Impact case study database

The Cardiff team’s research on the molecular mechanisms underlying tumour growth in TSC patients, and the effectiveness of mTOR inhibitors to reduce tumour growth, resulted in changes to international disease management guidelines. Their work also provided the basis for a successful lobbying campaign by the UK charity, the Tuberous Sclerosis Association, for the NHS to commission mTOR inhibitors for TSC patients.

4.1 International guidelines

Cardiff research contributed to the 2013 publication of Surveillance and Management Clinical Guidelines, developed from the 2012 International Tuberous Sclerosis Complex Consensus Conference. The new international guidelines recommended mTOR inhibitors as first line treatment for renal angiomyolipomas and are considered the international standard for clinical management of TSC [5.1]. Referring to the Cardiff research paper [3.5], the guidance states that: “For asymptomatic, growing angiomyolipoma measuring larger than 3 cm in diameter, treatment with an mTOR inhibitor is the recommended first-line therapy” [5.1, table 3, p.19 ].

The Tuberous Sclerosis Alliance (TS Alliance) is a US-based charity which commands a multi-million-dollar research budget and aims to improve treatment options, access to care and awareness of TSC both in the US and internationally. The TS Alliance sponsored the development and dissemination of these guidelines, and in describing Cardiff’s role, notes: “ The evidence provided by Cardiff University’s research was an essential factor in the process leading to the change in policy and clinical practice that has now become established globally” [5.2]. In 2017, the TS Alliance awarded Sampson their highest honour, the Manual R. Gomez Award, in recognition of Cardiff’s impactful research [5.2].

4.2 NHS clinical commissioning policy statements on everolimus

Prof Bissler summarised the importance of Cardiff research in the approval of mTOR inhibitors, including everolimus, as a treatment strategy for TSC: *“Following [Cardiff] work identifying and characterizing the TSC2 gene my group in Cincinnati and yours in Cardiff undertook phase IIb studies to establish initial evidence for safety and efficacy of sirolimus treatment for this important manifestation of TSC **[3.5]*…These foundational studies lead to our registration trial using everolimus, and finally the approval of such mTORC1 inhibitor therapy” [5.3, 5.4].

In 2015, NHS Wales was the first UK health service to commission mTOR inhibitors for the treatment of angiomyolipomas in TSC, prior to appraisal of everolimus by NICE [5.5]. This included a 2-year deal with Novartis, who agreed to invest £1.3M to run an observational study of patients being treated with everolimus, as part of plans for future appraisal of the treatment [5.5].

Despite the commissioning of mTOR inhibitors for Welsh patients, access to treatment in England required individual patient funding requests (IPFR) to access the drug. The Tuberous Sclerosis Association, a UK charity representing TSC patients, discovered that IPFRs for mTOR inhibitor treatment were rarely successful, with fewer than 5 approved in 2014-2015 [5.6]. Following the success of trials, including Cardiff’s TESSTAL trial, the Tuberous Sclerosis Association lobbied and campaigned for mTOR inhibitors to be commissioned by NHS England for the treatment of TSC patients in England [5.6]. As a result, in 2016 NHS England: “reviewed the evidence and concluded that it is sufficient to enable everolimus (Votubia®) to be routinely commissioned and therefore available to children from three years of age and adults with TSC-associated AMLs” [5.7]. The evidence described in the commissioning statement included the Cardiff-led TESSTAL trial [3.5, 5.7].

4.3 UK guidelines for management and surveillance of TSC

Sampson was an author of new 2019 UK Guidelines for Management and Surveillance of TSC, which were developed through repeated online surveys of 86 UK clinicians and researchers, as well as consultation with the Tuberous Sclerosis Association. The two surveys constituted a Delphi process, by which a consensus was reached [5.8]. Cardiff research [3.4, 3.5] underpins these UK guidelines, which state that “ There was a consensus that growing AMLs measuring ≥3cm in diameter should be treated with mTOR inhibitors”. These were the first UK guidelines to be produced on management of TSC, with the importance of these guidelines noted by the Tuberous Sclerosis Association on their website: “ Publication of the UK TSC clinical guidelines was a defining moment in the diagnosis, treatment and management of people living with TSC, with the guidelines helping to drive improvements in the consistency and quality of care that people with TSC receive from the NHS” [5.9].

4.4 Improved patient outcomes

In addition to Cardiff’s trials into mTOR inhibitors for treatment of TSC, retrospective and prospective studies conducted by other centres showed that TSC patients treated with mTOR inhibitors showed shrinkage of renal tumours and a greatly reduced risk of bleeding, confirming significant patient benefits from the research [5.4].

As further evidence, the Tuberous Sclerosis Association estimated that up to 11,000 people in the UK live with this challenging condition, and describe the improvements to patients’ quality of life: “The impact of successful treatment of renal angiomyolipoma with mTOR inhibitors on patient quality of life has been immense as the treatment can be taken by patients orally within the comfort of their home, while previous surgical and embolization approaches required hospital admission and caused permanent damage to renal function. As it is directed to the underlying disease mechanism, the treatment also benefits patient’s skin lesions and epilepsy, further contributing to improvement in quality of life” [5.10].