| Status: Supported for use via the One Wales Medicines process | |
Using the agreed starting and stopping criteria, ustekinumab can be made available within NHS Wales for the treatment of inflammatory bowel disease in children and young people aged 6 to 17 years: for ulcerative colitis following loss of response, non-response or intolerance to anti-TNF therapies and vedolizumab; for Crohn’s disease following loss of response, non-response or intolerance to anti-TNF therapies. The risks and benefits of the off-label use of ustekinumab for this indication should be clearly stated and discussed with the patient to allow informed consent. Providers should consult the relevant guidelines on prescribing unlicensed medicines before any off-label medicines are prescribed. At the latest review of this recommendation in April 2024, the decision by the One Wales Medicines Assessment Group was to retain the current advice with no changes required. Next review: this decision will be reviewed again after 2 years or earlier if new evidence becomes available. |
Darllen yn Gymraeg / Read in English
Beth benderfynodd Grŵp Asesu Meddyginiaethau Cymru’n Un?
Gellir rhoi ustekinumab i drin clefyd llid y coluddyn (IBD) mewn plant a phobl ifanc 6 i 17 oed. Mae IBD yn achosi poen bol difrifol a dolur rhydd; y ddau brif fath yw llid briwiol y coluddyn a chlefyd Crohn.
Dim ond pan nad yw therapïau gwrth-TNF a vedolizumab wedi gweithio y gellir rhoi ustekinumab i trin llid briwiol y coluddyn. Dim ond pan nad yw therapïau gwrth-TNF wedi gweithio y gellir rhoi ustekinumab i trin clefyd Crohn.
Bydd ustekinumab ar gael i gleifion cymwys sydd wedi cofrestru gyda phractis meddyg teulu yng Nghymru, hyd yn oed os oes angen iddynt dderbyn eu triniaeth y tu allan i Gymru.
Nid yw ustekinumab wedi'i drwyddedu i drin IBD mewn plant a phobl ifanc, felly os caiff ei ddefnyddio i drin IBD fe’i gelwir yn ddefnydd “all-drwydded”. Pan gaiff meddyginiaeth ei defnyddio yn “all-drwydded”, rhaid i'ch meddyg, neu feddyg eich plentyn, esbonio'n glir i chi y risgiau a'r manteision o gymryd y feddyginiaeth. Dylai eich meddyg roi gwybodaeth glir i chi, siarad â chi am eich opsiynau a gwrando'n ofalus ar eich barn a'ch pryderon. Darllenwch ein taflen wybodaeth i gleifion am ddefnydd di-drwydded ac all-drwydded o feddyginiaethau.
Mae Grŵp Asesu Meddyginiaethau Cymru'n Un ac AWTTC yn adolygu'r penderfyniad hwn yn rheolaidd i weld a oes unrhyw dystiolaeth newydd a allai effeithio ar y penderfyniad hwn.
Am fwy o wybodaeth am glefyd llid y coluddyn ewch i: IBD UK
What did the One Wales Medicines Assessment Group decide?
Ustekinumab can be given to treat inflammatory bowel disease (IBD) in children and young people aged 6 to 17 years. IBD causes severe tummy pain and diarrhoea; the two main types are ulcerative colitis and Crohn’s disease.
Ustekinumab can only be given to treat ulcerative colitis when anti-TNF therapies and vedolizumab have not worked. Ustekinumab can only be given to treat Crohn’s disease when anti-TNF therapies have not worked.
Ustekinumab will be available to eligible patients who are registered with a GP practice in Wales, even if they need to receive their treatment outside Wales.
Ustekinumab is not licensed to treat IBD in children and young people, so using it to treat IBD is called “off‑label” use. When a medicine is used “off-label” your doctor, or your child’s doctor, must clearly explain the risks and benefits of taking the medicine. The doctor should give you clear information, talk with you about the options available and listen carefully to your views and concerns. Read our patient information leaflet about unlicensed and off-label use of medicines
The One Wales Medicines Assessment Group and AWTTC review this decision regularly to see if there is any new evidence that may affect this decision.
For more information on inflammatory bowel disease visit: IBD UK
Starting criteria: Patients aged 6 to 17 years with ulcerative colitis following loss of response or non-response to anti-TNF inhibitors and vedolizumab or when anti-TNF inhibitors and vedolizumab cannot be tolerated or are contraindicated.
Patients aged 6 to 17 years with Crohn’s disease following loss of response or non-response to anti-TNF inhibitors or when anti-TNF inhibitors cannot be tolerated or are contraindicated.
Screening: Ustekinumab may have the potential to increase the risk of infections and reactivate latent infections. Caution should be exercised when considering the use of ustekinumab in patients with a chronic infection or a history of recurrent infection. Patients should be evaluated for tuberculosis infection and anti-tuberculosis therapy considered prior to initiation of ustekinumab in patients with a history of latent or active tuberculosis in whom an adequate course of treatment cannot be confirmed1,2.
Dose induction: Induction treatment is administered intravenously as a weight-based dose of about 6 mg per kg (maximum 520 mg, see also below) administered over one hour.
| Child’s weight | Dose to be prescribed |
| < 55 kg | 260 mg |
| 55 kg - 85 kg | 390 mg |
| > 85 kg | 520 mg |
Maintenance: Maintenance treatment is administered as a subcutaneous injection, given at week 8 after induction. Adult patients receive a 90 mg injection, children should receive a body surface area-adjusted dose (considering a standard adult of 1.73 m2), see suggested dosing below:
| Child’s weight | Dose to be prescribed |
| < 40 kg | 45 mg |
| > 40 kg | 90 mg |
After this, dosing every 12 weeks is recommended. Clinical benefit can be observed from 8 weeks following intravenous induction3. Patients who have not had an adequate response 8 weeks after the first subcutaneous dose (week 16) may have a second subcutaneous dose at this time, to allow for delayed response. Patients who lose response on 12-weekly dosing may benefit from an increase in dosing frequency to every 6-8 weeks, according to clinical judgement.
Subcutaneous maintenance doses may be administered at home by the patient or a carer following suitable training.
Outcome data, including dosing frequency and duration of treatment, should be collected to inform future policy changes.
Monitoring:
Stopping criteria:
Outcome data, including reasons for stopping treatment, should be collected to inform future policy changes.
Continuation of treatment: At 12 months, patients should be assessed to determine whether treatment should continue. Treatment should only continue if there is clear evidence of ongoing clinical benefit. Regular reassessment to determine whether continued treatment is justified should be done at least every 12 months.
References:
Health boards will take responsibility for implementing One Wales Medicines Assessment Group decisions and ensuring that a process is in place for monitoring clinical outcomes.
This is a summary of new evidence available and patient outcome data collected, to inform the review. It summarises any new evidence available and patient outcome data collected since the One Wales assessment in February 2023.
Background: Ulcerative colitis (UC) and Crohn’s disease (CD) are the two main forms of inflammatory bowel disease (IBD). They are lifelong, chronic conditions that follow an unpredictable relapsing and remitting course and can cause significant morbidity. IBD negatively affects the quality of life of children and adolescents based on its impact on the physical, emotional and social wellbeing of these patients, especially if poorly controlled.
Clinicians in Wales consider there is an unmet need and have identified a cohort of people who could benefit from this treatment. This includes children and young people (CYP) aged 6 to 17 years who have failed current treatments in the pathway and where there is no alternative licensed therapy to meet their needs. These patients may be dependent on steroids to control the disease and would be at risk of complications and repeated surgical interventions if their inflammatory bowel disease is poorly controlled. This medicine was therefore considered suitable for assessment via the One Wales process.
Current One Wales decision: Supported
Licence status: Off-label use for this licensed medicine. [Confidential information removed]
Guidelines: There have been no relevant updates to existing guidelines identified.
Licensed alternative medicines or Health Technology Assessment advice for alternative medicines: No new medicines or Health Technology Assessment advice reported.
Effectiveness: A repeat literature search conducted by AWTTC identified two papers which analysed the clinical effectiveness of ustekinumab pertinent to the recommendation. These included a retrospective study and a systematic review, both published in 2023. Overall results are comparable to those seen in the original evidence report with an indication that benefits with ustekinumab are sustained.
The retrospective study by Koudsi et al (2023) evaluated the short- and long-term effectiveness of ustekinumab therapy in paediatric IBD (n = 53). Forty-eight patients (90%) had a diagnosis of CD and 5 (9.4%) had UC. All patients included in this study were resistant to anti-TNF agents prior to receiving ustekinumab. The mean age at diagnosis was 9.8 years old (range 2.3–16 years) and mean disease duration was 6.7 years (range 1.1–13.6 years). The mean and the median duration of follow up were respectively 13 months and 10.5 months (range 1–51 months). The study reported significant improvement in health index and biological parameters. Mean weight increased 3 months after treatment induction, from 45 kg (range 21.5–70.5 kg) at baseline to 49 kg (range 23.3–73 kg) (p < 0.001), a significant increase was also reported in body mass index. Paediatric Crohn's Disease Activity Index (PCDAI) and Paediatric Ulcerative Colitis Activity Index (PUCAI) improved with ustekinumab treatment. The mean PCDAI at baseline was 28.7 (range 5-85) decreasing to 18.7 (range 0–75) after 3 months of treatment and dropping to 10 (range 0–35) at the last follow-up. Similarly, the PUCAI showed a significant improvement, 25 (range 15‑40) at 3 months and 18.3 (range 0–35) at the last follow-up, compared to 47 (range 25–65) at baseline. At 3 months, levels of the inflammatory marker, C-reactive protein (CRP) was normalised in 75% of patients which is consistent with the equivalent retrospective adult study as well as in the UniStar study included in the previous report. Nine patients (16%) were steroid-free at inclusion, 31 (58%) at 3 months, and 33 (62%) at the last follow-up.
In all patients, the initial intravenous (IV) ustekinumab dose was weight-adjusted (6 mg/kg) and the first subcutaneous (SC) dose was 90 mg, 8 weeks after the first dose. Twenty-four patients were escalated to 4-weekly dosing at 3 months.
During the 13 months of follow-up, 9 patients had adverse effects. The more frequent ones were fatigue in 3 patients (3%) and headache in 3 patients (3%). Ustekinumab treatment was discontinued in 15 patients (28%); this was due to a lack of efficacy in 8 patients (53%), loss of response in 5 patients (33%), recurrent respiratory tract infections in 1 patient (6.7%) and exacerbation of an associated chronic recurrent multifocal osteomyelitis in 1 patient (6.7%).
Fang et al (2023) conducted a systematic review evaluating the efficacy and safety of ustekinumab in paediatric IBD. Eleven studies were included, comprising 370 patients (n = 326 CD patients; n = 44 UC/IBD unspecified patients). Some of these studies were included in the original evidence report.
For CD, the pooled primary outcome of clinical remission rate reported in 6 studies was achieved by 34% (73/204) of patients (range 18.2 to 42.0%) at 8-16 weeks. For maintenance therapy, reported in 4 studies, the pooled remission rate was 46% (60/129) (range 30.3 to 66.67%) at 1 year. In UC patients, only one study reported the clinical remission rate which was 60% at 1 year. The corticosteroid (CS)-free clinical remission rates were 22.73% for CD (one study) and 24% (one study) for UC/IBD-U at 8–16 weeks. For maintenance treatment, the pooled CS-free clinical remission rate in CD patients reported in three studies at 1 year was 45% (42/96) (range 27.3% to 59.5%). These results are consistent with a real-world adult study (ENEIDA). In UC patients, the pooled CS-free clinical remission rate from two studies at 1 year was 46% (16/35) (range 44% to 50%). The differences in clinical response and remission rate should be interpreted with caution due to small patient numbers and variance in definition of response. From five studies, endoscopic remission and response ranged from 0–37.5% (0/5-3/8) and 9.1-100% (1/11 – 8/8) respectively in patients with CD. For UC, only one paediatric study with a small sample size reported an endoscopic improvement rate which was 63.6% (7/11) with median follow-up time of nearly 1 year. About one half (44.2%) of patients required reduction in dose interval and 62.75% of patients continued ustekinumab therapy at 1 year or until their final visit (week 8-16 or 26, depending on study). Ustekinumab was discontinued in 1.4% (5/370) of patients due to adverse events. Serious adverse events were reported in 3.5% (13/370) of patients. One patient had a suspected anaphylactic reaction to an intravenous re‑induction dose but tolerated subsequent subcutaneous doses in a monitored clinical setting.
Safety: Adverse events reported in the studies were consistent with those previously reported, most commonly respiratory tract infection, fatigue and headache. No new safety concerns with ustekinumab were identified. Outcome data provided by the tertiary centre in Cardiff reported no patients discontinuing treatment due to adverse events.
Cost-effectiveness: No relevant cost-effectiveness analyses were identified in the repeat literature search.
Budget impact: Thirteen patients have received treatment with ustekinumab over the last 12 months; twelve at the tertiary centre in Cardiff and Vale UHB and [confidential data removed]. Of these, nine commenced treatment prior to the availability of ustekinumab through the One Wales decision in March 2023; treatment before this would have been initiated following agreement through the Individual Patient Funding Request (IPFR) process. The actual number of patients who received treatment over the past 12 months is lower than the original estimate of 22 new patients per year.
The patent on Stelara® expires in Q1 2024, it is anticipated a number of suppliers will launch biosimilars in Q2 2024, this may reduce the treatment cost originally calculated in the last report.
Impact on health and social care services: Minimal.
Patient outcome data: Data have been provided for all thirteen patients. Eleven have been treated for CD, six patients currently remain on an 8-weekly dosing schedule and the remainder are receiving treatment every 4-6 weeks. [Confidential data removed]. The discontinuation rate is comparable to that used in the original submission although higher than that reported in a retrospective study in paediatric CD patients which estimates the probability of remaining on ustekinumab for 12 months to be 76.9%.
Evaluation of evidence: No significant new evidence has been published which challenges the current One Wales advice. The number of children on treatment is lower than the budget impact estimates used in the evidence summary report. Treatment is being tolerated. AWTTC recommends continuing access in Wales to ustekinumab for the treatment of inflammatory bowel disease in children and young people: for ulcerative colitis following loss of response, non-response or intolerance to anti-TNF therapies and vedolizumab; for Crohn’s disease following loss of response, non-response or intolerance to anti-TNF therapies.
Next review date: April 2026
References: a full reference list is available on request.
Disclaimer: This document includes evidence published since the last review or full assessment of this medicine for the indication under consideration. It does not replace the original full evidence status report. Any previous reviews and the original full evidence status report are available from this webpage in the document history section.
Care has been taken to ensure the information is accurate and complete at the time of publication. However, the All Wales Therapeutics and Toxicology Centre (AWTTC) do not make any guarantees to that effect. The information in this document is subject to review and may be updated or withdrawn at any time. AWTTC accept no liability in association with the use of its content. An Equality and Health Impact Assessment (EHIA) has been completed in relation to the One Wales policy and this found there to be a positive impact. Key actions have been identified and these can be found in the One Wales Policy EHIA document.
Information presented in this document can be reproduced using the following citation: All Wales Therapeutics & Toxicology Centre. One Wales Interim Decision. Ustekinumab for the treatment of inflammatory bowel disease in children and young people: for ulcerative colitis following loss of response, non-response or intolerance to anti-TNF therapies and vedolizumab; for Crohn’s disease following loss of response, non-response or intolerance to anti-TNF therapies (OW25). 2024
Medicine details |
|
| Medicine name | ustekinumab |
| One Wales decision status | Supported for use via the One Wales Medicines process |
| Reference number | OW25 |
| Decision issue date | February 2023 |
| Date of last review | April 2024 |
| Review schedule | Every 2 years |