Omalizumab for previously treated chronic spontaneous urticaria

Clinical effectiveness

4.1 The Committee heard from the clinical and patient experts about the nature of the condition. It heard that chronic spontaneous urticaria is characterised by persistent itching, which can interfere with activities of daily living and sleep. The Committee heard from patient experts that severe chronic spontaneous urticaria can be unbearable, disabling, affect quality of life, result in patients being unable to work, and disrupt family interactions. The Committee heard how the disease can change the way a person looks, can make a person feel self‑conscious and can cause painful angioedema.

4.2 The Committee discussed the natural history and current management of chronic spontaneous urticaria. It heard from clinical experts that chronic spontaneous urticaria is a naturally remitting disease, that around 50% of patients have complete resolution of the symptoms within 6 months and that up to 90% of patients have complete resolution within 5 years. The Committee also heard that the duration of the disease does not predict the severity of the disease, but in patients who had the disease for years it was less likely to go into spontaneous remission. The Committee heard that H₁‑antihistamines are the standard first‑line treatment for chronic spontaneous urticaria, and are often used at up to 4 times the dose specified in the marketing authorisation. The Committee heard that, although certain H₁‑antihistamines are labelled as 'non‑sedating', patients often experience sleepiness. The Committee also heard that there is no licensed treatment option for patients whose disease does not respond to H₁‑antihistamines but, in practice, clinicians offer patients H₂‑antihistamines and leukotriene receptor antagonists (LTRAs). The Committee heard from the clinical experts that there is limited evidence on the effectiveness of H₂‑antihistamines in patients whose disease is non‑responsive to H₁‑antihistamines and the use of H₂‑antihistamines in clinical practice is decreasing. The Committee noted that a recent clinical guideline jointly issued by the European Academy of Allergy and Clinical Immunology, the Global Allergy and Asthma European Network, the European Dermatology Forum and the World Allergy Organization, referred to in the company's submission, does not recommend H₂‑antihistamines for treating chronic severe urticaria. The Committee heard that treating with LTRAs may help some, but not all, patients. The Committee took into account the comment received during consultation that H₂‑antihistamines are an out‑of‑date treatment for chronic spontaneous urticaria. It discussed the company's explanation for positioning omalizumab in a population whose disease had an inadequate response to H₂‑antihistamines and noted that the positioning was based on the inclusion criteria of the GLACIAL trial. The Committee also heard from the clinical and patient experts that patients with severe disease may need oral corticosteroids.

4.3 The Committee heard that patients with severe chronic spontaneous urticaria whose disease does not respond to the initial treatments are often offered immunosuppressants such as ciclosporin. The Committee heard that ciclosporin can be effective, but can also cause serious adverse effects. The Committee noted that ciclosporin may cause hypertension, hyperlipidaemia, and hepatic and renal impairment. The Committee also heard from a patient expert that she had gained weight, which she attributed to taking ciclosporin. The Committee further heard from the patient expert that ciclosporin helped relieve her symptoms such as itching and hives, but her overall health had declined because the treatment caused sleepiness, lethargy, and restricted her work and leisure activities. The Committee also heard from the clinical experts that, because of the risks of serious adverse effects, ciclosporin is reserved mainly for patients with severe chronic spontaneous urticaria. The experts estimated that approximately 70% of patients with severe urticaria take ciclosporin. The Committee also heard that patients who take ciclosporin need close monitoring of liver and renal function and therefore need frequent visits to GPs and hospitals.

4.4 The Committee discussed where omalizumab would fit in the treatment pathway of chronic spontaneous urticaria. The Committee heard from the clinical experts that the guideline recommends omalizumab at the same point in the pathway as immunosuppressants, such as ciclosporin. However, because of funding restrictions in the NHS, omalizumab is currently usually available only to patients in England whose condition does not respond to ciclosporin. The Committee heard from the clinical experts that they would offer patients omalizumab instead of ciclosporin because omalizumab is licensed for this condition, has a very good safety profile, and patients need less monitoring than with ciclosporin. The Committee heard from the patient and clinical experts that, when patients with severe disease take omalizumab, their disease improves rapidly within 1 to 2 weeks after the first dose and in many patients their symptoms resolve completely. The Committee heard that patients taking omalizumab can often stop taking other drugs such as H₁‑antihistamines, H₂‑antihistamines, LTRAs and corticosteroids. The Committee heard that omalizumab controls symptoms, but is not 'disease‑modifying'; in most patients, the condition relapses within 4 to 6 weeks of stopping omalizumab and patients need treating again. The Committee noted the consultation comment that, because of funding restrictions, clinical experience with omalizumab in England is from a population whose disease has not responded to immunosuppressants and which is more difficult to treat than the population considered in the decision problem.

4.5 The Committee discussed the company's decision problem, noting that the company had chosen a narrower population than the population specified in its marketing authorisation and the NICE scope. The company positioned omalizumab for use after standard treatment with H₁‑antihistamines (up to 4 times the licensed dose), with LTRAs and H₂‑antihistamines, whereas the scope and marketing authorisation specified using omalizumab after an inadequate response to H₁‑antihistamines. Based on what the clinical experts said about when omalizumab would be used in clinical practice in England (see section 4.4), the Committee concluded that the company had targeted omalizumab at a clinically appropriate population and that omalizumab could be considered as a third‑ or fourth‑line option in the pathway, in the same place as immunosuppressants. The Committee noted that the company had not provided analyses using immunosuppressants (such as ciclosporin, mycophenolate mofetil or methotrexate) as comparators for omalizumab, even though they had been listed as comparators in the final scope for this appraisal. The Committee noted that, in its submission, the company had agreed that immunosuppressants (particularly ciclosporin), although used off‑label, are appropriate comparators for omalizumab and provided a summary of the evidence on their effectiveness. The Committee noted both the company's and the Evidence Review Group's (ERG's) comments that the evidence from randomised trials on the effectiveness of ciclosporin in chronic spontaneous urticaria is very limited, and did not allow for a robust indirect comparison with omalizumab. The Committee concluded that ciclosporin was an appropriate comparator in this appraisal but understood that, because of the lack of robust clinical evidence, no formal comparison could be made.

4.6 The Committee considered the evidence on the clinical effectiveness of omalizumab, noting that the company included evidence from a single phase III trial, GLACIAL. It noted that the company included 2 more phase III trials, ASTERIA I and ASTERIA II, as supporting evidence. The Committee noted that the GLACIAL trial was primarily a safety trial, although it heard from the company that it was powered for efficacy. The Committee questioned why the main efficacy studies, ASTERIA I and ASTERIA II, were not included by the company in its main analyses. It heard from the company that the ASTERIA trials included patients on licensed doses of H₁‑antihistamines, and only a small proportion of the trial populations took higher doses of H₁‑antihistamines or H₂‑antihistamines. The Committee noted that the patients in the GLACIAL trial had chronic spontaneous urticaria for several years and reflected the patients that clinicians in England would treat with omalizumab. The Committee agreed that the patients in the GLACIAL trial were similar to those who would be offered omalizumab, and concluded that the results from the GLACIAL trial were generalisable to clinical practice in England.

4.7 The Committee discussed whether the outcome measures used in the GLACIAL trial were meaningful and considered whether they were used in clinical practice. The Committee noted that the primary efficacy outcome, weekly itch severity score, and the outcome used in the model to capture clinical effectiveness, urticaria activity score over 7 days (UAS7), do not take into account many other aspects that are important to patients with chronic spontaneous urticaria, such as pain, red skin and angioedema. The Committee heard from the patient expert that she had never been asked to score her disease with the measures used in the clinical trials. The Committee heard from a clinical expert that the measures, particularly those measuring health‑related quality of life, are useful and should be used by clinicians. The Committee also heard that patients are currently often required to complete several of the outcome measures when applying for funding for omalizumab. In general, however, clinicians do not consider these measures key in choosing who to treat, or when to continue treating, with omalizumab. The Committee concluded that, although the measures had limitations, the outcomes in the trials were relevant for this appraisal.

4.8 The Committee discussed the results of the clinical trials. It noted that omalizumab was associated with statistically better outcomes compared with placebo in most of the clinical and quality‑of‑life outcome measures. The Committee noted that, in the GLACIAL trial, the mean weekly itch severity score rapidly decreased after the first dose of omalizumab and stayed lower with omalizumab than with placebo throughout the 24‑week treatment period. The Committee noted that patients in the placebo arm had lower weekly itch severity scores compared with the baseline. It heard from the clinical experts that this could be because of increased use of the rescue medication, diphenhydramine, in the patients randomised to placebo. The Committee also noted that, in the GLACIAL trial, the weekly itch severity score for patients randomised to omalizumab increased after stopping treatment at 24 weeks and reached the same level as for patients on placebo at week 40. The Committee noted that this quick onset and offset of effectiveness was consistent with what it had heard about the clinical experts' experience of using omalizumab in clinical practice. The Committee also noted that omalizumab increased angioedema‑free days and improved sleep. The Committee also considered the meta‑analysis of the GLACIAL and ASTERIA I and II trials done by the ERG, thereby including a wider population, and noted there was little difference between these results and those using analyses from the GLACIAL trial only. The Committee concluded that omalizumab improves symptoms in chronic spontaneous urticaria.

4.9 The Committee discussed how long patients are treated with omalizumab in England, and whether clinicians apply 'stopping rules'. The Committee discussed this separately for patients who benefit from omalizumab ('responders') and for those who do not ('non‑responders'). It noted that the summary of product characteristics for omalizumab does not specify treatment duration or any stopping rules, but states 'prescribers are advised to periodically reassess the need for continued therapy' and 'clinical trial experience of long‑term treatment beyond 6 months in this indication is limited'. The Committee heard from the clinical experts that they would stop treatment after a course of 6 doses to see if a patient's disease had gone into spontaneous remission. The Committee noted that, for patients whose disease does not respond to omalizumab, the company assumed that they would stop treatment at 16 weeks. The Committee heard from the clinical experts that it is usually clear much earlier (after the first 2 doses) whether a patient will have a response to omalizumab. The clinicians noted that, nonetheless, patients are usually offered 4 doses. The Committee noted the new evidence submitted by the company in response to consultation, which suggested that a large proportion of patients have a response after the first dose and the proportion of 'responders' continues to increase with each subsequent dose up to 4 doses, and that few additional patients had a response after 4 doses (see section 3.59). The Committee concluded that most patients who are going to have a response will do so by the fourth dose, and that it is appropriate that clinicians consider stopping omalizumab at or before the fourth dose if there is no response.

4.10 The Committee considered the safety data for omalizumab. It noted that, in all 3 clinical trials, adverse events in the omalizumab arm and placebo arm were comparable. The Committee noted that, because of a risk of anaphylaxis immediately after administering omalizumab, the advice in the summary of product characteristics is that treatment for anaphylactic reactions should always be available during omalizumab treatment. The Committee understood from the clinical experts that anaphylaxis is very rare and the risk decreases with each dose, but that precautionary measures are needed, and that generally omalizumab is given at centres with resuscitation facilities.

Cost effectiveness

4.11 The Committee considered the company's economic model, the assumptions on which the company based its choice of model parameters, the revised analyses presented in response to consultation on the draft guidance, and the critique and exploratory analyses performed by the ERG. The Committee noted that, to capture the clinical effectiveness of omalizumab, the company did not model relative risk but instead used individual patient data from the GLACIAL trial to estimate the proportions of patients in each health state at any given time. The Committee noted that relatively small changes in symptoms could lead to a change in health state and, conversely, patients can remain in the same health state despite relatively large changes in symptoms. The Committee noted that the model compared omalizumab only with no further pharmacological treatment, and not with other relevant comparators such as ciclosporin. Noting that such comparisons were not possible, the Committee accepted the company's choice of comparator, but noted uncertainty around some of the assumptions used in the model.

4.12 The Committee was concerned about how the company had defined treatment response in the original model in which the company had defined response as achieving an absolute level of UAS7 of 6 or less and the definition did not take into account the baseline (pre‑treatment) UAS7. The Committee noted that the revised model maintained the original definition of response for patients with moderate disease at baseline, whereas, for patients with severe urticaria at baseline, the company applied the revised definition of a UAS7 of 16 or less. The Committee noted the ERG's comment that the revised definition may still not identify all patients who have a clinically significant response. The ERG would have preferred the definition of response to reflect an absolute decrease of 10 points or more on the UAS7 scale, in line with clinical opinion. The Committee understood that, given the structure of the model, it was not possible to implement response as an absolute decrement in UAS7. The Committee accepted that the revised definition of response is closer to how clinicians would consider a response than the original definition, but was aware that it may not capture all 'responders'.

4.13 The Committee discussed the probability of a patient's disease relapsing as estimated in the model by first focusing on the cumulative relapse rate seen in the GLACIAL trial. The Committee understood that the company calculated the relapse rate separately for patients in the mild urticaria, well‑controlled urticaria and urticaria‑free health states using the proportion of patients in each state and the relapse rates seen in the GLACIAL trial up to the end of the observational follow‑up period (40 weeks). The Committee noted that the revised cumulative proportion of patients whose disease relapses at 40 weeks in the GLACIAL trial (16 weeks after the end of treatment), after accounting for patients whose disease goes into spontaneous remission, ranged from around 49% (for well‑controlled urticaria) to around 62% (for urticaria‑free and mild urticaria). Based on the clinical experts' opinion, the Committee had expected the cumulative relapse rate at 16 weeks to be close to 100%. The Committee noted the consultation comment that the difference may reflect that, compared with the trial patients, patients in England who have had omalizumab to date reflect a population whose disease is refractory and has not responded to immunosuppressants (see section 4.4). The Committee concluded that, in the NHS, patients who would have omalizumab before having immunosuppressants may have a longer relapse‑free period and the probabilities for relapse estimated in the revised model for the immediate post‑treatment period are therefore plausible.

4.14 In addition to discussing relapse in the immediate post‑treatment period, the Committee discussed the company's original and revised approaches to extrapolating the probability of relapse over the 10‑year time horizon. The Committee noted that, in the original analyses, when extrapolating relapse data after the 16‑week post‑intervention observational follow‑up period in the GLACIAL trial, both the company and the ERG assumed that the disease relapses by 64 weeks in all patients who had a response to omalizumab. The Committee noted that this assumption was based on an observational study (Metz et al. 2014), which reported the times to relapse for patients who had previously had omalizumab. The Committee noted that the Metz et al. study reported 64 weeks as the longest relapse‑free period, and most for patients in the study the relapse‑free period was between 4 and 8 weeks. On the Committee's request, the company used a linear function in its revised model to extrapolate relapse that decreased the time to relapse for all 'responders' (see section 3.49). The Committee noted the company's comment received in response to consultation that using a linear extrapolation underestimated the time to relapse when omalizumab is used in a population whose disease has an inadequate response to standard treatment with H₁‑antihistamines including high doses, or to LTRAs with or without H₂‑antihistamines. The Committee recalled the clinical testimony about quick relapse after stopping omalizumab and also noted that cumulative relapse rates available from the post‑treatment period of the GLACIAL trial showed a linear trend. Therefore, the Committee did not accept the company's view that linear extrapolation is a 'worst‑case' scenario. The Committee concluded that, because of a lack of robust evidence, long‑term relapse rates used in the model were uncertain and linearly extrapolating relapse data from the GLACIAL trial was the most plausible scenario.

4.15 The Committee discussed modelling spontaneous remission. The Committee noted that the company's original approach predicted an improbably high median duration of disease (20.8 years), whereas it heard from the clinical experts that spontaneous remission occurs in approximately 90% of patients within 5 years. The Committee noted that the ERG's approach (see section 3.44) predicted a median duration of disease of 6 to 7 years, which was also higher than that expected by clinicians. The Committee was aware that the company, in its original model, used incorrectly reported data from the text of the publication by Nebiolo et al. (2009) whereas the ERG used the data derived from the correctly‑reported Kaplan–Meier curves in the same publication. The Committee was satisfied that the company acknowledged its error, and concluded that the company had used the correct data in its revised base case.

4.16 The Committee noted that the company based the utility values in the model on the pooled EQ‑5D scores collected in the GLACIAL, ASTERIA I and ASTERIA II trials. The Committee noted that the utility value used for the severe health state was 0.712 and discussed whether this was too high. The Committee heard from the patient expert that severe disease is considerably disabling, affecting her all day long, every day and felt this figure should be much lower. The Committee questioned whether the high value might reflect the wide range of UAS7 values (28 to 42) used by the company to define the severe health state. Following consultation, the Committee noted that the average UAS7 value for patients with severe disease was 34.1, which was close to the midpoint of the range used to define the severe health state. The Committee therefore concluded that this did not explain the apparent high utility value for the severe health state. The Committee then discussed whether the EQ‑5D, reflecting pain but perhaps not all other features of urticaria (such as change in appearance, red skin) would capture the true disutility associated with chronic urticaria. It concluded that some aspects of the quality‑of‑life impact may not be included in the EQ‑5D.

4.17 The Committee noted that the company assumed that patients whose disease responded to the first course (6 doses, after which the patient stops regardless of response) of omalizumab and then relapsed could have an unlimited number of further courses of omalizumab. The Committee noted that there was limited evidence on the effectiveness of repeat courses of omalizumab and heard from the clinical experts that, in their experience, re‑treating with omalizumab was effective. The Committee noted the comments by the company, received in response to consultation, that published observational studies, the pharmacokinetics of omalizumab and experience with omalizumab in severe persistent asthma supported an assumption that the treatment effect is maintained on repeated courses. The Committee concluded that the evidence available to date does not support a waning effect on subsequent repeated courses of omalizumab and therefore it is reasonable to assume a constant effect.

4.18 The Committee discussed the model validation exercise submitted by the company in response to the Committee's request. The Committee noted that, for patients having omalizumab, the model accurately predicted the proportions of patients in the 'responder' health states as per the original definition of response (a UAS7 of 6 or less) at week 40 as seen in the GLACIAL trial. However, it noted that the model underestimated the response in the comparator 'no further pharmacological treatment' arm. The Committee heard from the company that the model incorporated data from the GLACIAL trial only for the first 24 weeks after starting therapy for the first time but, unlike the GLACIAL trial, modelled patients in the base‑case analysis could relapse and be re‑treated between 24 and 40 weeks after first starting therapy. The Committee was not convinced that re‑treatment in the omalizumab arm would result in a lower proportion of 'responders' in the comparator arm. The Committee concluded that there were major concerns about the model in that the modelled data from the trial for the placebo arm seemed to overestimate the effectiveness of omalizumab.

4.19 The Committee noted that, in the company's revised base‑case analysis for the combined population with moderate and severe disease, the incremental cost‑effectiveness ratio (ICER) was approximately £28,000 per quality‑adjusted life year (QALY) gained. The Committee agreed that there was some uncertainty around the results of the model particularly because it underestimated the response in patients in the comparator 'no further pharmacological treatment' arm of the trial (see section 4.18). Because of this, the Committee concluded that the resulting ICERs generated by the company's cost‑effectiveness model were likely to underestimate the true ICER. Therefore, the Committee concluded that omalizumab as an add‑on therapy for treating chronic spontaneous urticaria in adults and young people aged 12 years and over could not be considered a cost‑effective use of NHS resources.

4.20 Having concluded that the company's revised base case underestimated the ICER and that omalizumab was not a cost‑effective option for the combined population with moderate or severe urticaria at baseline, the Committee discussed whether there are any other factors not reflected in the analyses that could affect the ICERs. The Committee noted that the model did not account for using fewer concomitant medications (such as H₁‑antihistamines, LTRAs and H₂‑antihistamines) or rescue treatments (such as corticosteroids), and taking these into account would decrease the ICER. The Committee also noted that, because of a cycle length of 4 weeks, the model did not fully capture the rapid relief of symptoms patients experience during the initial weeks after starting omalizumab. The Committee considered that omalizumab may relieve symptoms, such as poor sleep, which is not adequately captured in the quality‑of‑life measures. The Committee agreed that incorporating these effects would decrease the ICER further. However, the Committee was also aware that there are certain other factors that could increase the estimated ICER, for example, continuing omalizumab beyond 2 doses in patients whose disease was not responding to omalizumab.

4.21 The Committee discussed whether omalizumab was innovative, and whether the economic analysis had captured all changes in health‑related quality of life. The Committee acknowledged that most people who receive omalizumab experience a dramatic and rapid improvement. The Committee also acknowledged the 'immunosuppressant‑sparing' effect of omalizumab, that is, eliminating or reducing the need for immunosuppressant treatment for severe urticaria. The Committee recognised the limitations of current treatments in terms of their off‑label use, adverse effects and requirements for additional monitoring, and agreed that omalizumab, with a better adverse‑effect profile and apparent rapid mode of action, could be considered innovative, and that many beneficial effects of omalizumab were not fully captured in the estimation of health‑related quality of life.

4.22 The Committee discussed the clinical testimony, consultation comments and views of patient experts about unmet need in patients with severe chronic spontaneous urticaria. The Committee noted that, for patients with severe disease at baseline, the revised base‑case ICER was lower than that for the combined (moderate and severe) disease and was around £26,000 per QALY gained. However, the Committee noted that the utility value underestimated the severity of disease in the model (see section 4.16), and that a more realistic value for severe disease would likely increase the incremental QALY gain and decrease the ICER to below £26,000 per QALY. The Committee also considered that patients with severe disease are presently treated with immunosuppressants, which have many adverse effects on patients' general health. The Committee was aware that, for patients with severe urticaria, the benefit of avoiding the side effects of immunosuppressant treatment was not accounted for in the analyses available and, considering the lifelong nature of these effects, the actual ICER for treating severe disease may decrease even further. Considering all these factors together, the Committee was persuaded that omalizumab could be considered to be a cost‑effective use of NHS resources only for patients who have severe urticaria, providing that treatment was not continued beyond a maximum of 4 doses for patients whose disease has not responded to treatment. The Committee also recommended that, for patients whose disease responds, clinicians stop omalizumab after 6 doses to check whether the disease has remitted. The Committee understood that the marketing authorisation for omalizumab specified treatment to be 'initiated by physicians experienced in the diagnosis and treatment of severe chronic spontaneous urticaria', but it agreed that omalizumab should be administered only under the management of a secondary care specialist in dermatology, immunology or allergy. The Committee therefore concluded that omalizumab is recommended as an add‑on therapy for treating severe chronic spontaneous urticaria in adults and young people aged 12 years and over only if:

4.23 The Committee also highlighted, given the lack of long‑term data in this area, the importance of establishing registries to collect data on long‑term outcomes in patients who receive omalizumab for chronic spontaneous urticaria.

4.24 The Committee discussed whether any equality issues needed consideration. It heard that, because of the risk of anaphylaxis, omalizumab could only be given under medical supervision. The Committee noted that people with physical disabilities or who live far from a treatment centre may therefore have limited access to the technology. The Committee noted that some centres provide transport for patients and, in some situations, community nurses administer omalizumab to patients at home. The Committee concluded that this is an issue of implementation rather than of equality. The Committee also heard that the summary of product characteristics advises that omalizumab should be administered with caution in people who have kidney or liver disease, as is already done for ciclosporin. The Committee concluded that this is a clinical and not an equality issue. The Committee also heard that chronic spontaneous urticaria is more prevalent in women and in the 20 to 40 year age group. However, the Committee concluded that it had not seen any evidence that its recommendation disadvantages women or people between the age of 20 and 40 years.