3 The technologies

3.1 This technology appraisal includes 7 different biological medicines (see table 1). In addition, for infliximab, there is an originator biological medicine and 2 biosimilar products available in the NHS. A biosimilar medicine is a medicine that is developed to be similar to an existing biological medicine. The technologies have different mechanisms of action. Adalimumab, etanercept, infliximab, certolizumab pegol and golimumab all inhibit the activity of tumour necrosis factor (TNF)‑alpha, a pro‑inflammatory mediator that is partly responsible for damage to the joints in rheumatoid arthritis. They are referred to as TNF‑alpha inhibitors. Tocilizumab inhibits the activity of interleukin‑6 (IL‑6), a pro‑inflammatory cytokine that is also partly responsible for damage to the joints in rheumatoid arthritis. Abatacept is a selective modulator of the T‑lymphocyte activation pathway. It binds to molecules on the surface of antigen‑presenting cells, preventing full activation of the T‑lymphocytes and interrupting the inflammatory process.

Table 1 Summary of the marketing authorisations for the technologies

Technology

MTX‑experienced RA

MTX‑naive RA

In combination with MTX

Mono‑therapy

SC or IV

Adalimumab

+

+

+

+

SC

Etanercept

+

+

+

+

SC

Infliximab

+

+

+

IV

Certolizumab pegol

+

+

+

SC

Golimumab

+

+

+

SC

Abatacept

+

+

IV or SC

Tocilizumab

+

+*

+

+

IV or SC*

Abbreviations: IV, intravenous infusion; MTX, methotrexate; MTX‑naive, disease not previously treated with methotrexate; RA, rheumatoid arthritis; SC, subcutaneous injection; +, licensed for use; MTX‑experienced, disease previously treated with methotrexate.

*Tocilizumab in methotrexate‑naive rheumatoid arthritis and the subcutaneous formulation are not part of this appraisal.

Adalimumab

3.2 Adalimumab (Humira, AbbVie), in combination with methotrexate, has a UK marketing authorisation for the treatment of moderate to severe, active rheumatoid arthritis in adults when the response to DMARDs, including methotrexate, has been inadequate and for the treatment of severe, active and progressive rheumatoid arthritis in adults not previously treated with methotrexate. Adalimumab can be given as monotherapy in case of intolerance to methotrexate or when continued treatment with methotrexate is inappropriate.

3.3 Adalimumab is contraindicated in people with active tuberculosis or other severe infections, and people with moderate or severe heart failure. The summary of product characteristics notes the following adverse reactions as very common: respiratory tract infections, leukopenia, anaemia, increased lipids, headache, abdominal pain, nausea and vomiting, elevated liver enzymes, rash, musculoskeletal pain and injection site reaction. For full details of adverse reactions and contraindications, see the summary of product characteristics.

3.4 Adalimumab is administered subcutaneously as a 40‑mg dose every other week. The net price of adalimumab is £352.14 per 40‑mg prefilled pen or prefilled syringe, or £352.14 per 40‑mg/0.8‑ml vial (British national formulary [BNF], July 2015). Assuming 26 doses per year, the annual cost of adalimumab is £9155.64. For adalimumab monotherapy, the dose may be increased up to 40 mg per week for people who have a decrease in response. Costs may vary in different settings because of negotiated procurement discounts.

Etanercept

3.5 Etanercept (Enbrel, Pfizer), in combination with methotrexate, has a UK marketing authorisation for the treatment of moderate to severe active rheumatoid arthritis in adults when the response to DMARDs, including methotrexate (unless contraindicated), has been inadequate, and for the treatment of severe, active and progressive rheumatoid arthritis in adults not previously treated with methotrexate. Etanercept can be given as monotherapy in case of intolerance to methotrexate or when continued treatment with methotrexate is inappropriate.

3.6 Etanercept is contraindicated in people with sepsis or who are at risk of sepsis, and people with active infections including chronic or localised infections. The summary of product characteristics notes the following adverse reactions as very common: infections and injection site reactions. For full details of adverse reactions and contraindications, see the summary of product characteristics.

3.7 Etanercept is administered subcutaneously as a 25‑mg dose twice weekly or alternatively as a 50‑mg dose every week. The net price of etanercept is £89.38 per 25‑mg prefilled syringe, or £178.75 per 50‑mg prefilled pen or prefilled syringe (BNF, July 2015). Assuming 52 doses per year, the annual cost of etanercept is £9295. Costs may vary in different settings because of negotiated procurement discounts.

Infliximab

3.8 Infliximab (Remicade, Merck Sharp & Dohme; Remsima, Napp Pharmaceuticals and Inflectra, Hospira UK), in combination with methotrexate, has a UK marketing authorisation for the reduction of signs and symptoms of rheumatoid arthritis as well as the improvement in physical function in adults with active disease when the response to DMARDs, including methotrexate, has been inadequate. It is also licensed for the treatment of severe, active and progressive rheumatoid arthritis in adults not previously treated with methotrexate or other DMARDs. The contraindications, adverse reactions and administration schedule are the same for all infliximab products (see sections 3.9 and 3.10), but both biosimilars are subject to additional monitoring in line with standard European Medicines Agency recommendations.

3.9 Infliximab is contraindicated in people with active tuberculosis or other severe infections, and people with moderate or severe heart failure. The summary of product characteristics notes the following adverse reactions as very common: viral infection, headache, upper respiratory tract infection, sinusitis, abdominal pain, nausea, infusion‑related reaction and pain. For full details of adverse reactions and contraindications, see the summary of product characteristics.

3.10 Infliximab is administered as an intravenous infusion at a dose of 3 mg/kg, with initial doses at 0, 2 and 6 weeks, and then every 8 weeks thereafter. For disease that has an inadequate response or loss of response after 12 weeks of treatment, consideration may be given to increasing the dose step‑wise by approximately 1.5 mg/kg up to a maximum of 7.5 mg/kg every 8 weeks. Alternatively, administration of 3 mg/kg as often as every 4 weeks may be considered. The NHS list price of originator infliximab (Remicade) is £419.62 per 100‑mg vial (BNF, July 2015). Assuming a weight per person of 70 kg, vial wastage and 3 initial doses followed by treatment every 8 weeks, the cost in the first year is £10,070.88, and then £8812.02 per year. Costs may vary in different settings because of negotiated procurement discounts. The NHS list price of infliximab biosimilars (Remsima, Inflectra) is £377.66 per 100‑mg vial (BNF, December 2015). Assuming a weight per person of 70 kg, vial wastage, and 3 initial doses in the first year followed by treatment every 8 weeks, the cost in the first year is £9063.84, and then £7930.86 per year. The infliximab biosimilars are available to the NHS at contract prices negotiated through the Commercial Medicines Unit. These prices are lower than the list price but are commercial in confidence.

Certolizumab pegol

3.11 Certolizumab pegol (Cimzia, UCB Pharma), in combination with methotrexate, has a UK marketing authorisation for the treatment of moderate to severe active rheumatoid arthritis in adults when the response to DMARDs, including methotrexate, has been inadequate. Certolizumab pegol can be given as monotherapy in case of intolerance to methotrexate or when continued treatment with methotrexate is inappropriate.

3.12 Certolizumab pegol is contraindicated in people with active tuberculosis or other severe infections, and in people with moderate or severe heart failure. The summary of product characteristics lists no adverse reactions as very common but notes that in clinical trials the most common adverse reactions were bacterial and viral infections. For full details of adverse reactions and contraindications, see the summary of product characteristics.

3.13 Certolizumab pegol is administered subcutaneously as initial 400‑mg doses at 0, 2 and 4 weeks, followed by maintenance doses of 200 mg every 2 weeks. Alternatively, administration of 400 mg every 4 weeks can be considered, once clinical response is confirmed. The net price of certolizumab pegol is £357.50 per 200‑mg prefilled syringe (BNF, July 2015). Assuming 3 initial doses of 400 mg followed by maintenance doses every 2 weeks, the cost (without the patient access scheme) in the first year is £10,367.50, (or with the patient access scheme, £6793) and then £9295 per year. Costs may vary in different settings because of negotiated procurement discounts.

3.14 The company has agreed a patient access scheme with the Department of Health. In the scheme, the first 12 weeks of therapy (currently 10 pre‑loaded syringes of 200 mg each) with certolizumab pegol are free of charge.

3.15 The Department of Health considered that the certolizumab pegol patient access scheme does not constitute an excessive administrative burden on the NHS.

Golimumab

3.16 Golimumab (Simponi, Merck Sharp & Dohme), in combination with methotrexate, has a UK marketing authorisation for the treatment of moderate to severe active rheumatoid arthritis in adults when the response to DMARD therapy including methotrexate has been inadequate, and for the treatment of severe, active and progressive rheumatoid arthritis in adults not previously treated with methotrexate.

3.17 Golimumab is contraindicated in people with active tuberculosis or other severe infections and in people with moderate or severe heart failure. The summary of product characteristics notes that upper respiratory tract infections are very common adverse events. For full details of adverse reactions and contraindications, see the summary of product characteristics.

3.18 Golimumab is administered subcutaneously as a 50‑mg dose every month on the same day each month. For people weighing more than 100 kg, a dose of 100 mg may be considered if the disease has an inadequate clinical response after 3–4 doses. The net price of golimumab is £762.97 per 50‑mg prefilled pen or prefilled syringe (BNF, July 2015). For people weighing less than 100 kg and assuming 12 doses per year, the annual cost of golimumab is £9155.64. Costs may vary in different settings because of negotiated procurement discounts.

3.19 The company has agreed a patient access scheme with the Department of Health, in which the 100‑mg dose of golimumab will be available to the NHS at the same cost as the 50‑mg dose.

3.20 The Department of Health considered that the golimumab patient access scheme does not constitute an excessive administrative burden on the NHS.

Abatacept

3.21 Abatacept (Orencia, Bristol–Myers Squibb) in combination with methotrexate has a UK marketing authorisation for the treatment of moderate to severe active rheumatoid arthritis in adults whose disease responded inadequately to previous therapy with 1 or more DMARDs including methotrexate or a TNF‑alpha inhibitor.

3.22 Abatacept is contraindicated in people with severe and uncontrolled infections. The summary of product characteristics notes that upper respiratory tract infections are very common adverse events. For full details of adverse reactions and contraindications, see the summary of product characteristics.

3.23 Abatacept is given by intravenous infusion at a dose of 500 mg for a person weighing less than 60 kg, 750 mg for a person weighing between 60 kg and 100 kg, and 1000 mg for a person weighing more than 100 kg. It is given initially at 0, 2 and 4 weeks, then every 4 weeks thereafter. The net price of abatacept for intravenous infusion is £302.40 per 250 mg vial (BNF, July 2015). For people weighing between 60 and 100 kg, the cost of treatment for the first year is £12,700.80 and then £11,793.60 per year (without the patient access scheme). Costs may vary in different settings because of negotiated procurement discounts.

3.24 Abatacept is given by subcutaneous injection at a dose of 125 mg once weekly regardless of weight. Subcutaneous abatacept can be started with or without a single initial intravenous dose (using the doses specified in section 3.23). The net price of abatacept for subcutaneous injection is £302.40 per 125‑mg prefilled syringe (BNF, July 2015). Assuming a weight per person of 70 kg, 1 intravenous loading dose followed by subcutaneous treatment doses every week, the cost (without the patient access scheme) of the initial intravenous dose is £907.20, and then £15,724.80 per year. Costs may vary in different settings because of negotiated procurement discounts.

3.25 The company has agreed a patient access scheme with the Department of Health in which abatacept will be available with a discount. The level of discount is commercial in confidence.

3.26 The Department of Health considered that the abatacept patient access scheme does not constitute an excessive administrative burden on the NHS.

Tocilizumab

3.27 Tocilizumab (RoActemra, Roche), in combination with methotrexate, has a UK marketing authorisation for the treatment of moderate to severe active rheumatoid arthritis in adults whose disease has responded inadequately, or adults who were intolerant, to previous therapy with 1 or more DMARDs or TNF‑alpha inhibitors. In these people, tocilizumab can be given as monotherapy in cases of intolerance to methotrexate or if continued treatment with methotrexate is inappropriate. In July 2014 the marketing authorisation for tocilizumab was extended to include treatment of severe active and progressive rheumatoid arthritis in adults not previously treated with methotrexate. A marketing authorisation for a subcutaneous formulation was granted in February 2014. The subject of this appraisal is the intravenous formulation of tocilizumab for rheumatoid arthritis that has been treated with methotrexate before.

3.28 Tocilizumab is contraindicated in people with active, severe infections. The summary of product characteristics notes the following adverse reactions as very common: upper respiratory tract infections and hypercholesterolaemia. For full details of adverse reactions and contraindications, see the summary of product characteristics.

3.29 Tocilizumab is administered as a dose of 8 mg/kg every 4 weeks. The net price of tocilizumab is £102.40 per 4‑ml (80‑mg) vial, £256.00 per 10‑ml (200 mg) vial, or £512.00 per 20‑ml (400‑mg) vial (BNF, July 2015). Assuming a weight per person of 70 kg, vial wastage, and 13 doses each year, the annual cost (without the patient access scheme) of tocilizumab is £9318.40. Costs may vary in different settings because of negotiated procurement discounts.

3.30 The company has agreed a patient access scheme with the Department of Health in which tocilizumab will be available with a discount. The level of discount is commercial in confidence.

3.31 The Department of Health considered that the tocilizumab patient access scheme does not constitute an excessive administrative burden on the NHS.

  • National Institute for Health and Care Excellence (NICE)