CRC advice/reccommendations Translarna 2016

Summary

The Department of Health and Social Care provided the Clinical Recommendations Committee's 2016 advice regarding the funding of Translarna for Duchenne Muscular Dystrophy. The committee recommended the drug be classified as a low priority due to inadequate evidence for clinical and cost effectiveness.

Key Facts

• The CRC recommended Ataluren (Translarna) as a LOW PRIORITY for DHSC funding in May 2016.
• The decision was based on inadequate evidence for clinical and cost effectiveness given other resource demands.
• NICE proposed funding Ataluren within a managed access agreement, which the CRC noted reflected the current evidence base.
• Duchenne Muscular Dystrophy is a rare disorder affecting 1-9 per 100,000 people, with an estimated 1-4 cases on the Isle of Man.
• Approximately 15-30% of DMD cases are caused by a nonsense mutation, potentially affecting around one person on the Isle of Man.

Data Disclosed

• 12 May 2016
• 09th February 2017
• 10th February 2017
• 1-9 per 100,000
• 1 and 4 people
• 15-30%
• 30 years of age
• 5 years
• aged 5 or over

Data Tables (3)

Full Response Text

Department of Health and Social Care Rheynn Slaynt as Kiarail y Theay Page 1 of 2 FOIA/DHSC/13 REQUEST UNDER THE FREEDOM OF INFORMATION ACT 2015 (“the Act”) Thank you for your request dated 09th February 2017. You asked for: “Please provide details of all Clinical Recommendations Committee advice provided on the use of Translarna for the past year” Response to your request: We are pleased to be able to provide a response to your request with answers to your question. Please find enclosed the following document: ‘Ataluren (Translarna) for treating Duchenne Muscular Dystrophy with a nonsense mutation in the dystrophin gene’ Your right to request a review If you are unhappy with this response to your Freedom of Information request, you may ask us to carry out an internal review of the response, by completing a complaint form and submitting it electronically or by delivery/post to the FOI Co-ordinator, Department of Health & Social Care, Chief Executive’s Officer, Crookall House, Demesne Road, Douglas, Isle of Man, IM1 3QA.
An electronic version and paper version of our complaint form can be found by going to our website https://www.gov.im/about-the-government/freedom-of-information/how-to-make-a- freedom-of-information-request/ Chief Executive Malcolm Couch Department of Health & Social Care Chief Executive’s Office Crookall House Demesne Road Douglas Isle of Man, IM1 3QA Direct Dial No: (01624) 656071 Email: FOI.DHSC@gov.im Website: www.gov.im/dhss Date: 10th February 2017 FOI Reference:
IM77467I

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FOIA/DHSC/13 Your review request should explain why you are dissatisfied with this response, and should be made as soon as practicable. We will respond as soon as the review has been concluded.
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01. Whether we have responded to your request for information in accordance with Part of the Freedom of Information Act; or
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In response to an application for review, the Information Commissioner may, at any time, attempt to resolve a matter by negotiation, conciliation, mediation or another form of alternative dispute resolution and will have regard to any outcome of this in making any subsequent decision.
Further information about Freedom of Information requests can be found on the Information Commissioner’s website at: https://www.inforights.im/information-centre/freedom-of- information. Should you have any queries concerning this letter, please do not hesitate to contact us. Yours Sincerely

Freedom of Information Team Department of Health and Social Care

Isle of Man Department of Health and Social Care Clinical Recommendations Committee (CRC) Policy Recommendation: Ataluren (Translarna) for treating Duchenne muscular dystrophy with a nonsense mutation in the dystrophin gene. Date of CRC consideration: 12 May 2016 The CRC recommends that: Ataluren for treating Duchenne muscular dystrophy with a nonsense mutation in the dystrophin gene should be considered a LOW PRIORITY for DHSC funding. After careful consideration, CRC concluded that the evidence for clinical and cost effectiveness is currently inadequate to support funding as a priority given all other calls on DHSC resources. CRC noted that the NICE recommendation to fund ataluren within an extended clinical study reflects the current inadequate evidence base. CRC understood that DHSC would be able to access ataluren at the price agreed for the managed access scheme. However, CRC concluded that funding for what will effectively be a clinical study could not be a priority for DHSC within currently available resources. Summary of evidence considered by CRC • Duchenne Muscular Dystrophy (DMD) is a rare, X-linked recessive disorder that mainly affects males. • The prevalence is 1-9 per 100,000, meaning we would expect to have between 1 and 4 people on the Isle of Man with the condition. • About 15-30% of DMD cases are caused by a specific gene mutation (nonsense mutation).
Around one person on the Isle of Man with DMD might have this mutation. • DMD causes progressive muscle weakness from childhood. Patients eventually lose the ability to walk. The condition affects other body systems leading to death from respiratory or cardiac failure at around 30 years of age. • Ataluren is a new drug which can restore muscle protein synthesis in patients with nonsense mutation DMD. • Ataluren has been considered by NICE and a final evaluation document setting out NICE’s recommendation was published in April. NICE’s final recommendation (highly specialised technology guidance) will be published in May. • If NICE approves ataluren, it will be mandatory for NHS England to fund it for English patients. • NICE has no status on the Isle of Man but Manx patients are treated within English specialised services and so a policy is required. • NICE are proposing to recommend ataluren for nonsense mutation DMD within a managed access agreement with the manufacturers. The drug would be an option for all nonsense mutation DMD patients aged 5 or over who are able to walk. The price agreed with the company is confidential. The agreement will run for five years and be subject to evaluation of clinical outcomes. • Clinical Effectiveness: NICE considered two randomised controlled trials (studies 070 and 020). Both studies included patients who were fully able to walk and patients whose walking ability had already started to decline. The studies both lasted for 48 months. Analysis of the 1

effects of ataluren in the full study populations did not show any benefit from ataluren compared to placebo. Sub-group analysis of patients who were already in the decline phase at study entry showed that ataluren did slow further decline in walking compared to placebo. This slowing of decline was highly valued by patients and parents. • The duration of the studies was too short to demonstrate impact of ataluren on loss of walking (not just decline) or mortality. • In clinical practice, specialists would want to prescribe ataluren for all patients over 5 who can still walk (with the intention of preventing/delaying onset of decline), not just those whose walking is already declining. The evidence of benefit across this whole group is uncertain. • Cost effectiveness: because of the uncertainties around clinical effectiveness and the assumptions around clinical course, it is not possible to precisely estimate how many Quality Adjusted Life Years ataluren may give compared to best supportive care. Estimates of the number of QALYs gained range from 2.389 to 8.562. The costs agreed in the managed access scheme are confidential so we have no estimate of incremental cost per QALY at this price. The cost per incremental QALY gained at list price is around £1.18 million. • The average cost of treatment per patient per year at list price is around £250,000. • NICE considers the incremental cost per QALY under the managed access scheme is appropriate value for money for the NHS. However, they note that the cost per QALY is significantly greater than other drugs covered by Highly Specialised Technology Guidance and that there are considerable uncertainties around clinical benefits. • Therefore, the managed access scheme will run for 5 years at the end of which monitoring and outcomes data will be reviewed to inform revised policy (which could include withdrawing NHS funding). • We have confirmed that DHSC could access ataluren at the cost agreed by NHS England for the managed access scheme. This cost cannot be included in this document as it is confidential.
Reason for requesting a policy recommendation: NICE published a final evaluation determination (FED) document covering the use of ataluren in Duchenne Muscular dystrophy (DMD) with a nonsense mutation in the dystrophin gene on 15 April 2016. The document has been sent to consultees, who had until 3 May 2016 to consider whether they wished to appeal against the recommendations in the FED and/or notify NICE of any factual errors. Final guidance on the use of ataluren in the NHS in England is expected to be published in May 2016 (as Highly Specialised Technology Guidance which will be mandatory in England). NICE guidance has no status in the Isle of Man. However, many care pathways for Isle of Man patients include referral to English NHS centres in the North West of England – particularly for tertiary/specialised care, which, as in this case, is commissioned for English patients by NHS England.
These centres routinely follow NICE guidance for their English patients and questions about funding arrangements for Manx patients therefore arise. We are aware of one Manx patient who would potentially be eligible for ataluren under the NICE FED recommendation. Although a rare condition, the cost of treatment (c£250,000 per annum) takes consideration out of the remit of the Individual Funding Request Panel (rarity grounds) and a policy recommendation from CRC is required.

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Background: the NICE FED recommends that: Ataluren, within its marketing authorisation, is recommended for treating Duchenne muscular dystrophy resulting from a nonsense mutation in the dystrophin gene in people aged 5 years and older who can walk, only when: • The company provides ataluren with the discount agreed in the patient access scheme • The conditions under which ataluren is made available are set out in the managed access agreement between the company and NHS England, which should include the conditions set out in sections 5.12-5.15 of the FED (see Appendix 1– includes discussion of monitoring arrangements, exit strategy etc.). Brief description of the condition and intervention: DMD is a severe, progressive, X-linked recessive genetic disorder that mainly affects males. The nonsense mutation is a particular gene mutation causing DMD. Other mutations can also cause DMD – so not all patients with DMD have the nonsense mutation. Symptoms of DMD usually appear by 3 years of age. The main symptom is progressive motor weakness but as the disease progresses all systems (including the heart, respiratory system and gastrointestinal tract) are affected. Physical function gradually declines and respiratory and cardiac failure usually lead to death before the age of 30. DMD has a severe impact on quality and length of life and on parents and carers. Current treatment options are limited. Corticosteroids can delay loss of walking but with significant side effects. Treatment and care is mainly supportive. Ataluren is an innovative drug which restores dystrophin production by enabling the protein synthesis mechanism in human cells to overcome the nonsense mutation. It has a conditional marketing authorisation in the UK for treating DMD resulting from the nonsense mutation in patients aged 5 years and older who can walk. The drug cannot work in DMD patients without the nonsense mutation. The continuation of the marketing authorisation is linked to analysis of the results from a Phase III study (study 020) which the manufacturers are required to submit to the European Medicines Agency. Sources of evidence: FED published by NICE, April 2016. Clinical Effectiveness: The NICE evaluation committee considered two studies submitted by the manufacturer. The first, Study 007, was a double-blind randomised placebo-controlled trial including 174 male patients with nonsense mutation aged 5 years or older. Patients received ataluren or placebo for 48 weeks. The primary outcome measure was mean change in 6-minute walk distance (6MWD) from baseline to week 48. Secondary outcomes included measures of muscle function and quality of life. Intention-to-treat analysis (i.e. analysis of all patients who entered the trial) showed no statistically significant difference between groups in change in 6MWD. Results were reanalysed to exclude 2 patients who had lower limb injuries before the baseline test. The re- analysis showed a difference of 31.3m in favour of ataluren. In a mixed model for repeated measures, the estimated mean difference between ataluren and placebo was 31.7m (p=0.0197) in the group taking 40mg/kg ataluren. This difference was statistically significant. No effect was seen in the group taking 80mg/kg. There were no significant differences in quality of life. In post-hoc analysis of patients in the decline phase (80% or less of predicted 6MWD at baseline) and in patients 3

with a baseline 6MWD of less than 350m, there were statistically significant lower reductions in 6MWD in the ataluren group compared to the placebo group. The second study considered was a randomised double-blind placebo controlled confirmatory study, Study 020. This included 228 male patients with nonsense mutation aged between 7 and 16 years.
At baseline, patients had to have a 6MWD of more than 150m but 80% or less of that predicted for weight and height. Patients were randomised to ataluren or placebo for 48 weeks. The primary outcome measure was change in 6MWD from baseline to 48 weeks. Secondary measures included other function assessments, quality of life and activities of daily living. Intention to treat analysis showed a 15m difference in change in 6MWD favouring ataluren over placebo, which was not statistically significant. In the subgroup of patients with baseline 6MWD between 300-400m, there was a benefit of 47m for ataluren which was statistically significant (p=0.007). Meta-analysis of the results from studies 070 and 020 (i.e. analysis of the pooled results from the two studies) of the patients in the ambulatory decline phase or with baseline 6MWD of 300-400m, showed statistically significant differences in favour of ataluren at 48 weeks. Results for functional analyses from Study 020 did not show any significant differences in the intention-to-treat group but did show statistically significant benefits for patients with a baseline 6MWD of 300-400m. The company regarded as ‘commercial in confidence’ data on patients who lost their ability to walk and data on activities of daily living. These data are not included in the FED. In reviewing the evidence, the evaluation committee noted that the intention-to-treat populations in the two studies were not the optimal patient group for detecting a treatment effect over the comparatively short time frame of 48 weeks. The intention-to-treat groups (the whole study populations) would have included some patients who were stable and would not have shown a decline over 48 weeks regardless of treatment. The evaluation committee concluded that Study 020 showed a benefi

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