Dinutuximab Beta for Treating Neuroblastoma: An Evidence Review Group and Decision Support Unit Perspective of a NICE Single Technology Appraisal.

As part of its Single Technology Appraisal (STA) process, the UK National Institute for Health and Care Excellence (NICE) invited the manufacturer (EUSA Pharma) of dinutuximab beta (Qarziba®) to submit evidence of its clinical and cost effectiveness for treating neuroblastoma. The BMJ Technology Assessment Group (BMJ-TAG) was commissioned to act as the Evidence Review Group (ERG), reviewing the submission from the company. The Decision Support Unit (DSU) was commissioned to review additional evidence submitted by the company and to undertake further analyses. This article presents the critical review of the company's submissions by the ERG and DSU, further analyses undertaken by the DSU, and the outcome of the NICE guidance. The clinical effectiveness for dinutuximab beta was derived from a phase III randomised controlled trial (RCT) that assessed the safety and efficacy of the addition of interleukin (IL)-2 to dinutuximab beta plus isotretinoin. This trial did not inform the relative effectiveness of dinutuximab beta versus isotretinoin alone, which was established practice in the UK for maintenance treatment. In the absence of direct evidence, the company initially conducted a naïve indirect treatment comparison against a historical control, and later performed a matching-adjusted indirect comparison (MAIC) against the isotretinoin arm of an RCT comparing dinutuximab alpha and isotretinoin. The company submitted a partitioned survival analysis model that calculated the incremental cost effectiveness of dinutuximab beta versus isotretinoin. The company's original incremental cost-effectiveness ratio (ICER) was £22,338 per quality-adjusted life-year (QALY) gained. However, the ERG were concerned that the company's ICER was not suitable for decision making, and thus carried out initial exploratory analysis as a first step to overcome the naïve estimation of treatment effectiveness in the model. The ERG's analysis estimated an ICER of £111,858 per QALY gained. In their revised analysis incorporating the MAIC and other changes as requested by the appraisal committee, the company's ICER was £24,661 per QALY gained. When the DSU incorporated longer-term isotretinoin data and made corrections to the model, the ICER increased to between £62,886 and £87,164 per QALY gained depending on the choice of survival model. A confidential Patient Access Scheme (PAS) decreased the ICERs. The ICERs with the PAS were over £40,000 per QALY gained, but the NICE committee additionally considered the patient population and its size, the disease severity, the potential for significant survival benefit and uncaptured health benefits, and recommended dinutuximab beta as a treatment option, subject to the company providing the agreed discount in the PAS.

Cost of Medications Recommended by Canadian Acne Clinical Practice Guidelines.

BACKGROUND: Acne affects a large proportion of the Canadian population and has psychosocial and financial consequences. OBJECTIVE: We provide cost information for treatments recommended by the Canadian acne guidelines. METHODS: Highest level recommendations were selected for 3-month usage cost. RESULTS: Three-month estimated treatment costs were as follows: topical retinoids ($14.40-$73.80), benzoyl peroxide (BPO; $6.75), fixed-dose BPO-clindamycin ($40.95-$44.10) and BPO-adapalene ($73.80), oral antibiotics ($25.20 for tetracycline 250 mg qid; $52.20 and $52.74 for doxycycline 50 mg bid and 100 mg od, respectively), and hormonal therapy ($26.46-$37.80 for ethinyl estradiol [EE] 0.030 mg/drospirenone 3mg and $75.60-108.99 for EE 0.035 mg/cyproterone acetate 2 mg). Oral isotretinoin 3-month costs ranged from $393.96 to $478.80. CONCLUSIONS: Awareness of costs of recommended treatments may facilitate improved outcomes by increasing procurement and adherence.

Usage and equity of access to isotretinoin in New Zealand by deprivation and ethnicity.

AIMS: Oral isotretinoin, for severe acne, was until March 2009 fully funded in New Zealand only if the prescription was written by a vocationally registered dermatologist. This funding restriction was argued on the basis of complexity of management and an appreciable risk of teratogenicity if given during pregnancy or within a month of conception. However, this funding restriction had the potential to create inequitable access barriers. This study was an audit examining the use of isotretinoin by deprivation level and ethnicity, in order to examine potential inequities in use. METHOD: Dispensed prescription data for funded isotretinoin, for the year ending June 2008, held in a national repository was analysed using simple descriptive methods based on ethnicity and deprivation level. The same analysis was carried out for cyproterone acetate with ethinyloestradiol, another acne pharmaceutical available on prescription with no funding restrictions. There was demographic data on 60% of prescriptions based on the health identification number NHI. RESULTS: People living in more deprived areas (as defined by NZDep Index) were less likely to use isotretinoin, as were Maori and Pacific people. The association with deprivation level was not present for cyproterone acetate with ethinyloestradiol, although disparities in use by ethnicity remained. CONCLUSIONS: Given there is no evidence for lower rates of acne for Maori and Pacific people, the reasons may include financial and other barriers.

Management of acne.

Precise classification methods are used to define acne according to type (comedonal, papulopustular, or nodular) and severity. The relative effectiveness of several topical and systemic agents has been established in clinical trials, making possible an algorithm of specific treatment decisions based on acne classification.

Low-dose schema of isotretinoin in acne vulgaris.

In severe papulopustular and in nodulocystic/conglobate acne, oral isotretinoin is the treatment of choice. It is also required for patients with moderate to severe acne, especially when acne scars start to occur A new therapeutic approach consists of a low-dose regimen of isotretinoin. We performed a comparative study of high- and low-dose schemas of isotretinoin per os for the treatment of acne. The purpose of this study was to assess the therapeutic effect and tolerability of low doses of isotretinoin in the treatment of acne vulgaris and compare low-dose with high-dose regimens. Sixty-four patients (35 women and 29 men) with different types and grades of acne vulgaris were divided into two treatment groups of 32 patients, in a trial that compared a low dose of 0.15-0.40 mg/kg per day with a high dose of 0.5-1.0 mg/kg per day. These regimens were analyzed with reference to clinical history of acne, baseline investigations, dose and response to isotretinoin, clinical and laboratory adverse effects, relapses and cost of therapy. The mean success rate of the low-dose schema was 69%. The total dose up to 120 mg/kg should be followed for optimal results (success rate of 91%) and avoidance of relapses. The low-dose schema produced fewer adverse effects and offered a very beneficial effect on pre-existing scarring. Our results confirm the beneficial effect of the low-dose schema. We recommend a total dose > or = 120 mg/kg, as this therapeutic regimen of isotretinoin has proven to be the most successful in preventing relapses and scarring.

The cost-effectiveness of isotretinoin in the treatment of acne. Part 1. A meta-analysis of effectiveness literature.

OBJECTIVES: This paper reports the results of a meta-analysis of isotretinoin treatment in moderate to severe acne. It forms part of a comprehensive investigation into the cost-effective treatment of acne in South Africa and as such establishes the clinical foundation for an economic model of acne management. This foundation includes an evaluation of the daily dosages, treatment durations, success rates, clinical effectiveness and relapse rates reported in published trials since 1981. METHODOLOGY: A predetermined protocol for the study established the scope, appropriate inclusion and exclusion criteria for peer-reviewed data, and the statistical rigour that would be applied to the selected data. Following an extensive literature search, data reflecting the effectiveness of isotretinoin were extracted, statistically assessed, described and reported. The combinability of the data was confirmed using analyses of variance and chi-square tests, as applicable. RESULTS: Isotretinoin consistently proved to be a highly effective agent in the treatment of moderate to severe acne vulgaris. The response rate determined by the meta-analysis indicated a clinical cure in 84.22% to 86.71% of patients treated. From the data considered, the average treatment duration was calculated to be 17.9 weeks (4 months). The relapse rate was low (21.45%) and dose-dependent. Optimal results were achieved by treating patients with a daily dose of 1 mg/kg and treating to a target cumulative dose of 120 mg/kg over the treatment duration. CONCLUSION: The results of this meta-analysis support the continued use of isotretinoin in the treatment of acne. The results are important in the field of pharmaceutical benefit management where they will assist in the optimal management of this health condition. The results will be used to develop a pharmaco-economic model to evaluate the various treatment regimens used for acne in South Africa.

The cost-effectiveness of isotretinoin in the treatment of acne. Part 2. A chronic medication plan profiling study.

OBJECTIVES: Aspects of current clinical practice, needed for a pharmaco-economic model of isotretinoin, were determined from an acne-profiling study on chronic medication plan data. The patient sample was analysed as a whole and as two subgroups, representing isotretinoin and oral antibiotic patients. The study focused on the prevalence of the condition, patient age and gender distributions, and pharmacotherapeutic patterns and costs. METHODOLOGY: Anonymous patient records from the Pharmaceutical Benefit Management (Pty) Ltd, Cape Town, chronic medication plan were screened and analysed using descriptive and inferential statistical methods. For all hypothesis tests, the significance level (alpha) was set a priori at 5% (0.05). In order to determine the distribution of costs among patient groups, cost-concentration curves were constructed. RESULTS: A total of 5,198 patient records were analysed, representing 3,546 acne patients (2.7% of applicants to the plan). The majority of patients were female (72.2%, median age 23 years), with male patients treated at a younger age (median age 19 years). The cyproterone/oestrogen combination was found to be the most frequently prescribed agent (25.2% of script items), followed by isotretinoin (15.6%). The oral antibiotics as a group accounted for 24.9% of script items, the leading agents being minocycline (10.1%) and doxycycline (7.1%). Isotretinoin (44.1%) represented the greatest expense, followed by hormonal therapies (24.7%) and oral antibiotics (16.7%). Female isotretinoin patients (55.1%) were older (median age 25 years), while the male patients were of an equivalent age to the collective sample. Patients treated with oral antibiotics represented the youngest group of patients (median age 20 years), with 57.8% being female. The annual pharmacotherapy expense per patient on oral antibiotics was R1 971.81 compared with R2 670.20 for all patients, and R6 140.81 for the isotretinoin group. For each of these groups there was an uneven cost distribution among patients. CONCLUSION: The treatment of acne represents a significant burden to funders, estimated at R7.2 million per 100,000 beneficiaries. The distinct age and gender distribution patterns, together with the uneven distribution of costs among patients, provide valuable information for the treatment and management of the condition. This information indicates that the introduction of clinically based, focused management principles supported by sound pharmaco-economic arguments will be required to manage acne effectively.

The cost-effectiveness of isotretinoin in the treatment of acne. Part 3. A cost-minimisation pharmaco-economic model.

OBJECTIVES: The cost-effectiveness of systemic isotretinoin therapy in the treatment of moderate to severe acne was assessed in a comparative cost-minimisation analysis. Systemic isotretinoin at the recommended daily dose of 1 mg/kg (cumulative dose of 120 mg/kg) was compared with: (i) oral antibiotics taken as chronic medication; (ii) a combination of chronic oral antibiotics and anti-androgen therapy; and (iii) isotretinoin prescribed only after two failed courses of oral antibiotics, as per South African guidelines. The perspective taken was that of the funder of health care, and the resources used were funder charges as a proxy for costs. METHODOLOGY: Statistical and epidemiological data as well as relevant costs from the previously reported meta-analysis and profiling study for acne therapy were used as the clinical basis for the construction of a cost-minimisation model. Additional costs were sourced from published pharmaceutical retail prices and professional rates. The South African treatment guidelines were used to define the frequencies associated with physician visits and pathology testing. Standard statistical methods were applied, as appropriate. From the above, a modified Markov process was used to model the costs associated with the four comparator treatment regimens over a period of 120 months. Suitable clinical and economic endpoints were defined so that comparison could be made between regimens. RESULTS: Assuming a relapse rate of 21.45%, it was found that isotretinoin therapy compares favourably with the other regimens. After 50 and 35 months, systemic isotretinoin cumulative costs were less than those incurred in oral antibiotic and oral antibiotic/anti-androgen therapy, respectively. For the stepped therapy of oral antibiotics followed by systemic isotretinoin, these break-even periods were 56 and 39 months, respectively. The cost per successfully treated patient receiving isotretinoin was R8941. This compares well with the cost for those patients receiving chronic oral antibiotics, which after 5 years amounted to R10 428 per patient. Sensitivity analyses proved these findings to be robust to variations in the isotretinoin relapse rate, and the cost of oral antibiotic therapy and the concomitant use of topical therapies. CONCLUSION: From the cost-minimisation model it is clear that where systemic isotretinoin is clinically indicated, the sooner such therapy is initiated the more cost-effective the outcome will be. If isotretinoin is prescribed on diagnosis of moderate to severe acne, then the cost of treatment is significantly reduced in the long term when compared with standard chronic oral antibiotic therapy.

How cost-effective is oral isotretinoin?

PURPOSE: To consider whether oral isotretinoin (Roaccutane/Accutane) represents good value compared with typical alternative treatments for moderate or severe acne. PROCEDURES: Published reports were reviewed on the comparative effectiveness of oral isotretinoin and its alternatives and on their relative costs. RESULTS: Observational studies of clinical and patient-assessed outcomes suggest that oral isotretinoin is much more effective than available alternatives. The costs of treatment with isotretinoin are greater in the first year, but substantial cost savings accrue in subsequent years. CONCLUSIONS: Isotretinoin is more cost-effective than long-term antibiotic therapy mainly because of its greater efficacy but also because of long-term cost savings. MESSAGE: The costs and benefits of alternative treatments for acne should be assessed over a period of at least 2 years, preferably longer. The higher initial cost of oral isotretinoin should not be a barrier to its use where the drug is clinically indicated.

Roaccutane treatment guidelines: results of an international survey.

BACKGROUND: Oral isotretinoin (Roaccutane) revolutionized the treatment of acne when it was introduced in 1982. METHODS: Twelve dermatologists from several countries with a special interest in acne treatment met to formally review the survey of their last 100 acne patients treated with oral isotretinoin. The primary purpose of the survey was to identify the types of acne patients who were prescribed oral isotretinoin and how the patients were managed. RESULTS: Of the 1,000 patients reviewed, 55% of those who received oral isotretinoin had those indications treated historically, i.e. severe nodular cystic acne or severe inflammatory acne, not responding to conventional treatment. Forty-five percent of patients who were prescribed oral isotretinoin however had either moderate or mild acne. Most patients in this group had moderate acne (85%). However, 7.3% had mild acne on physical examination. The criteria for prescribing oral isotretinoin in this less severe group of patients included acne that improves < 50% after 6 months of conventional oral antibiotic and topical combination therapy, acne that scars, acne that induces psychological distress and acne that significantly relapses during or quickly after conventional therapy. Treatment is usually initiated at daily doses of 0.5 mg/kg (but may be higher) and is increased to 1.0 mg/kg. Most of the physicians aimed to achieve a cumulative dose of > 100-120 mg/kg. Mucocutaneous side-effects occur frequently but are manageable while severe systemic side-effects are rarely problematic (2%). The teratogenicity of oral isotretinoin demands responsible consideration by both female patients and their physicians. Significant cost savings when treating acne patients with oral isotretinoin as compared to other treatment modalities were further proven in this study. CONCLUSIONS: Our recommendation is that oral isotretinoin should be prescribed not only to patients with severe disease but also to patients with less severe acne, especially if there is scarring and significant psychological stress associated with their disease. Acne patients should, where appropriate, be prescribed isotretinoin sooner rather than later.

Isotretinoin (roaccutane) usage--a South African consensus guideline. National Dermatology Working Group.

OBJECTIVE: This guideline has been developed in order to recommend the correct and safe usage of isotretinoin (Roaccutane) in the treatment of acne and related conditions. Aspects such as correct dosage related to the patient's weight and the minimal requirement in relation to blood tests and physician visits have been addressed. OPTIONS: Isotretinoin is known to be the treatment of choice for severe acne. Familiarity with the drug has lowered the threshold for its use in lesser degrees of acne, particularly when scarring is occurring and other options outlined in the guideline have failed or are either unsuitable or not tolerated. OUTCOMES: Severe acne causes permanent physical damage and frequently equally severe psychological damage. The correct use of isotretinoin increases the chance of complete cure, thus maximising the chance of meeting the patient's expectations. EVIDENCE: Studies have shown that the patient may expect the chance of permanent cure to be between 60% and 80% at a dose ranging from 0.5 to 1 mg/kg body weight per day for a period of 16-20 weeks. Recent evidence suggests that a cumulative dose of 120 mg/kg body weight during the course at a daily dose of 0.75 mg/kg body weight or greater may be more important than the duration of treatment. VALUES: The National Dermatology Working Group consisting of 11 consultant dermatologists, all with considerable experience in the use of isotretinoin therapy for acne, using the current literature as back-up, reached consensus on the contents of the document. The document was presented to the Congress of the South African Dermatology Society in May 1997. It was subsequently sent to all registered dermatologists in South Africa for comment. BENEFITS, HARM AND COSTS: Correct use of isotretinoin will often effect cure and at worst considerably improve acne. Side-effects due to hypervitaminosis A, while almost inevitable, are uncomfortable rather than dangerous. The potential for teratogenicity is stressed. Isotretinoin is an extremely expensive drug, but studies have shown that it is cost-effective when compared with prolonged treatment with other modalities in what is usually a chronic condition. RECOMMENDATIONS: The optimal dosage recommended is a cumulative dose of 120 mg/kg body weight with a daily dose as close to 1 mg/kg body weight as possible. Isotretinoin is used for severe acne, lesser degrees of acne where scarring is seen, and in patients who do not respond to or cannot tolerate other treatment modalities. VALIDATION: This guideline is similar to those recommended by other groups outside South Africa. It has been scrutinised by all the practising dermatologists in the country. It is endorsed by the Medical Association of South Africa.

Effect of isotretinoin on the quality of life of patients with acne.

Acne is the commonest skin disease, and affects 85% of teenage boys and 80% of teenage girls. More than half of teenagers with acne will obtain advice on treatment from family, friends and pharmacists. However, in 1992 there were approximately 3.5 million consultations for acne with primary care physicians in the UK. Of these, approximately 51 000 were referred for specialist advice. It is clear that rationalisation of acne treatment based on cost-effective analysis will have potential benefit in terms of usage of resources. This article reviews the current epidemiological data on acne, and demonstrates that acne now affects members of a population who are no longer at school, but are in work or tertiary education. This article argues that, due to this shift, the social and economic consequences of acne are quite different from those that occurred 10 years ago. Finally, the article discusses the cost effectiveness of competing therapies for acne, and examines isotretinoin in terms of cost per disease-free years and the utility of the treatment in cost per quality-adjusted life years (QALYs).

Isotretinoin: cost-benefit study.

Isotretinoin is a well-established, effective treatment for severe nodulocystic acne. An important consideration which may limit the prescription of isotretinoin is its cost. Based on a literature review, we have compared isotretinoin with the conventional combination of antibiotics and topical therapies for the treatment of severe nodulocystic acne in terms of cost and benefit. Our results show that when duration of treatment is considered, isotretinoin is cheaper and significantly more effective.