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Ajay Verma, Consultant Gastroenterologist and Physician, Kettering General Hospital NHS Trust; Anusha Patel, Regional Homecare Lead Pharmacist and High Cost Medicines Pharmacist, Kettering General Hospital NHS Trust 

 

Introduction

Kettering General Hospital NHS Foundation Trust covers a population of 311,000 people across north Northamptonshire and south Leicestershire.1 The Department of Digestive Diseases manages hundreds of patients each year with inflammatory bowel disease (IBD), including over 300 on biologic high cost therapies. 

Inflammatory bowel disease is a debilitating condition for many patients, with more severe cases becoming increasingly common. Effective treatment can reverse the course/progressive nature of the disease, and can prevent significant surgery requirements and significant periods of ill health for patients.2,3 Infliximab is a monoclonal antibody that has been successfully used at the trust for several years to treat some of the most unwell patients with IBD. A total of 95 patients with IBD were treated with intravenous (IV) infliximab at Kettering General Hospital during the past year. Of these, two patients were treated with a combination of Flixabi® and Inflectra®, and 89 patients received Inflectra (the US product name for Remsima®). 

Biosimilar medicines are often used in place of original, or reference, biological products, such as monoclonal antibodies, once they are out of patent because they usually provide a more cost-effective alternative. While they are not identical to the original biological products, biosimilars are comparable in terms of their clinical efficacy, safety, and tolerability.2,4 Some biosimilars are available in different preparations, with IV and subcutaneous (SC) versions each having their own advantages. Until earlier in 2020, infliximab was only available as an IV formulation, so the addition of SC infliximab provides another welcome treatment option for patients with IBD. 

Kettering General Hospital NHS Trust was the first centre to switch patients with IBD from an IV version of any biosimilar infliximab to an SC version (Remsima SC). The reasons for switching, how the switch was implemented, early experiences of the switch, and advice on how to achieve a successful switch are discussed below. 

Infliximab 

Infliximab is a chimeric monoclonal antibody that inhibits the pro-inflammatory cytokine tumour necrosis factor (TNF)-alpha.5 It has been used to treat IBD for several years because of its ability to reduce symptoms and induce intestinal mucosal healing in many patients.5,6 Infliximab is recommended for treatment of moderately to severely active ulcerative colitis (UC) in adults or, as IV infliximab, for severely active UC in children aged 6 to 17 years, if they have not responded to, or are unable to tolerate or have contraindications to, conventional treatment.2,7 It is recommended for treatment of adults or, as IV infliximab, for children aged 6 to 17 years with severe active Crohn’s disease (CD), or adults with active fistulising CD whose disease has not responded to conventional therapy, or who are intolerant of or have contraindications to conventional therapy.3,8 Patients who respond to treatment should continue with treatment, with assessment at least yearly, and an option to try a withdrawal from treatment once in stable clinical remission.3,7–9 

Infliximab has been available as an IV treatment since its approval by the European Medicines Agency (EMA) in 1999.4 The biosimilar Remsima IV was approved for use in Europe for treating CD and UC in 2013.4,10 The first subcutaneous form of infliximab, Remsima SC, which gives patients an option to self-administer infliximab, was licensed by the EMA in 2019 for the treatment of rheumatoid arthritis.11 Remsima SC has recently been granted a marketing authorisation by the EMA for five additional indications: CD, UC, ankylosing spondylitis, psoriatic arthritis, and psoriasis.12

Intravenous infliximab is administered by IV infusion, with a recommended dose of 5 mg/kg at weeks 0, 2, and 6, and then every 8 weeks.7,9 Remsima SC is prescribed for adults ≥18 years of age at a single dose, irrespective of patient body mass index, of 120 mg infliximab solution for injection in either a pre-filled syringe or pen to be administered every 2 weeks.5 In addition to removing the need for patients to attend hospital regularly for IV infusion, having a simpler single dosing option, irrespective of BMI, means that in some patients there may be cost savings for commissioners compared with the IV formulation. 

Reasons for switching to SC infliximab biosimilar 

Although transition to Remsima SC was already underway, the main driver for the switch to SC infliximab at Kettering was the COVID-19 pandemic, and a fear that hospital resources might quickly become overwhelmed with critically ill patients with COVID-19. The pandemic was predicted to peak in April 2020. The decision to implement the switch was reached in mid-March, and the approval documentation was ready by the end of March 2020. In addition to relieving pressure on hospital resources, giving patients with IBD who were being treated with IV infliximab the option of switching to an SC version would reduce the number of patients needing to attend the hospital for infusions and would reduce their risk of contracting COVID-19. 

The pharmacy team at the trust had experience of using SC infliximab to treat rheumatoid arthritis and suggested that it might be a helpful option for gastroenterology at this time. Recent trial data had shown that the efficacy and safety of SC infliximab in treating CD and UC were comparable with IV infliximab.13,14 A phase I open-label randomised controlled trial in patients with moderate to severe CD indicated that the mean serum concentration of infliximab achieved for patients with SC infliximab was consistently higher than for patients who were given IV infliximab (see Table 1).12,13 This could be a result of the more frequent administration of SC infliximab, which is given fortnightly. While the treatment had not been licensed for IBD in March 2020, the extended licence was due to be approved by the EMA in a few months’ time.10 

Table 1: Mean serum concentration of infliximab in patients with CD receiving SC infliximab was shown to be consistently higher than for patients who were given IV infliximab12
 Remsima IV
5 mg/kg
Remsima SC 
120 mg
Remsima SC 
180 mg
Remsima SC 
240 mg
Pre-dose concentration (μg/mL)

Week 2

N

12

11

12

6

Mean ± SD

24.67±8.29

21.95±4.80

22.53±9.50

15.66±10.23

Week 6

N

12

11

12

6

Mean ± SD

11.49±10.06

12.73±6.97

13.04±14.19

6.60±6.40

Week 14

N

12

10

12

6

Mean ± SD

2.98±3.60

14.09±6.27

17.51±12.46

22.88±19.46

Week 22

N

11

9

11

6

Mean ± SD

1.71±1.74

15.67±4.32

16.23±10.08

22.33±14.61

Week 30

N

10

9

10

5

Mean ± SD

1.22±1.45

15.83±3.84

20.97±13.54

29.00±15.51

Week 38

N

10

9

9

5

Mean ± SD

1.12±1.61

16.98±4.75

22.45±13.28

27.20±14.74

Week 46

N

9

9

7

5

Mean ± SD

1.90±2.51

12.95±6.25

22.40±15.72

26.04±14.44

Week 54

N

8

9

7

5

Mean ± SD

1.55±1.92

15.40±7.44

20.89±10.42

26.00±18.53

Discussions with senior gastroenterology colleagues at Kettering and at other trusts were reassuring because they all agreed that the data meant they would have no concerns switching patients to SC infliximab. Box 1 summarises the advantages of SC infliximab compared with IV infliximab, both for patients and hospital trusts. 

Box 1: Benefits of using SC infliximab compared with IV infliximab

Benefits for patients:

  • significant time savings without regular hospital visits for IV infusions
  • greater autonomy, making work, study, and travel easier
  • access to help and advice via a helpline
  • medicine provided at home on a 3-monthly basis
  • being able to stay at home and away from hospital during the COVID-19 pandemic.

Benefits for hospital trusts:

  • reductions in staff time:
    • the fixed dose of infliximab SC means pharmacists do not have to calculate and make up individual doses of IV infliximab, which needs to be undertaken in aseptic units (this also frees up resources for other purposes)
    • IBD nurses do not have to cannulate patients or administer IV infusions
  • increased capacity of infusion chairs for other patients
  • reduced traffic around the hospital
  • increased car parking capacity at the hospital.

Planning the switch 

The experience of using SC infliximab in rheumatology helped the pharmacy team with planning and implementing the switch. Because the SC preparation had not yet been licensed for use in gastroenterology at that time, the homecare lead pharmacist liaised with other stakeholders, including members of the gastroenterology department, the chief pharmacist, members of the contracts team, and the local clinical commissioning group (CCG) to work out the best way to proceed. A quality assurance technician, who is experienced with the use of off-label and unlicensed medicines in chemotherapy, was able to advise about the process needed to use an off-label medicine. 

The authors of this article produced a document detailing the need to expedite use of SC infliximab during the pandemic, which included data relating to its efficacy and safety, and a budget impact model. A risk assessment was carried out and was signed off by the trust’s medical director. The risk assessment completed included aspects such as the risk of: 

  • non-compliance with an SC therapy 
  • misadministration in the patient’s home setting 
  • a lack of response 
  • a failure of the supply chain resulting from demand in use of SC infliximab due to the COVID-19 pandemic 
  • unsustainable budget impact with implications for continued use.

Blueteq 

Blueteq software has been a requirement in the trust for CCG-commissioned medicines since 2015, with implementation of the extended version for management of high cost drug use and individual funding requests being rolled out across different departments over the 5 years since then. The software is used to send requests for new medicines to the appropriate commissioner and is a useful tool to audit medicine usage. It also ensures appropriate use of high cost medicines as recommended by NICE or any locally made agreements between commissioners. Having the system in place has enabled a more collaborative approach between the hospital and the CCG, and a greater understanding among the clinical team about the information commissioners need when it comes to requesting high cost drugs. 

Identifying suitable patients for the switch 

The switch was to be available for patients with CD or UC who were stable on IV infliximab regardless of previous biosimilar usage, and not for those experiencing periods of flare. It was important to assess patients individually and the decision about whether to offer a switch to SC infliximab was based on each patient’s health status. Suitable patients who were keen to switch to SC infliximab were counselled so that they understood what the treatment involved and were able to give fully informed consent to treatment. 

Implementing the switch 

The switch began with administration of the first doses of Remsima SC on 30 March 2020, and patients with CD or UC, who were eligible for treatment with SC infliximab, were offered the opportunity to switch to the SC treatment when they attended the hospital for their regular IV infusion appointment. If they were agreeable, they were counselled by the IBD nurses, who gained their consent to treatment, and demonstrated how to administer SC infliximab correctly so that they would be able to use the treatment safely at home. 

Homecare was not an option for patients with IBD at the beginning of the pandemic, when capacity was reserved for chemotherapy and other treatments, therefore the patient packs and coolboxes that patients needed were stored in the pharmacy and provided to IBD nurses along with patient training materials to give to patients when they attended. Regular communication between members of the pharmacy team and the gastroenterology department was important to ensure optimal procurement of SC infliximab. This meant that enough stock would be available for patients when attending the hospital but without any wastage. 

Patients who wished to use SC infliximab were given 3 months’ supply along with a sharps bin to dispose of their needles safely. Before their next 3-month supply was due, the pharmacy department assisted the gastroenterology nurses to complete the paperwork that would transfer patients to the homecare service, which would then take over the supply of their medicine. 

Two-weekly follow-up appointments by phone with the homecare lead pharmacist were offered to patients if they had any questions about their medicines. They also had access to an IBD helpline (run by Kettering General Hospital IBD nurses) for support. Unless they had any problems, patients would then continue using SC infliximab until their usual annual review. 

Switch outcomes 

Patient response 

The first six patients with CD or UC were switched at the end of March 2020, with more patients also being transferred to SC infliximab when they came for their IV infusion appointment. A total of 30 patients have been switched so far, which is approximately 30% of the IBD patients receiving infliximab at the hospital. Patients on IV infliximab biosimilar continue to be considered on a case by case basis. 

Some patients initially had concerns about whether SC infliximab would be as effective as IV treatment, but were satisfied when the efficacy data was discussed with them. However, generally, patients were happy to be able to self-treat and understood the reasons behind the switch. Not having to attend the hospital for IV treatment during the height of the COVID-19 pandemic was an obvious advantage. The case study in Box 2 gives one patient’s account of switching to SC infliximab. 

Box 2: Case study

J, aged 18, was one of the first (and youngest) patients to switch to SC infliximab. His Crohn’s disease was stable, maintained on IV Infliximab for >12 months after a difficult disease course through his mid-teens. When SC infliximab was discussed, he was keen to switch as it gave him more freedom immediately, reduced his concerns about contracting COVID-19 after being advised to practice strict social distancing to reduce his risk, and would allow him to continue taking infliximab with ease when he started at university. J previously had concerns about how he would manage to return to Kettering General Hospital for infusions without disrupting his future university studies and had discussed with his consultant whether his medication would need to be changed or his care transferred to another IBD team based in the same city as the university he would eventually be attending.

 

On outpatient follow up a few weeks after switching, J expressed his delight that he had not noticed any difference in his condition on switching (remaining well) and that he could continue with taking infliximab and stay under the care of the same consultant when he went to university. J had found the switch to home SC treatment straightforward and it had not caused him any issues.

Efficacy and tolerability 

Detailed results for the patient cohort at the trust are not yet available, but a full picture of switch outcomes will be available in summer 2021. However, the emerging results indicate that SC infliximab appears to be effective for use in stable patients with CD or UC who were previously treated with IV infliximab, without any major adverse effects. Initial drug therapeutic monitoring results look promising: early trends suggest that drug levels are maintained and possibly increased, though this needs to be further evaluated over time, and there has not been a significant drop-off in patients’ response to infliximab or increase in antibody formation above what would normally be expected with IV infliximab. 

The only adverse effects reported so far are mild local skin reactions experienced by two patients, who have subsequently switched back to the IV formulation as a result of this. 

Hospital outcomes 

The switch was achieved quickly, from the decision first being made to switch on 26 March 2020 to the first patients being switched to SC infliximab on 30 March 2020. The gastroenterology treatment area at Kettering General Hospital was (and remains) under pressure due to the number of gastroenterology patients requiring treatment, and switching patients from IV to SC infliximab has been beneficial in freeing up capacity for other patients. 

As a result of the switch, gastroenterologists at Royal Liverpool and Broadgreen University Hospitals NHS Trust approached Dr Verma in April 2020 to find out more about how the switch was managed. The authors of this article provided information and documentation to help staff at Liverpool effectively switch patients with IBD who were being treated in their NHS trust to SC infliximab. This collaboration between teams in different NHS trusts has enabled a significant number of patients with IBD to benefit from self-treating with SC infliximab and the teams will continue to share efficacy and safety data to ensure the best possible outcome for patients. 

Addressing potential barriers to switching 

Because of the increased risk to patients attending hospital and the need to free up hospital resources during the COVID-19 pandemic, switching needed to be implemented rapidly, which could potentially have been a barrier. However, planning and implementing the switch was achieved without too many difficulties. Ensuring also that good communication was maintained with colleagues and patients alike meant that everyone was well informed and confident about the switch. 

A potential future barrier is that the trust is in a block contract until April 2021, which means that drugs are now paid for within the block. The finance director will therefore be responsible for assessing the cost implications of different medicines. It is hoped that any cost worries will be offset by looking at the budget impact of SC infliximab holistically, in terms of IBD patients self-treating at home and reducing the use of hospital resources. Additional wider benefits from the availability of an SC formulation as an alternative to an existing IV formulation are applicable to the whole health economy, and are often not obvious. The availability of an SC formulation means that patients are more likely to be treated at home (aligning to the NHS 10-Year plan: Providing care closer to Home15), VAT savings are released, and capacity is released within IV suites, improving NHS efficiency and making better use of restricted resources. 

Box 3 summarises the key points to consider for a successful switch to SC infliximab. 

Box 3: Advice for a successful switch from IV infliximab to SC infliximab biosimilar
  • Involve all stakeholders, including commissioners, in  discussions about the switch at the earliest opportunity

  • Build a good relationship with your CCG pharmacists if you do not already have one

  • Approach staff in trusts that have already succeeded in switching for advice and to view their documentation

  • Get organised—carry out a risk assessment, provide safety and efficacy evidence for SC infliximab, outline the holistic cost benefits of switching, including reductions in workload and freeing up of infusion chairs, and train staff who will be involved in carrying out the switch

  • Prepare patients for the switch and explain the changes involved

  • Communicate with the pharmacy team and homecare team to set up new procedures

  • Set up a system to record patients’ blood results and any adverse effects to enable easy monitoring of the outcomes of switching.

Future plans 

Subcutaneous infliximab provides another route for administration, with the added bonus that patients can self-treat at home, and is a welcome addition to the trust’s treatment armoury for IBD. 

Further work will be undertaken to assess whether SC infliximab can be offered as an option for treating ankylosing spondylitis, psoriatic arthritis, and psoriasis, the other conditions covered by the recent EMA marketing authorisation;12 for example, infliximab is normally reserved for very severe cases of psoriasis, but the SC formulation might be beneficial earlier in the treatment pathway. 

Changes in commissioning intentions following the release of the Revised arrangements for NHS contracting and payment during the COVID-19 pandemic16 will have an impact on future drug procurement, and it is difficult to make predictions for future applications of SC infliximab in Kettering General Hospital NHS Foundation Trust. It is fair to state, however, that based on the benefits described in Box 1, and the heritage/experience we have for infliximab as a treatment option, we would consider adding this formulation alongside IV infliximab in the pathway, possibly for earlier use. 

Conclusion 

Infliximab is one of the the oldest biological agents yet is still used extensively due to its efficacy, especially in some of the patients with a high burden of disease. The SC formulation allows us to offer an effective treatment with the convenience of homecare, and it offers another welcome treatment option for patients with IBD. 

The switch to SC infliximab at Kettering has been successful because, in addition to the benefits described above of switching to SC infliximab, it has enabled a proportion of patients with IBD to avoid attending hospital for IV infusions during the COVID-19 pandemic. Many patients were afraid to come to the hospital because of worries about catching COVID-19 and the switch to SC infliximab provided a timely solution for concerned patients with IBD. With the necessary systems in place, patients with IBD now have the opportunity to administer infliximab at home where possible, reducing their need to attend hospital appointments, as well as reducing the burden on hospital resources. 

The success of the switch was a result of exceptional collaborative decision making by a large number of stakeholders, which was made easier by long established relationships between staff at the trust and the CCG. This meant they were rapidly able to put together a budget impact model and risk assessment, which were signed off without challenge in order to keep patients safe and at home. Members of the clinical team are proud of how well they worked together to deliver a new service for patients at a time of potential crisis. 

Initial results of the switch look promising, with SC infliximab appearing to be effective in patients with CD or UC, with few cases of adverse reactions reported, and with positive drug therapeutic monitoring results. Patients who have switched to the SC formulation benefit from not needing to attend hospital and the hospital benefits by increasing capacity in the IV infusion unit and by freeing up time for IBD nurses and pharmacists. 

A collaboration with staff in Liverpool means that many more IBD patients have been able to switch to SC infliximab and data sharing between trusts will continue to provide more information about the safety and efficacy of this treatment. 

Conflicts of interest 

The authors have received honoraria from Celltrion and other pharmaceutical companies. Dr Verma has also received sponsorship for travel to conferences. 

References 

  1. Kettering General Hospital NHS Foundation Trust. Annual report and accounts 2018/19. Available at: www.kgh.nhs.uk/download.cfm?ver=1671
  2. Harbord M, Eliakim R, Bettenworth D et al. Third European evidence-based consensus on diagnosis and management of ulcerative colitis. Part 2: Current management. J Crohns Colitis 2017; 11 (7): 769–784. 
  3. Torres J, Bonovas S, Doherty G et al. ECCO guidelines on therapeutics in Crohn’s disease: medical treatment. J Crohns Colitis 2020; 14 (1): 4–22. 
  4. Milassin A, Fabian A, Molnar T. Switching from infliximab to biosimilar in inflammatory bowel disease: overview of the literature and perspective. Ther Adv Gastroenterol 2019; 12: 1–11. 
  5. Celltrion Healthcare UK Ltd. Remsima 120mg solution for injection in pre-filled pen. Summary of product characteristics. July 2020. www.medicines.org.uk/emc/product/11101/smpc/
  6. Crohn’s & Colitis Foundation. Fact sheet: biologics. Available at: www.crohnscolitisfoundation.org/sites/default/files/2019-06/ medications-biologic-therapy.pdf (Accessed 24 August 2020) 
  7. NICE. Infliximab, adalimumab and golimumab for treating moderately to severely active ulcerative colitis after the failure of conventional therapy. Technical appraisal guidance TA329. NICE, 2015. Available at: www.nice.org.uk/TA329
  8. NICE. Crohn’s disease: management. Clinical guideline NG129. NICE, 2019. Available at: www.nice.org.uk/ng129
  9. NICE. Infliximab and adalimumab for the treatment of Crohn’s disease. Technical appraisal guidance TA187. NICE, 2010. Available at: www.nice.org.uk/ta187
  10. European Medicines Agency. Remsima infliximab. Available at: www.ema.europa.eu/en/medicines/human/EPAR/ remsima#assessment-history-section (Accessed 02 September 2020) 
  11. European Medicines Agency. Remsima infliximab. Assessment report on extension(s) of marketing authorisation, EMA/CHMP/548703/2019, September 2020. Available at: www.ema.europa.eu/en/medicines/human/EPAR/ remsima#assessment-history-section (Accessed 02 September 2020) 
  12. European Medicines Agency. Remsima infliximab. Extension of indication variation assessment report, EMA/376884/2020, June 2020. www.ema.europa.eu/en/medicines/human/EPAR/ remsima#assessment-history-section (Accessed 02 September 2020) 
  13. Reinisch W, Jang B, Borzan V et al. A novel formulation of CT-P13 (infliximab biosimilar) for subcutaneous administration: 1-year result from a Phase I open-label randomised controlled trial in patients with active Crohn’s disease. J Crohns Colitis 2019; 13 (Suppl 1): S066–S067. 
  14. Schreiber S, Leszczyszyn J, Dudkowiak R et al. Noninferiority of novel subcutaneous infliximab (CT‑P13) to intravenous infliximab (CT-P13) in patients with active Crohn’s disease and ulcerative colitis: week 30 results from a multicentre, randomised controlled pivotal trial. United Eur Gastroent 2019; 7 (10): 1412–1413. 
  15. NHS. The NHS Long Term Plan. Available at: www.longtermplan.nhs.uk (Accessed 02 September 2020) 
  16. NHS. Revised arrangements for contracting and payment during the COVID-19 pandemic. Available at: www.england.nhs.uk/coronavirus/wp-content/uploads/ sites/52/2020/03/COVID-19_NHS-contracting-and-payment_26- March.pdf (Accessed 02 September 2020)

This supplement has been commissioned and funded by Celltrion Healthcare UK Ltd and developed in partnership with Guidelines in Practice. Celltrion Healthcare UK Ltd suggested the topic and authors and carried out full medical approval on all materials to ensure compliance with regulations. The sponsorship fee included honoraria for the authors. The views and opinions of the authors are not necessarily those of Celltrion Healthcare UK Ltd, or of Guidelines in Practice, its publisher, advisers, or advertisers. 

No part of this publication may be reproduced in any form without the permission of the publisher. 

CTHC-UK-219B (1)

Date of preparation: October 2020