Evaluating ravulizumab for aHUS treatment

Article No. 442

23 June 2021

Today NICE ( The National Institute for Health and Care Excellence) concluded its evaluation of ravulizumab for treating aHUS by publishing its Final Guidance on the matter. After an evaluation which has taken almost one year to the day to carry out , NICE have concluded that:

In the committee’s preferred analyses, ravulizumab was considered a cost effective use of NHS resources compared with eculizumab. Therefore, ravulizumab is recommended as a treatment option for people with aHUS who have not had a complement inhibitor before, or whose disease has responded to at least 3 months of eculizumab treatment.

Within the next three months (2 months in Wales) all English patients with a confirmed aHUS diagnosis will be eligible to access ravulizumab as their treatment by their National Health Service care providers free at the point of delivery..

What has led to that conclusion?

First of all a decision had to be made on what alternative treatment would ravulizumab be compared with to determine its cost as well as clinical effectiveness.

Back in the autumn of 2019 a meeting was held to determine the scope of the evaluation and at that time it was proposed that ravulizumab would be compared with plasma exchange and dialysis. All stakeholder disagreed with that approach and maintained it should be compared with eculizumab. It took at least six months to re think it but eventually it was decided that ravulizumab would just be compared with eculizumab. However two technology comparisons could not be done by the NICE evaluation process for very rare diseases as now aHUS was no longer an orphan disease because it already had a  treatment ( eculizumab). Instead ravulizumab would follow its  standard technology appraisal pathway.

aHUS alliance Global Action was invited as a consultee to provide patient input. This it did with the help of patients from the USA,  who had experience of both technologies, and the UK who had expectations from the new technology. It nominated a patient expert to participate. A research document was produced as evidence to the evaluating committee  in early October 2020, and then there was a waiting period  during which the evidence of other stakeholders was shared to those participating and responses given to issues the committee might have. The “ravulizumab for aHUS” evaluation  Committee was scheduled to meet in April 2021.

There were no questions raised about the patient evidence submission. More focus was on the clinical effectiveness of ravulizumab as shown by the two trials. Also stopping treatment and starting treatment strategies were explored.

This is reflected in the contents of NICE committee Final Guidance which shows the reasoning behind that guidance. NICE has a open and transparent approach to its processes and puts key documents on line for the public. The Final Guidance can be read in full ( 20 pages) at this link HERE.

Some of the highlights from the document are listed below:

  • It is recommended only if the company provides ravulizumab according to the
    commercial arrangement (see section 2). (para 1.1)
  • The list price is £4,533 for 300 mg per 3 ml concentrate for solution for infusion
    vial; £16,621 for 1,100 mg per 11 ml concentrate for solution for infusion vial
    (excluding VAT; company submission). (para 2.2)
  • The company has a commercial arrangement (simple discount patient access
    scheme). This makes ravulizumab available to the NHS with a discount. The size
    of the discount is commercial in confidence. (para 2.3)
  • Treatment with ravulizumab may be stopped if adequate renal response is observed (issue 6,
    see ERG report table 1) (para 3)
  • The potential future launch of biosimilars of the comparator drug eculizumab (Soliris, Alexion
    Pharmaceuticals) is not relevant to this appraisal of ravulizumab (para 3)
  • The patient experts explained that the fortnightly infusions make it difficult for people to work, socialise and join in with family life. People also face the personal, logistical and financial challenges of travelling to have their infusions. People would have ravulizumab
    by intravenous infusion every 8 weeks, reducing these challenges greatly compared with eculizumab. The patient experts explained that if ravulizumab were recommended by NICE, people would most likely prefer ravulizumab over eculizumab because of the lower treatment frequency. They noted that longer gaps between treatment reduces the treatment burden, so people who have ravulizumab are likely to have better quality of life than those who have eculizumab. They also noted that they can return to work and arrange holidays. (para 3.1)
  • The clinical experts at the committee agreed that most people with suspected aHUS would be offered eculizumab as a first-line treatment, so ravulizumab would be offered as a second-line treatment once the disease had responded to eculizumab. However, the clinical
    experts also commented that there are some people who could have ravulizumab first
    line: if there is sufficient evidence that aHUS is the correct diagnosis even ahead of
    final test results, for example, if there is a family history of aHUS. ( para 3.3)
  • The committee noted that there was no clinical evidence directly comparing ravulizumab with eculizumab because both trials were single-arm studies. It concluded that ravulizumab was clinically effective but agreed that the lack of comparative data made assessing
    comparative effectiveness (and any consequent cost-effectiveness analyses) very
    challenging. (para 3.4)
  • The committee noted that clinical practice varies around the world, and the ERG said it was possible some of the patients in Asia (in the trial) did not have aHUS as per UK diagnostic criteria. The clinical experts agreed that it was possible some patients in the trial did not have aHUS, or that the disease had progressed beyond the usual point of diagnosis in UK practice. (para 3.5)
  • The committee agreed that there was uncertainty in the trial results because of their design, enrolment, and use of genetic testing. But overall, it concluded that the results were generalisable to people seen in NHS practice. ( para 3.5)
  • There was no trial directly comparing ravulizumab with eculizumab. So the company did indirect treatment comparisons to show the similar effectiveness of the 2 treatments….The committee agreed that the data were uncertain, but accepted it was biologically plausible that ravulizumab and eculizumab may be similarly effective, because of their similar mechanisms of action (para 3. 6)
  • The company assumed equal clinical effectiveness and quality of life for ravulizumab and eculizumab in their economic model. It also assumed that children, young people and adults with aHUS would all have an equal quality of life. The company did a discrete choice experiment and determined that a quality-of-life utility gain of 0.013 could be added for ravulizumab, because of the reduced frequency of infusions. ( para 3.9)
  • The committee agreed the long-term safety and efficacy of ravulizumab remained uncertain, but it was plausible that it would show similar performance to eculizumab. The committee also agreed that it would take the uncertainty into account in its decision making. (para 3.11)
  • The clinical experts commented that the decision to stop and restart treatment could be made multiple times,but that this would be down to the individual situation of the person with aHUS and the observed results of them stopping treatment. The clinical experts said
    this approach may work for some people but not for others. The clinical experts also stated that there were no data to support this approach, and that people may not want to stop and restart treatment multiple times. (para 3.13)
  • The ERG said that current guidelines suggest treatment for aHUS should be lifelong. But several arguments in the literature propose that people may choose to stop treatment when renal response has reached an adequate level. The ERG expected that this would be supported by the SETS study. The company accepted this argument at technical engagement and updated its economic model to reflect this approach. Stakeholders said that this would be supported by SETS, and that people would want to stop in this case. The clinical experts
    agreed that although SETS was designed to study eculizumab, its results would
    apply to ravulizumab in practice. (para 3.14)
  • The ERG highlighted that the patent for eculizumab is set to expire in the next 3 years, so biosimilar eculizumab treatments are likely to enter the market… The committee agreed that they should not be considered in this appraisal. The committee asked for availability of biosimilars to be factored into future reviews of ravulizumab and its cost effectiveness. (para 3.16)
  • Using the committee’s preferred assumptions and including the revised confidential discount for ravulizumab, ravulizumab was as effective and cost less than eculizumab in both the  company’s base case and the ERG’s preferred base case, when equivalent efficacy was assumed. The exact savings and incremental cost-effectiveness ratio (ICERs) are commercial in confidence and cannot be reported here. (para 3.17)
  • Pregnancy was one of the exclusion criteria for the clinical trials. The summary of product characteristics states that ravulizumab may be offered to pregnant women after an assessment of risks and benefits. The committee acknowledged this and concluded that there were no relevant equality issues. (para 3.18)

All of which demonstrates the thoroughness in which decisions are made about spending considerable health resource on a small number of patients to make their lives better.

It may be done in different ways in different countries around the world whether done by  private insurance, hospital pharmacies or public health policy decision makers ( Global Action would be interested to hear about ravulizumab decisions in other countries)  but the core process is the same.

It takes many people collectively working many hundreds of hours to gather, analyse and discuss the evidence in an evaluation of a new technology for the treatment of patients.  ( For transparency a copy of the Committee Papers are published today , all 515 pages of them.)

Some times  the result is not what was hoped for and all has been in vain.

But for aHUS patients affected by this result it is a progressive step change in their treatment which makes life for those needing treatment for aHUS much freer and easier.