NICE and the controversy over a ‘clinically distinct disease’ designation

Payers worldwide are struggling with a new generation of precision medicines that come with a hefty price tag. Ben Hargreaves finds that the UK’s NICE is once again caught between ensuring cost-effective treatments and calls for greater access to new treatments.

The UK’s National Institute for Health and Care Excellence (NICE) has a reputation for being particularly stringent in its evaluation of the cost-effectiveness of treatments. There have been a number of high-profile cases in recent years where companies have been knocked back based on their pricing of treatments. In 2021, bluebird bio’s treatment, Zynteglo (betibeglogene autotemcel), was rejected by NICE, despite agreeing to supply the treatment at a confidential discount. More recently, there was the surprise rejection of AstraZeneca and Daiichi Sankyo’s Enhertu (trastuzumab deruxtecan) due to the institute’s use of a disease severity modifier threshold.

Biogen recently became another company that faced a setback during NICE’s review process. The case relates to Qalsody (tofersen), an antisense oligonucleotide that is used to treat amyotrophic lateral sclerosis (ALS) and is licensed from Ionis Pharmaceuticals. Last year, the treatment was provided accelerated approval by the FDA, despite some contention over its clinical efficacy.

In the UK, the point of contention for the company and patient groups against NICE is the choice of appraisal route for the drug. The choice of the ‘Single Technology Appraisal (STA)’ route makes the likelihood of the treatment being deemed cost-effective far less likely, potentially ending current patients’ access to the treatment in the longer term.

The two paths

The STA route is undertaken by NICE when a single, new technology is compared with the standard of care for the indication in question.  Its purpose is to appraise the health benefits and the costs of those technologies referred to the organisation. A decision is reached based on the clinical and economic evidence principally provided by the manufacturer or sponsor.

However, there is another route that Biogen was pushing for Qalsody to be analysed under – the highly specialised technology (HST) route. This is reserved for drugs that treat very rare conditions, but also needs to fulfil six other criteria to be considered. Some of the other factors include that the target patient is distinct for clinical reasons, the condition is chronic and severely disabling, and the need for national commissioning of the technology is significant.

The key difference between the two routes, from a manufacturer’s point of view, is that the STA route has a cost threshold of £20,000 to £30,000 per quality-adjusted life year (QALY). By contrast, this budget is increased to £100,000 per QALY for the HST route.

Distinct disease or not?

For its Qalsody treatment, Biogen had applied for the HST route, but was designated STA. The company then appealed this decision only for the original decision to be upheld. Biogen had argued that because the treatment would only be delivered to patients with motor neuron disease (MND) who have alterations of the SOD1 gene, this would allow it to be classified as being delivered to a very small population. The MND Association stated that this subset of patients would only comprise 2% of people with MND, estimating this to be between 60-100 individuals in the UK. Products tailored towards rare diseases that affect fewer than one in 50,000 people in England are appraised through the HST route.

The reason that NICE decided to review Qalsody through the STA route was due to the organisation not considering SOD1 MND a ‘clinically distinct disease’, stated the UK Motor Neuron Disease Clinical Studies Group (UK MND CSG) in an open letter.

UK MND CSG responded to this: “This is an out-dated concept in the current era when it is recognised that disease classifications based solely on consideration of clinical features are an inadequate way of making an accurate, and indeed even ‘precision’, diagnosis that lends itself to targeted ‘precision treatment’. It is completely at variance with the overwhelming consensus of clinicians and scientists working globally in neurodegenerative diseases that SOD1 is a distinct entity with a completely different pathological basis to the other 98% of MND.”

The pricing debate

The outcome of NICE’s decision is that it is ‘highly unlikely’ that Qalsody will receive a positive appraisal from NICE, added UK MND CSG. The open letter also indicates that Biogen will choose not to submit an application to the UK Medicines and Healthcare products Regulatory Agency (MHRA) for approval of the treatment. 

For Biogen, this would mean the loss of a substantial market within the larger European area. From a business perspective, this has a big commercial impact on a product that sells only in small volumes. In the US, the product is priced at $14,230 per dose and the treatment is delivered once every 28 days, after initial loading doses. Bloomberg noted that peak annual sales estimations for the treatment are approximately $200 million.

For patients, this will also mean that those in England are unlikely to be able to gain access to the treatment beyond current Biogen programs. The company confirmed that the Early Access Program and on-going Qalsody clinical trials will remain open to all eligible patients. With NICE having told patient organisations that its decision on the route designation is final, this may mean another case where a drugmaker chooses not to market its drug in the country. 

“Of further concern is the chilling impact this will have on pharmaceutical companies to bring their future innovative science and clinical trials to the UK, given the perception it will create that there is no effective route to market for precision medicine or rare disease therapies. This is completely contrary to the UK government's stated ambition for the Life Sciences sector,” stated UK MND CSG.

This represents a greater question facing pharma and payers worldwide. The rise of precision medicine, rare disease treatments, and even more advanced technologies, such as gene therapies, means that difficult decisions are being made more regularly on access to treatments. As these treatments target fewer people or require fewer doses, the price tags have risen in kind. Regardless of NICE’s final decision, the debate over pricing and access is likely to rumble on into the future.