where possible validated by the care team, should be considered when assessing the effectiveness of DMT use in patients with SMA-PV	17/18 (94)
14	As the functional changes observed in patients with SMA-PV treated with DMTs may be subtle, it is advised that caregivers and family members record or diarise any perceived changes which may be shared with the MDT	18/18 (100)
Monitoring functional changes following treatment with SMN1 replacement therapy or during SMN2-targeted therapy in patients with SMA-PV
15	In patients with SMA-PV, the choice of motor assessment measure should be accurate enough to capture the patient's level of functional ability at presentation, as well as any changes following treatment with DMTs	17/18 (94)
16	Polysomnography, cardiorespiratory polygraphy, and carbon dioxide monitoring should be considered when assessing respiratory function in patients with SMA-PV. Breathing studies (maximal inspiratory pressure, maximal expiratory pressure, and sniff nasal inspiratory pressure) and spirometry may also be considered, where appropriate	16/18 (89)
17	In patients with SMA-PV whose motor function is too severely impaired to detect measurable changes through standard assessments following treatment with DMTs, it is advisable to investigate subtle changes in fine motor function. Examples may include changes in eye movement, facial expression and finger dexterity (e.g., the ability to gesture or interact with touchscreens, switches, or communication aids)	18/18 (100)
18	Indicators of improved respiratory function in patients with SMA-PV treated with DMTs may include increased hours off ventilation, improved cough or speech strength, and reduced frequency of respiratory tract infections, hospitalisations related to exacerbation, or need for suctioning or antibiotics	18/18 (100)
Monitoring changes in QoL following treatment with SMN1 replacement therapy or during SMN2-targeted therapy in patients with SMA-PV
19	Employing a combination of direct clinical observations, discussions with the patient and/or caregivers and PROMs (e.g., SMA-QoL, SRI, PedsQL, or SF-36 or SF-12 in adult patients) is recommended to generate a comprehensive understanding of QoL in patients with SMA-PV treated with DMTs	18/18 (100)
20	Additional indicators of improved QoL may include increased social interaction and/or school engagement and reduced hospitalisations, infections or need for secretion management	18/18 (100)
Additional considerations and considerations for future research
21	Research priorities should include the harmonisation of QoL data and patient- and/or caregiver-reported outcome measures and their integration with clinician-reported data in national registries for patients with SMA-PV treated with DMTs. Additional endpoints may include the impact of DMTs on healthcare resource use and caregiver burden	18/18 (100)
22	To quantify the subtle changes associated with DMT use in patients with SMA-PV, a validated functional assessment tool which employs remote video recording and biometric data (e.g., from wearable devices) should be considered	17/18 (94)

DMT, disease-modifying therapy; MDT, multidisciplinary team; PedsQL, Paediatric Quality of Life Inventory; PROMs, patient-reported outcome measures; PV, permanent ventilation; QoL, quality of life; SF-12, Short Form 12 Item Survey; SF-36, Short Form 36 Item Survey; SMA, spinal muscular atrophy; SMA-PV, spinal muscular atrophy with permanent ventilation; SMA-QoL, Spinal Muscular Atrophy Quality of Life; SMN1, survival motor neuron 1 gene; SMN2, survival motor neuron 2 gene; SRI, Severe Respiratory Insufficiency Questionnaire.

^aNumber of voting participants selecting a Likert response indicating agreement (‘Somewhat Agree’, ‘Agree’, or ‘Strongly Agree’).

^bConsensus was defined as ≥75% agreement.

^cStatement 3 was revised after initially failing to achieve consensus (72% agreement) in voting round 1.

^dAlthough Statement 7 achieved consensus (100% agreement) in voting round 1, it was revised to capture feedback from the Patient Advisory Panel.

Overarching statements regarding DMT use in patients with SMA-PV

Both Statements 1 and 2 confirm the overall expert consensus that, in the case of a clear clinical indication, patients with SMA-PV should not be precluded from access to SMN-enhancing treatment with SMN2-targeted therapies (risdiplam and nusinersen); thus, the panel called for modification to current access to SMN2-targeted therapies. Importantly, Statement 1 recommends adopting a minimum period of 6 months to assess treatment response in patients with SMA-PV. This interval reflected a pragmatic assessment period that, at the time of statement development, was consistent with the assessment schedules used in the managed access agreements for risdiplam and nusinersen.16, 17, 18 This recommendation was considered appropriate irrespective of whether the patient had previously received SMN1 replacement therapy.

Statement 3 initially recommended that cost should not preclude access to DMTs. Although this position was broadly supported by the PAP, several Delphi panel members expressed disagreement in voting round 1, noting that cost–benefit considerations are essential for informing reimbursement decisions. In response, the statement was revised to acknowledge the importance of balancing cost and benefit while maintaining a view that costs alone should not be a barrier to access. PAP feedback on the revised statement remained broadly supportive, particularly in retaining the principle that cost alone should not determine access to DMTs.

Considerations before initiating DMTs in patients with SMA-PV

The overarching statements (Statements 1, 2, and 3) advised that patients with SMA-PV should have access to DMTs. However, the decision to treat is still associated with various considerations.

Statement 4 provides some guidance regarding candidacy. Decisions are likely to vary on a case-by-case basis and may be influenced by factors such as age and disease stage, extent of disease progression, concurrent illness, mode of ventilatory support, level of ventilator dependency, potential to wean off PV support, and DMT route of administration. Reference to local guidelines is recommended.

Statement 5 emphasises that patients and their caregivers should be involved in the decision-making process and, in particular, contribute to choosing individual treatment goals and the timing of their assessment within the initial 6-month period.

If the decision is made to initiate treatment with DMT, Statement 6 recommends that a full, multidisciplinary approach is maintained to address respiratory, nutritional, and orthopaedic needs throughout treatment, as well as management of comorbidities that may affect treatment outcomes.

Considerations following treatment with SMN1 replacement therapy or during SMN2-targeted therapy in patients with SMA-PV

The Delphi panel agreed that ongoing care after initiation of DMTs should be guided primarily by international standards of care,^9,10 which focus on management of respiratory, bulbar, and musculoskeletal function, as described in Statement 7. Although this statement achieved consensus in round 1, it was revised by the steering committee in response to PAP feedback. Specifically, PAP feedback highlighted that new UK standards of care in development were expected to place greater emphasis on QoL considerations,²⁹ and suggested that ongoing care should aim to maintain the highest perceived QoL possible. The steering committee therefore proposed an amendment acknowledging the importance of maintenance of QoL throughout treatment, which was subsequently agreed by the Delphi panel. PAP feedback on the revised statement was supportive.

The Delphi panel agreed that patient management should initially be reviewed biannually by the full multidisciplinary team, with the option to reduce the frequency to annual reviews in adult patients with stable respiratory and bulbar symptoms (Statement 8). These reviews may inform decisions to continue, discontinue, or switch treatment. As with the initial decision to start DMT (outlined in Statements 4 and 5), decisions regarding continuation are individualised and require consideration of multiple factors. A key consideration is whether there is evidence of treatment benefit, with examples provided in Statement 9, and the definition of treatment benefit and ongoing monitoring of potential benefit are explored in depth in Statements 12–20 and are central to guiding management decisions. Discontinuation of a DMT should be approached sensitively, with discussion involving the patient and their caregiver and with continued access to supportive or palliative care (Statement 10). Similarly, decisions to switch treatment should be made on a case-by-case basis, involving the full multidisciplinary team and relevant experts (Statement 11). As with the initial DMT, response to any subsequent therapy should be closely monitored over a 6-month period.

Defining clinical benefit in patients with SMA-PV treated with DMTs

The panel agreed that assessment of clinical benefit should not rely solely on clinical outcome measures but instead should adopt a broader approach that incorporates patient- and caregiver-reported outcomes and observations (Statement 12). This recommendation reflects the limited validation of standard outcome measures in the SMA-PV population and reduced suitability of some clinical tools due to respiratory constraints.

Given the importance of patient and caregiver input, the panel further recommended that the reliability of such observations be strengthened through validation by the care team (Statement 13) and consistent documentation, such as regular diary entries (Statement 14). Patient and caregiver observations have been used as indicators of clinical benefit in real-world studies. For example, a study of 42 patients on invasive mechanical ventilation employed qualitative interviews to capture patient- and caregiver-perceived respiratory improvements after treatment with nusinersen.³⁰

Monitoring functional changes following treatment with SMN1 replacement therapy or during SMN2-targeted therapy in patients with SMA-PV

For ongoing monitoring of motor function, the Delphi panel acknowledged that standard assessments such as Hammersmith Infant Neurological Examination module 2 and Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders have been used to assess treatment benefit in patients with SMA-PV both in clinical trials^31,32 and real-world studies.^30,33, 34, 35, 36 However, panel experience indicated that the feasibility to perform such assessments may vary on a case-by-case basis owing to respiratory limitations. In addition, even when such assessments are possible, the expected improvements may be too subtle to detect. As such, Statement 15 recommends that careful consideration is given to the choice of motor assessment to maximise the accuracy and value of data collected.

Statement 16 outlines the recommendation for assessing changes in respiratory function in patients with SMA-PV, drawing on both Delphi panel experience and published approaches. For example, the SUNFISH trial of risdiplam employed measures such as sniff nasal inspiratory pressure, maximal inspiratory pressure, and expiratory pressure,²² and a survey of French healthcare providers in SMA specialist centres recommended monitoring CO₂ levels.³⁷

Recognising that standard motor assessments may not be appropriate for all patients with SMA-PV, Statement 17 recommends capturing additional indicators of motor improvement, such as changes in eye movement, facial expression, and finger dexterity. These subtle changes have been highlighted in a retrospective study of patients with SMA Type 1 with chronic respiratory failure, for whom standard assessments lacked sensitivity.³⁶

Beyond direct measures of respiratory function, Statement 18 recommends that improvements may also be indicated indirectly (e.g., increased hours off ventilatory support and reduced hospital admissions). Several real-world studies have reported such indirect improvements in patients with SMA-PV treated with DMTs. A study of patients with SMA Type 1 observed a reduction in daytime use of non-invasive ventilation, fewer pulmonary infections, and decreased need for daytime secretion aspiration in patients with invasive ventilation, over 12 months of treatment with SMN2-targeted therapy.³⁴ Another study reported an increase in median (interquartile range) time off ventilation per day from 8 (8–10) to 10·5 (8–13) hours over a mean follow-up period of 7·64 months in patients treated with onasemnogene abeparvovec.³³ A separate study reported reduced hospitalisations in four of 12 patients with SMA Type 1 after 2 years of treatment with nusinersen.³⁸ However, interpretation of these findings should be cautious: patients with SMA Type 1 who initiate non-invasive ventilation have been shown to experience fewer hospitalisations than those with tracheostomy even in the absence of DMTs.³⁹ In uncontrolled real-world settings, where multiple management strategies are employed, it remains challenging to attribute positive outcomes to any single intervention.

Monitoring changes in QoL following treatment with SMN1 replacement therapy or during SMN2-targeted therapy in patients with SMA-PV

A range of QoL assessments are available for SMA and play an important role in evaluating the overall treatment benefit alongside clinical outcomes. Consistent with the approach to assessing motor and respiratory function, the Delphi panel recommends that QoL measures are used in combination with patient and caregiver observations (Statement 19). These observations may include indicators such as increased social interaction or reduction in events that negatively affect QoL, including hospitalisations (Statement 20).

Additional considerations and considerations for future research

Given the lack of a standardised approach for assessing treatment benefit in patients with SMA-PV, Statement 21 underscores a need for harmonising patient- and caregiver-reported outcome measures and integrating them with clinician-reported outcomes. This statement also highlights the importance of incorporating other types of outcome domains, particularly caregiver burden and resource utilisation. Finally, although the consensus statements recommend a range of outcome measures, there remains a strong need for a new validated tool capable of detecting subtle changes in motor function in this patient population (Statement 22). The development and validation of such a tool should therefore be considered a future research priority.

Discussion

This UK-based modified Delphi consensus process is the first initiative specifically designed to address the unmet clinical needs of patients with SMA-PV. The process resulted in 22 expert consensus recommendations informed by the available evidence and clinical expertise that challenge current treatment exclusions and advocate for more inclusive and personalised care. The key recommendations are that PV should not preclude access to DMTs and that access to DMTs for an initial 6-month period, accompanied by personalised treatment goals, should be undertaken. Additionally, these recommendations emphasise the importance of recognising subtle yet meaningful improvements in functional ability and QoL in this population. The statements were developed and endorsed by a multidisciplinary panel of specialists involved in paediatric and adult SMA care and were informed by advisory feedback from the PAP comprising individuals with SMA-PV, caregivers, and advocacy representatives. Although UK-based, the recommendations are anticipated to be relevant internationally.

There is a clear and pressing need for clinical guidance in the SMA-PV subgroup, which faces a substantial burden and limited access to treatment. Caregivers have identified avoidance of PV as a key driver in treatment decision-making,⁴⁰ yet patients with SMA-PV have largely been excluded from pivotal clinical trials and, at the time of statement development, from access to DMTs.16, 17, 18, 19 At the time this research was performed, these consensus statements were especially timely, given the anticipated review of the NICE managed access agreements based on feedback from clinical experts and patient advocacy groups.16, 17, 18^,41

The panel strongly supported broadening access criteria to include this subgroup and recommended a minimum of a 6-month period to evaluate treatment benefit. These recommendations were informed by clinical trial and real-world evidence, albeit from small patient cohorts, demonstrating benefit in patients with SMA-PV.30, 31, 32, 33, 34, 35, 36^,38 Importantly, the recommended 6-month period should be interpreted as a minimum interval before formal reassessment of treatment benefit rather than as a validated threshold by which all clinically meaningful treatment effects would necessarily be expected to occur. Given the heterogeneity of SMA-PV and the challenges associated with measuring treatment response in this population, clinically meaningful benefit may include improvement, stabilisation, prevention or slowing of further deterioration, respiratory stability, and patient- or caregiver-valued changes. Accordingly, absence of measurable motor improvement at 6 months should not necessarily be interpreted as absence of treatment benefit.

The limited evidence base reflects the broader challenge of evidence generation in rare disease subpopulations, where traditional evidence thresholds are difficult to meet owing to small patient numbers and exclusion from pivotal clinical trials. For SMA-PV, this challenge is compounded by the lack of validated criteria for assessing clinical benefit. Existing treatment-response criteria and stopping rules may therefore be difficult to apply in this subgroup.16, 17, 18 Furthermore, treatment effects in SMA-PV may be subtle and not adequately captured by conventional motor outcome measures alone. As reflected in Statements 12–20, meaningful changes may encompass respiratory stability, communication, fatigue, fine motor function, bulbar function, QoL, caregiver burden, or maintenance of existing abilities. Many individuals with SMA-PV retain meaningful abilities (e.g., communication, wheelchair use, or computer operation) that have a substantial impact on patients’ QoL beyond respiratory function. These abilities are highly valued by patients and their families,42, 43, 44 and the opportunity to maintain or improve them through the use of DMTs should be considered. A reconsideration of evidentiary standards is therefore essential.

Importantly, recognition of these broader treatment goals does not diminish the importance of ongoing multidisciplinary care. Patients with SMA-PV should continue to receive comprehensive multidisciplinary management in accordance with established international standards of care for SMA. Within these recommendations, references to supportive care should be interpreted in this context, encompassing respiratory, nutritional, musculoskeletal, and other supportive interventions.^9,10 Equally, families who, after careful multidisciplinary discussion, decide that PV or continued treatment is not in the best interests of their child must be supported in opting for a palliative approach.

The potential implications of expanding access to DMTs for patients with SMA-PV should be evaluated through a comprehensive budget impact model that accounts for all relevant resources use. However, given the small size of this patient population in the UK, the overall financial impact is expected to be limited. Paediatric data are more readily available than adult estimates: a 2019 UK survey reported that there were 87 children with SMA Type 1 and 72 children with SMA Types 2 or 3 receiving long-term ventilatory support,⁴⁵ compared with just 12 and 67 children, respectively, in a similar 2008 survey.⁴⁶ Current evidence suggests that this upward trend may be reduced if the UK adopts newborn screening for SMA,47, 48, 49 which is now widely implemented in many regions across the world, including Asia, Australasia, USA, and most of mainland Europe,⁵⁰ leaving the UK as a clear outlier. Early diagnosis enables earlier treatment initiation, which is expected to reduce the chance of progression to PV.⁴⁸ Although the Delphi panel agreed that treatment cost alone should not determine access to DMTs, they also acknowledged the importance of conducting resource–benefit analyses on a case-by-case basis to support informed decision-making.

The statements developed by this Delphi panel address a critical gap in clinical guidance for demonstrating treatment benefit in patients with SMA-PV. A broad, multidimensional approach is advocated, encompassing motor and respiratory function, QoL, and patient- and caregiver-reported outcomes. Where standard assessments are unsuitable, the panel proposes practical alternatives (e.g., observing changes in facial expression or eye movement) that reflect meaningful improvements in fine motor skills. These indicators are valued by patients and families and can offer important insights into treatment response. The panel also calls for the development and validation of a formal motor assessment tool with greater sensitivity than existing measures. This aligns with published expert opinion, including recommendations from French SMA specialists who have highlighted the limitations of current tools and the need for ‘unofficial’ evaluations in this subgroup.³⁷ Although not discussed during the Delphi consensus process, the authors note that it would be beneficial if future clinical trials were to look more comprehensively at this patient group and prioritise the development of reliable markers of disease progression or stabilisation, potentially supported by industry collaboration with clinical networks.

These recommendations aim to catalyse improvements in both clinical care and research. They support the adoption of consistent outcome measures across registries and studies and encourage the development of more-sensitive assessments tailored to SMA-PV. Digital solutions may play a key role in this evolution. For example, smartphone apps such as Floodlight have been used to assess dexterity in multiple sclerosis,⁵¹ and wearable devices with inertial measurement units have measured upper limb function in stroke survivors.⁵² Such innovations could help to generate robust and comparable data to support evidence of clinical benefit and facilitate access to DMTs for patients with SMA-PV.

The strengths of this study include the use of a rigorous, structured consensus methodology (modified Delphi), full engagement of a multidisciplinary expert panel experienced in adult and paediatric SMA care, and integration of patient and caregiver perspectives via the PAP. The process adhered to established reporting standards (ACCORD) and achieved 100% participation across voting rounds, enhancing the reliability of the findings. The inclusion of real-world evidence and clinical experience helped to address gaps in trial data and ensured that the recommendations are grounded in practical care realities. Importantly, the consensus statements offer actionable guidance for clinicians and policy-makers, with potential applicability beyond the UK. The high level of agreement observed during the first voting round may reflect the specialist composition of the panel, shared clinical experience in managing this highly specialised population, and the development of carefully considered draft statements informed by the available evidence and the expert insights of the steering committee. Although consensus was defined using the combined proportion of participants selecting ‘Somewhat Agree’, ‘Agree’, or ‘Strongly Agree’, review of the response distributions demonstrated that agreement was generally driven by moderate-to-strong levels of agreement, with ‘Agree’ or ‘Strongly Agree’ representing the modal response for all consensus statements (Supplementary Table S4).

Limitations include the UK-specific composition of the expert panel, which may affect generalisability to other healthcare systems. Although the recommendations are expected to be relevant internationally, differences in access pathways, reimbursement structures, and care models may influence their applicability. Additionally, the consensus process was informed by a targeted literature review rather than a systematic review, which may have excluded some relevant studies. The absence of formal validation for the proposed outcome measures, particularly those based on patient and caregiver observations, highlights the need for future research to develop and validate tools tailored to the SMA-PV population. As with all Delphi studies, these recommendations represent expert consensus informed by the available evidence and should be interpreted in the context of the broader evidence base. Decisions regarding treatment access, reimbursement, and policy should consider the totality of available evidence, including clinical trial data, real-world evidence, patient experience, and health technology assessment requirements. However, in rare and under-studied populations such as those with SMA-PV, expert consensus may provide important complementary insights when conventional evidence remains limited. This study was initiated and funded by Roche Products Ltd. Although the sponsor had no role in the development, drafting, voting, analysis, or interpretation of the consensus statements, and the modified Delphi process was led independently by the Chair and supporting steering committee members, the potential for perceived sponsor influence inherent to industry-funded research should be considered when interpreting the findings. Finally, although the PAP provided valuable input, its role was advisory and non-voting, which may have limited the extent of patient-led influence on the final recommendations. This reflected the specialist clinical focus of the statements, for which formal voting was restricted to clinical experts, while still allowing patient and caregiver perspectives to be considered during the consensus process.

In conclusion, this modified Delphi consensus process has produced a set of practical patient-centred recommendations for SMA healthcare providers, patients, and caregivers. These statements offer a foundation for clinical practice, policy reform, and future research, with the potential to improve access to DMTs and outcomes for this underserved population.

Contributors

MS served as Chair and was responsible for the overall design of the modified Delphi consensus process, including development of the methodology, selection of panel members, definition of consensus criteria, oversight of statement development and revision, and final endorsement of the consensus statements. CMB, EC, and AKS formed the steering committee and supported the Chair in designing the Delphi process, developing the initial statement questionnaire, reviewing panel feedback, and contributing to statement refinement between voting rounds. MS, CMB, EC, and AKS had access to and verified the underlying study data, including Delphi voting responses and consensus outputs.

GB, AC, LE, CE, MAI, RK, MTO, RP, MP, SR, SS, HT, SW, TW, and EW participated as Delphi panel members. They completed the initial questionnaire and all voting rounds, and provided clinical expertise and feedback that informed statement refinement.

ZR contributed as an author representing the study funder and reflecting the origin of the research concept. ZR had no involvement in the development of statements, voting, analysis, or interpretation of the consensus findings.

All authors contributed to drafting or revising the manuscript for important intellectual content and approved the final version for submission.

Data sharing statement

Aggregated Delphi survey data supporting the findings of this study are included in the article and its Supplementary Materials.

Declaration of interests

MS has received honoraria for presenting at meetings and participating in scientific advisory boards of Biogen Inc., Novartis AG, and F. Hoffmann-La Roche AG. She is also a principal investigator of clinical trials sponsored by Biogen Inc. and F. Hoffmann-La Roche AG.

CMB has received honoraria for presenting at meetings and participating in scientific advisory boards of Biogen Inc., Novartis AG, and F. Hoffmann-La Roche AG. CMB has received grants from Biogen Inc. and F. Hoffmann-La Roche AG.

GB has received speaker and/or consulting fees from Biogen Inc., Entrada Therapeutics, F. Hoffmann-La Roche AG, Novartis Gene Therapies, PTC Therapeutics, Pfizer Inc., and Sarepta Therapeutics Inc. GB has received grants from F. Hoffmann-La Roche AG, Novartis Gene Therapies, and Sarepta Therapeutics Inc. GB has received funding (to University College London [UCL]) from F. Hoffmann-La Roche AG, Italfarmaco S.p.A., Pfizer Inc., Santhera Pharmaceuticals Holding AG, and Sarepta Therapeutics Inc. GB is a Principal Investigator of clinical trials sponsored by BioMarin Pharmaceutical Inc., F. Hoffmann-La Roche AG, Novartis AG, NS Pharma Inc., Pfizer Inc., Percheron Therapeutics Ltd., ReveraGen BioPharma Inc., Sarepta Therapeutics Inc., and Scholar Rock. GB is also co-principal investigator of the SMA REACH and North Star UK networks.

AC has received honoraria for presenting at meetings and participating in scientific advisory boards from Biogen Inc., F. Hoffmann-La Roche AG, and Novartis AG. AC has been sponsored to attend scientific meetings by F. Hoffmann-La Roche AG, Italfarmaco S.p.A., Novartis AG, and Santhera Pharmaceuticals Holding AG. AC is a principal investigator for clinical trials sponsored by Argenx SE, Astellas Pharma Inc., Dyne Therapeutics Inc., Italfarmaco S.p.A., Santhera Pharmaceuticals Holding AG, Sarepta Therapeutics Inc., and Scholar Rock.

LE has received honoraria for presenting at meetings and participating in scientific advisory boards from Biogen Inc. and F. Hoffmann-La Roche AG.

MAI has received funding to attend conferences from Biogen Inc., F. Hoffmann-La Roche AG, and Novartis AG.

RK has received funding to attend conferences from F. Hoffmann-La Roche AG and Novartis AG.

MTO has received honoraria for presenting at meetings and participating in scientific advisory boards, and funding to attend meetings and conferences, from Biogen Inc., F. Hoffmann-La Roche AG, and Novartis AG. MTO has also received grants from F. Hoffmann-La Roche AG. MTO is a principal investigator of a clinical trial sponsored by Biogen Inc.

MP has received honoraria for presenting at meetings and participating in scientific advisory boards from Biogen Idec Ltd, NICE Consulting, Novartis Pharmaceuticals UK Ltd., and Roche Products Ltd.

SR has received honoraria for presenting at meetings and participating in scientific advisory boards from Biogen Inc., F. Hoffmann-La Roche AG, and Novartis AG.

TW has received honoraria for presenting at meetings/symposia and participating in scientific advisory boards from Biogen Ltd., F. Hoffmann-La Roche AG, ITF Pharma UK, Lupin Ltd., and Novartis AG.

EW has received consultancy fees from Biogen Ltd., F. Hoffmann-La Roche AG, and Novartis Gene Therapies.

ZR is an employee of Roche Products Ltd.

AKS, EC, CE, RP, SS, HT, and SW declare no competing interests.