Written by Bob Steven, group CEO, MPS Society

Estimated reading time: 6 minutes

Having been on a “Rare” journey with my family for 25 years and as the group CEO of the MPS Society, a highly respected patient organisation, and Rare Disease Research Partners, our not-for-profit clinical trial support arm that operates globally, I have seen a lot of changes that are helping our communities to “Live A Rare Life Better”.

With the development of enzyme replacement therapies, substrate reduction therapies and gene therapies, what was once science fiction is now science fact.

However, whilst the science has developed, much of the global regulatory understanding and ecosystems have not kept pace with the innovation.

The problem with traditional clinical trials

The purpose of a randomised controlled trial (RCT) is to determine the effectiveness of a potential new treatment or therapy by minimising bias through random assignment of study subjects to either an active treatment group or to a control group receiving either a placebo or standard of care (SOC).

In rare diseases, the progression of the condition is often slow, variable and progressive, especially when neurological involvement is present. When determining the efficacy of a potential treatment or therapy, RCTs need to be run over multiple years with one group receiving the potential new treatment or therapy and another group receiving either a placebo or the current SOC. Both groups are assessed over the course of the clinical trial and the outcomes are compared to reach a conclusion.

I find it incomprehensible that the placebo-controlled or even SOC RCT (right to choose) approach is insisted upon in rare and ultra-rare diseases by many regulators where the patients with neurological involvement and even those without, will be consigned to significant and irreversible decline, often leading to a shortened life of increased pain and discomfort for not only the patient but their whole family and support network.

Consider a child with a rapidly progressing neurodegenerative condition. In a traditional two-year RCT, half the children receive a placebo whilst irreversible brain damage occurs. By the time the trial concludes, and treatment becomes available, these children may have lost cognitive abilities, mobility or communication skills that can never be recovered. For families, this isn’t just a clinical endpoint—it’s watching their child’s future disappear whilst an effective treatment sits locked away in a trial protocol.

A better way forward: biomarkers

In my opinion, this approach is both fundamentally flawed and unethical, especially when science has been showing us another way for some time.

For these tiny populations, should we be using innovative solutions and early indicators, such as biomarkers, that are reasonably likely to indicate the effect/efficacy of a potential treatment or therapy early in the course of a disease?

A real-world example: mucopolysaccharidosis type II

In MPS for example, we have identified biomarkers that would allow this approach to be incorporated within the clinical trial design and that would lead to numerous benefits.

If we take the example of mucopolysaccharidosis type II (Hunters disease) which both my sons have, the scientific community widely accepts that heparan sulphate(HS) accumulates in the cerebrospinal fluid (CSF) of individuals with neurological involvement but not in those who are classically described as attenuated (no brain/neurological involvement). This can be measured accurately using mass spectrometry. What is essential to understand here is that if HS is present it indicates that there is already disease progression in the brain, even if it cannot yet be outwardly observed. If HS levels are reduced by a potential treatment or therapy it indicates that there is an effective intervention and the disease can be slowed or halted before unnecessary and irreversible symptoms have developed.

Conversely If the level of HS is not affected, the treatment or therapy is likely to be ineffective, and it then allows the potential of an earlier fail in a clinical trial which is as equally important as success for all concerned. It allows the patient in conjunction with their clinician to look at other treatment alternatives and clinical trials and allows the pharmaceutical manufacturer (sponsor) to move on more quickly to another trial without pouring money into an ineffective therapy or treatment.

If the clinical trials become less costly by using biomarkers as an effective endpoint it will have the effect of encouraging more investment into the rare disease arena because the financial risk will be greatly reduced. For small biotech companies and academic researchers, the difference between a £50 million five-year RCT and a £10 million two-year biomarker-driven trial can mean the difference between attempting a treatment development or abandoning it entirely.

Using heparan sulphate (HS) as an example of a biomarker that can be a surrogate endpoint in a clinical trial demonstrates what is possible and as a follow up to validate this approach, a managed access agreement over 2-5 years could be put in place. This would serve to allow further patient data to be collected but also importantly allow some financial benefit for the sponsor, completely negating the need for RCTs.

In early discussions with the MHRA (Medicines and Healthcare products Regulatory Agency), they have been willing to consider the merits of this approach, and in the USA several treatments or therapies are progressing via the FDA (Food and Drug Administration) Accelerated Approval Pathway. Unfortunately, and inexplicably NICE (National Institute for Health and Care Excellence) and the EMA (European Medicines Agency) have to date been more sceptical about biomarkers and this is acting as a roadblock to innovation and the possibilities of new treatments and therapies being developed for the rare community have been greatly reduced. 

A call to action

To all regulators I would simply say that it is time to follow the path science has laid before you. The benefits are undeniable and indeed extend far beyond what is currently calculated within a cost benefit analysis such as the QALY (Quality Adjusted Life Year) calculation.

Can we, in good conscience, continue to use randomised control trials which unnecessarily lead to harm to patients when there are alternative and better solutions?

The science is here. The biomarkers are validated. The regulatory frameworks exist in some jurisdictions. What we need now is the will to implement change globally, before another generation of children loses precious time, abilities, and quality of life to outdated trial methodologies.

Our families cannot wait another 25 years for regulatory systems to catch up with scientific reality. Don’t you think that our communities deserve the chance to “Live A Rare Life Better”, a life that many of us already take for granted!

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