These trials are multi-centre and are being offered in a number of countries. There is a total target number for each trial, so recruitment is competitive. If places are filled by other countries, recruitment will close.

• Lead clinicians and Patient Groups signed overarching consent to the terms of the MAAs. Individually patients have signed consent for treatment. ‘Informed consent’ is essential when there is a contract. Nowhere was it highlighted that enrolment in the MAA would prevent participation in clinical trials of novel therapies.
• Each updated MAA now describes that the treatment (nusinersen or risdiplam) may only be given as a ‘monotherapy’, but the term ‘monotherapy’ is not defined. It was generally understood that this referred to a requirement that a patient may only receive one SMN-dependent therapy at a time. This wording was not part of the initial Nusinersen MAA (July 2019), and was only introduced in February 2022. Version 2 of the Nusinersen MAA after the Risdiplam MAA was introduced in December 2021.
• An MAAs purpose is to collect clinical and cost effectiveness data where there is uncertainty about the risk/benefit of a novel therapeutic intervention so that the National Institute of Health and Care Excellence (NICE) can, when the MAA ends, make an informed recommendation for future funding. This is not disputed, and data needs to be as ‘clean’ as possible. However, people receiving nusinersen or risdiplam through the MAA process are not in a clinical trial. Many will be receiving other prescribed drugs for various reasons. Physiotherapy input will vary greatly between people as will their day-to-day activity levels, diets etc. These and other factors that may impact on outcomes are not controlled for in the data collection.
• Approximately 5% of the total number of patients enrolled on the nusinersen and risdiplam MAAs would be eligible for these combination trials. Their data could be removed from the main data collection with little or no impact on the overall finding, which will anyway be supplemented by other global data collection.

• If people receiving nusinersen or risdiplam through the MAA process cannot take part in a clinical trial, enrolment into the trials will not be based on clinical criteria/priorities but will depend on where a person lives – people living in England, Wales and Northern Ireland will not be able to take part in the clinical trials.
• People in the UK who have received Zolgensma – the ‘one-off’ gene therapy treatment that is not subject to an MAA in England – are not subject to the same limitations as those who receive nusinersen or risdiplam through a MAA.
• These inequities will last until at least 2025 when these MAAs end
• Evaluating further treatments as part of a controlled clinical trial is the ‘next step’ in optimizing care and quality of life for those living with SMA. Denying groups of people the right to participate in these studies refuses them the right to strive towards better outcomes.
• The limits placed on patient opportunities may lead to decisions to join trials overseas bringing with it safety and financial impacts.
• One of the companies involved in these trials is also the manufacturer of one of the SMN-dependent treatments prescribed via MAA. This decision could inadvertently give them a competitive edge as the only company to be able to conduct a trial of an ‘antimyostatin’ drug across the UK.

• Trial sites in the UK have already invested a significant amount of time and energy setting up specific trials
• Working to set up a trial that never happens is detrimental to morale and makes it harder to recruit and retain expert staff to run clinical trials.
• The trials present no additional cost to the NHS. All costs relating to the investigational drugs are covered by the pharmaceutical and biotech companies carrying out the trials.
• The reputation of the UK as a centre for neuromuscular research could be significantly undermined because companies will not see the UK as a reliable country to carry out clinical trials. This goes against the recommendations set out in the 2022 England Rare Disease Action Plan, which states that: “By working in partnership across the NHS, regulators, research funders, industry, medical research charities, academia, and government, we can create a clinical research ecosystem which is more efficient, more resilient, and more effective than ever before.”
• The UK might no longer be attractive to leading clinicians and researchers because the opportunities to be part of exciting clinical research are limited.
• In the longer-term NHS, NICE and UK Centres will not have any clinical experience with these new drugs which will impact on the efficiency of appraisals and recommendations including the availability of expert clinical advice and the roll-out of any potential treatment programme.