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Can a ‘double standard’ in paediatric medicine provide a framework to restructure repressive medical


A Small Girl wearing pink reading a book

By Rayyan Zafar an Honorary Research Assistant for Drug Science


Can a ‘double standard’ in paediatric medicine provide a framework to restructure repressive medical cannabis policies?


In 2019, a drug called Zolgensma came to market. This drug used a particularly innovative gene therapy technique to treat infants suffering with an extremely rare and catastrophic neuromuscular condition called Spinal Muscular Atrophy (SMA). This is a genetic disorder that produces progressive muscle wasting due to the build up of the toxic SMN protein. Children born with this genetic defect will have a loss of motor neurons from birth that leads to failures in standing or sitting, swallowing, and eventually breathing. Left untreated they will go on to develop severe respiratory failure as the muscles in their lungs cease to work so the majority of these children die by the age of 2.


Zolgensma works by inserting a functioning piece of the gene ‘SMN1’, which is deficient in children with SMA, into the damaged motor neurons. This stops the build-up of the SMN protein and allows for over 65% of children given this medication to achieve motor milestones that would not have been possible without treatment.


This drug is clearly an innovation in gene therapy but it comes with a price tag of $2.125 million per treatment, making it the most expensive drug in the world. Despite this cost Zolgensma was licensed without being subjected to the same requirements as most other drugs: it did not require an Randomised Control Trial (RCT). The data submitted to the medical regulators consisted of an open label single-arm (no-placebo) study involving 36 patients between the ages of 2 weeks and 8 months.


The primary evidence of the effectiveness came from 2 clinical endpoints:


  1. The proportion of patients achieving the milestone of sitting without support for at least 30 seconds at 18 months of age.

  2. Survival at 14 months of age.


The results were that 10/21 met endpoint 1 and 13/21 met endpoint 2. A natural history control group of other patients was used for comparison.


Based on these findings the FDA, EMA and MHRA authorised the drug under the orphan drug regulations [drugs for rare conditions] and in the UK, it was immediately made freely available on the NHS.


Zolgensma is not unique in skirting the constraints of RCTs. Newly licensed pharmaceutical indication is frequently approved without any controlled trial results. A recent systematic review found that between 1999 and 2014 over 76 unique indications were granted without RCT results. Indeed, there are some studies where effect sizes are so large of certain that it would be neither ethical to conduct RCTs or plausible to mask them due to the observed sizes. However, as we can see from the results of the Zolgensma study, the results did not extend therapeutic benefit in all cases.


These approaches do not ascribe to the regimented frameworks in place for authorising novel pharmacological agents. This begs the question of why Zolgensma and other drugs are provided such diplomatic status.

Lessons learned: restructuring the system


So how did Zolgensma gain approval as a medicine with only a single-arm open label design with a very limited number of participants?

Public Support Ultimately the answer to this remains ambiguous to this day. It is well noted that there was phenomenal public pressure to approve the drug, and this was spearheaded by examples of celebrities whose children suffered with SMA. The patient advocacy groups for SMA are amongst the most vocal and well-organised in the world with important links with internal government department and medical legislators. The move from doctors to patients in advocating for their needs is a paradigm shift in medical. In the case of Zolgensma this approach was successful, and it can go a long way to encourage politicians to push change in policy.

Facts Data integrity and proven safety and efficacy are considered to be the most important judgements in the authorisation of a new medicine. Whilst the importance of RCTs cannot be denied they should not be viewed as a panacea in methodological approaches for clinical studies.


It is clear that some single-arm open label studies provide necessary and sufficient data for legislators to feel comfortable in providing market authorisation. We go further and suggest such bodies pay attention to data that emerge from observational studies in the real world. We have recently published on such a study in ten children suffering with rare treatment-resistant paediatric-onset epilepsies showing an average reduction of 80% in monthly seizure frequency following medical cannabis. This study also highlighted that in all patients observed the current mainline treatments did not work and there were no serious adverse events or deaths reported (Zafar et al 2020). We are now extending this study in 25 patients with similar conditions and our data suggests that in this group there is an 84% reduction in seizure frequency across the group (Zafar et al 2021 in prep). Results from this study will be published later this year.


Through Zolgensma we have a framework wherein novel paediatric medicines in highly unmet areas of clinical need can be dynamically assessed within the current model. Recently the National Institute of Clinical and Health Care Excellence (NICE) issued a position statement to support the role of real world evidence and patient reported outcomes in providing evidence for the assessment of efficacy of novel interventions . We support the authorities in their understanding that where safety and efficacy can be proven for a given indication where it is unethical to conduct RCTs that other types of data can be used. This same judgement should be afforded to new medicines proven effective to treat childhood epilepsies.

Costs The heavy financial burden facing the NHS today means rational and evidence-based assessments of treatment cost are required. This process begins with health economic analysis by the Department of Health and Social care (DHSC) and the NICE. In the case of Zolgensma, it is clear that the cost of over $2million dollars per treatment is most exceptional. To date, there are no long term follow up studies to ascertain whether an individual will be okay with just one dose or will need more. Further, there are also implications of how effective the drug is, whilst it appears to reduce mortality, albeit in only 50% of individuals in the small study, those that do survive are subjected to a life of disability. Ultimately this disability requires the support of numerous parts of the health and social care systems. As a result, this is an expensive disease to treat. The funds for Zolgensma are acquired through NICEs highly specialised technology scheme. This scheme considers drugs for very rare conditions and has stringent criteria for approval.


Why are treatments for rare forms of childhood epilepsy non-responsive to conventional anti-epilepsy drugs not accorded the same considerations? Our recent study found that medical cannabis was extremely effective in these patients, yet the parents are forced to pay for the medication themselves, often facing bills of several thousand pounds per month. The usual reason given why their treatments are not paid for on the NHS is that there is no good RCT evidence. Yet the success of the parents intervention not only clearly improves the life quality of their children but also saves the NHS a lot of money. Supporting children with such epilepsies before medical cannabis interventions is estimated to amount to £100,000 a year from intensive care treatment, intubation, medicines, costs for doctors and nurses and other healthcare staff as well as emergency callouts. Yet medical cannabis would only cost the NHS £35,000 a year but it is denied them. This raises a critical question – why is medical cannabis not considered under the same NICE specialised technology scheme as Zolgensma given the close similarities in patient cohort, evidence base and reported clinical outcome?

Concluding remarks Similar to Zolgensma, medical cannabis could and should be made available to all patients free on the NHS. Given the emergence of a clarified framework wherein rare paediatric disorders can be treated with effective novel pharmacological interventions, is it not timely that legislators consider supporting the case for these seriously ill children?


The bedrock of medical prescribing is cornered on evidence of safety and efficacy. These foundations were initially laid over half a century ago with the sole focus to protect our children. We call on the government, policy makers and legislators to afford the same privileges delivered to children suffering with SMA to those with epilepsy to restore trust in the medical establishment.


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