What Is Known?
- Use of infliximab is in pediatric inflammatory bowel disease has been recommended since 2010, and biosimilar medication has been available in the United Kingdom since 2015.
- Survey and small cohort studies have demonstrated similar rates in efficacy and adverse events between infliximab originator and biosimilar; there is no large-scale national data to date.
What Is New?
- Biosimilar infliximab is likely as efficacious and safe as originator infliximab, at initiation and initial follow-up in a large multicentre pediatric cohort.
- Use of biosimilar infliximab instead of originator could result in significant savings estimate of 10% to 30%.
The incidence and prevalence of inflammatory bowel diseases (IBDs), comprising Crohn disease (CD), ulcerative colitis (UC), and IBD unclassified, is increasing with around 1 in 10 cases presenting before adulthood (1). Pediatric inflammatory bowel disease (PIBD) is associated with more extensive disease, higher disease activity, and higher rate of complications compared to adult-onset IBD (2). Worldwide, estimates of PIBD prevalence rates are lacking, but data suggest increasing incidence (3).
Treatment of PIBD with anti-tumour necrosis factor (TNF) therapy, including infliximab (IFX) and adalimumab (ADA), is increasing (4,5). IFX has been licensed for use in PIBD, and recommended nationally in the United Kingdom (UK) since 2010 (6). IFX biosimilar (IFX-B) drugs have been available in the UK since 2015.
The World Health Organization defines biosimilar medication as “a biotherapeutic product which is similar in terms of quality, safety, and efficacy to an already licensed reference biotherapeutic product” (7). The European Society of Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) advocate giving high priority to performing pediatric trials with long-term follow-up to support the European Medicines Agency approval of using biosimilars for infliximab, including treatment of pediatric IBD (4). Post-marketing surveillance programs in PIBD are recommended internationally, as is long-term data on switching children and young people who are stable on originator medication to biosimilar medication.
British survey (8) and Scottish cohort (9) data have demonstrated efficacy of anti-TNF therapy historically, but also highlighted the potential for serious adverse effects to occur with administration. In 1 prospective UK audit of patients newly starting anti-TNF therapy, 77% of patients with CD responded to induction and 65% entered remission, with adverse events (AEs) affecting 3% of IFX administrations (10).
Routinely collected data from the UK IBD biologics registry is the first to include IFX-B drugs, (Inflectra and Remsima) as alternatives to the originator Infliximab (IFX-O) (Remicade) in a diverse population-based PIBD cohort. IFX-B drugs are costed at approximately 30% to 50% cheaper than IFX-O, but data on effectiveness and safety profile are limited (4).
Commenced in 2006, the UK IBD audit is a national gastrointestinal audit, with reports available online (www.rcplondon.ac.uk/ibd) since initial reporting in 2008. Outcome data on pediatric and adult patients with CD (9) and UC (11,12) are published. Unselected, large-scale national data will help quantify and categorize AEs wherein real-life clinical data are lacking. We aimed to collect data on anti-TNF therapy in UK PIBD practice to assess short-term effectiveness, safety, and cost of using IFX-B drugs compared IFX-O in biologic naive PIBD.
Details on the UK IBD biologics audit have been extensively described previously (10). Briefly, hospital or represented health board or trust sites were eligible to participate in the audit if they prescribe and administer anti-TNF therapy to their pediatric patients with IBD. Data were completed on a voluntary basis. A total of 27 sites participated, including 19 of 25 specialist UK pediatric IBD sites, representing a broad subset of PIBD patients across the UK.
Data from children enrolled in the Personalized Anti-TNF Therapy in CD study (PANTs, clinicialtrials.gov identifier: NCT03088449) was also used. PANTs is a prospective, uncontrolled, cohort study investigating response and drug reactions to IFX and ADA in patients with active luminal CD. Collected clinical data aligned with biological therapy audit, and patients were included if he or she had diagnosis of IBD and started on biological therapy in the appropriate timeframe.
Children and young people with a diagnosis of IBD who were 18 years or younger when newly started on infliximab for IBD from March 1, 2015 were eligible for inclusion. Patients already receiving anti-TNF therapy before this date were excluded from the primary analysis but a historical cohort of patients receiving infliximab originator was used for comparative effectiveness and safety data.
As described, data were collected prospectively and entered into a secure, bespoke web-based database (10). All treatment decisions and data entry were at the discretion of the treating physician/clinical team. Data capture for the results included here ended on February 29, 2016.
Adequate pre-treatment screening was defined as having had a chest radiograph, Mantoux or Gamma interferon test, and hepatitis B serology performed before the commencement of infliximab.
Disease Severity, Response to Treatment, Remission Rate, and Adverse Events
Disease phenotype was diagnosed using the Montreal criteria (13), and Pediatric Global Assessment (PGA), Pediatric Crohn's Disease Activity Index (PCDAI) or Pediatric Ulcerative Colitis Activity Index (PUCAI) scores were collected at initial and follow-up treatments. Disease response is defined as PCDAI decrease of >15 and PUCAI score of >20 (14,15). Disease remission is defined as PCDAI or PUCAI score of <10. Disease activity is defined as quiescent, mild, moderate, and severe, according to PGA (16). One patient was assessed via Harvey Bradshaw Index (17).
Historical cohort controls were biologic-naïve patients who enrolled in the UK IBD biologics audit from September 2011 until February 2015 and commenced infliximab originator. Acute infusion reactions were defined by the treating clinical team. Unlimited numbers of follow-up treatments are permitted and any AEs recorded.
In February 2016, NICE published a position statement on use of biosimilar medicines in the UK, stating that use of biosimilars can reduce costs, allowing more treatment with new medicines, as long as the appropriate follow-up and monitoring systems are in place to manage risk and patient needs and expectations (18), including real-life examples of how hospital sites have planned and managed the introduction of biosimilars in practice.
Cost was determined at the market value distributed at the time of analysis from the recent award of a national framework agreement by National Procurement Scotland (19) as well as published data from the NICE Health Technology Assessment (20). Projected estimate of savings were calculated by including the number of patients in the study being commenced on IFX-O instead of IFX-B, using an average weight of 40 kg per patient, therefore requiring 2 vials of biologic per infusion, with approximately 9 infusions in the first year.
Data analysis was overseen by a medical statistician (L.J.W.). Data were analyzed using SPSS version 19 (IBM Corp. Released 2010; IBM SPSS Statistics for Windows, Version 19.0. Armonk, NY). Data manipulation were performed using SAS software v9.4 for Windows (SAS Institute Inc, Cary, NC). SAS and all other SAS Institute Inc. product or service names are registered trademarks or trademarks of SAS Institute Inc. P values obtained from median PCDAI data were calculated using the Mann-Whitney U test. Comparisons of proportions were analyzed by the χ2-test or, where numbers in cells were small, by the Fisher's exact test.
As an audit of clinical practice, ethical permission was not applied for.
By February 29, 2016, data were available for 278 individual patients: 230 patients with complete audit data (demographic, disease, and initial treatment data) from the UK IBD audit and 48 pediatric patients from the PANTS study (supplementary figure 1, Supplemental Digital Content 1, https://links.lww.com/MPG/B370).
Of patients newly started on anti-TNF therapy, 63% (n = 175) were started on IFX-O, and 29% (n = 82) were started on IFX-B. Patient subgroups by IBD subtype were comparable: age at diagnosis was 12 to 13 across groups, age at initial treatment was 14 across groups, and time from diagnosis to commencement of biologic was 0.89 to 1.32 years (Table 1 and supplementary table 1, Supplemental Digital Content 2, https://links.lww.com/MPG/B371).
Pre-treatment screening data were available for 149 patients commenced on IFX-O and 62 patients commenced on IFX-B. Screening was completed in 44% of patients commenced on IFX-O compared with 52% of patients started on IFX-B (see supplementary table 2, Supplemental Digital Content 3, https://links.lww.com/MPG/B372). The majority of patients received screening for chest radiograph (92%) and gamma interferon/Mantoux screen (81%); 39% of patients newly commenced on anti-TNF therapy did not receive screening for hepatitis B, a mandatory component for adequate screening (see supplementary table 3, Supplemental Digital Content 4, https://links.lww.com/MPG/B373).
Median PCDAI scores at baseline were similar between IFX-O and IFX-B groups, 36 (20,48) (n = 42) compared to 28 (20,40) (n = 29) respectively (P = 0.08), as was concomitant therapy, 95% for both groups, and immunosuppression rates, 150/175 (86%) for IFX-O and 65/82 (79%) for IFX-B (P > 0.05) (Table 2). Disease severity at initial treatment by disease subgroup is shown in supplementary table 4 (Supplemental Digital Content 5, https://links.lww.com/MPG/B374).
At 3-month follow-up, PCDAI score was 5 for patients commenced on IFX-O (n = 19) and 0 for patients commenced on IFX-B (n = 15) (P = 0.35). Response to treatment was 28/33 (85%) and 19/22 (86%) (P = 1) and remission was achieved in 25/37 (68%) and 19/24 (79%) for both groups, respectively (P = 0.32) (Table 3). We compared 2015–2016 new starters on anti-TNF therapy with historical data from similar patients in previous audits, that is 398 patients started on IFX-O from 2011 to 2015.
At 3 months, no significant difference in disease remission rates was seen. For IFX-O, 140/201 (70%) (2011–2015) achieved remission compared to 25/37 (68%) (2015–16) (P = 0.84) (see supplementary table 5, Supplemental Digital Content 6, https://links.lww.com/MPG/B375). Similarly, no significant differences were demonstrated for disease response rates, for IFX-O, 152/197 (77%) (2011–2015) compared to 28/33 (85%) (2015–2016) (P = 0.37).
At initial treatment, 3/175 patients commenced on IFX-O experienced AEs, compared with 0/82 reported AE in the IFX-B group (P > 0.05). At 3 month follow up, 4/76 patients commenced on IFX-O experienced AE and 2/39 in the IFX-B group (P > 0.05) (see Table 4). The most common AE at 3-month follow up were rash (n = 2) and fever (n = 2) (see supplementary table 6, Supplemental Digital Content 7, https://links.lww.com/MPG/B376). When compared with historical controls at baseline (n = 734 for IFX-O) and 3-month follow-up (n = 377 for IFX-O), no difference in AE was demonstrated at baseline or follow-up.
Local procurement rates differ across distributors in the UK, Europe, and worldwide. In Scotland, average cost saving per vial suggested at 38% reduction from the originator (IFX-O) to the biosimilar (IFX-B) (19). Elsewhere in the UK, NICE has published the list price for IFX-O (Remicade) at £419.62 per 100 mg vial (excluding IFX-O) and list price for IFX-B (Inflectra and Remsima) at £377.66 per 100 mg vial, approximately 10% lower (20).
List prices usually differ substantially from locally negotiated procurement rates, and data on exact the range of procurement rates, however, offered nationally and internationally remain unpublished and non-transparent.
Based on estimated and averaged local procurement rates for the total number of infusions carried out, savings were estimated to be around £875,000 (998,526 Euros, 1,177,488 USD) over a 1-year period, based on the patients included in this audit alone.
This national UK cohort of PIBD patients commenced on IFX-B therapy shows no difference between initial effect and safety data when compared with IFX-O. Despite national and international recommendations for use of biosimilars in clinical practice for PIBD (4,21,22), few post marketing surveillance studies have been published to inform clinicians on the efficacy and safety of biosimilar medication in PIBD (23). There are no randomized controlled trials published on the initiation of infliximab biosimilar in pediatric or adult IBD to-date.
Initial data from 36 CD pediatric patients from 3 Polish hospitals who completed induction therapy with IFX-B suggested that induction therapy with IFX-B is as effective with a similar side effect profile to that reported for IFX-O, with no unexpected AEs (24). Follow-up was after 3 induction doses at week 14.
Prospective clinical data of 40 patients starting IFX-B for the first time, equating to 190 infusions, was collected across 2 pediatric gastroenterology networks in Scotland, UK. IFX-B was associated with a significant clinical improvement in CD post-induction at 12 weeks, including disease remission, PCDAI, and biochemical markers (19). Another prospective observational study is enrolling children and young people with IBD newly starting IFX-B (ClinicalTrials.gov identifier: NCT02326155). Study authors aim to assess efficacy and safety of IFX-B over a 5-year follow up period.
Due to the paucity of published pediatric data on use of biosimilar medication in IBD, the majority of conclusions regarding safety and efficacy to date have been from observations from adult-only cohorts. Data from a national prospective cohort study across 12 sites in Hungary looked at disease outcomes of 210 consecutive adult patients with IBD following induction with IFX-B. At week 14, 79 (81.4%) of CD and 45 (77.6%) of UC patients showed clinical response and 52 (53.6%) of CD and 34 (58.6%) of UC patients were in clinical remission (25). Similar results were noted in 10 centers across the Czech Republic (26).
A recent systematic review of eleven observational studies looking at 829 adult patients’ disease outcomes concluded that IFX-B was associated with excellent clinical efficacy and safety profile. Pooled rates of clinical response at 8 to 14 weeks were for CD 0.79 (95% CI = 0.65–0.88) and for UC 0.74 (95% CI = 0.65–0.82). At 24 to 30 weeks, rates were for CD 0.77 (95% CI = 0.63–0.86) and for UC 0.77 (95% CI = 0.67–0.85) (27). AEs were rare.
Our study demonstrated that before initiation of biologic treatment, complete screening for pediatric patients is not being performed in the UK to a high standard. Screening data were only available for 85% of patients started on IFX-O, of which 44% had complete screening for Hepatitis B and Tuberculosis. For patients commenced on IFX-B, 76% had screening information available, and only 52% had completed screening. Clinicians should continue to aim for all patients to be screened for especially for Hepatitis B as well as Tuberculosis before commencing anti-TNF therapy.
For new starters of anti-TNF therapy, this UK-wide, unselected cohort was the first to demonstrate short-term efficacy in both response to treatment and remission achieved at 3-months. As with this and previous audits (10), documentation at follow-up can, however, be improved. In the IFX-O group, at baseline, 24% (42/175) of patients had PCDAI score recorded. This decreased to 11% (19/175) at 3-month follow-up. Similarly, in the IFX-B group, 35% (29/82) of patients had PCDAI recorded, and only 18% (15/82) had data recorded at 3-month follow-up. In order to be able to evaluate the efficacy of biologics long-term, clinicians should record disease activity, for example, PCDAI or PGA, at every visit; longitudinal data are required to determine response to treatment and disease remission.
Few AEs were noted at baseline and at 3-month follow-up in the IFX-B group; short-term use of IFX-B is safe. Few systematic and controlled data are published on the risk of infusion reactions to IFX-O in the adult or pediatric population (28), though rates observed in this study are consistent with previously published studies (24–28).
It is well documented that anti-TNF therapy, and biologics as a medication subclass, are one of the most costly medications available in the UK. Based on this study alone, a significant cost savings of £875,000 (998,526 Euros, 1,177,488 USD) estimated. This is, however, likely to vary significantly within and across different countries. In the UK, cost for IFX-B varies, and is subject to discount according to negotiation rates on behalf of the local strategic health authority (19,20,29,30).
Our results are consistent with a savings estimate of 10% to 30%, based on a pan-European study for a 1-year period (31). A budget impact model for the introduction of IFX-B in treating autoimmune disease was calculated, and significant cost savings were estimated with the introduction of IFX-B in biologic-naïve patients and those who switched from IFX-O to IFX-B. Compared to conclusions drawn from a recent multi-center Scottish observational study on biosimilar use in pediatric IBD where savings up to 38% were observed (19), our results may be conservative
The main limitation of this study is the lack of completeness of data capture, reflecting the unselected, self-submitted nature of data collection. Clinicians within the district general hospitals and tertiary pediatric gastroenterology centers must enter the patient's details into an online database after clinical review, reflecting the patchiness of detailed information at baseline and follow-up. In particular, data on serological markers at baseline and follow-up, such as hemoglobin, platelets, C-reactive protein, erythrocyte sedimentation rate, bone profile, vitamin D, and fecal calprotectin would be useful in further understanding degree of mucosal healing, inflammation, and bone density in patients newly started on IFX-O or IFX-B. Future studies in smaller, more defined clinical cohorts should include these parameters where possible.
Results from our study complement the current literature. Future research should look at the effects of switching pediatric patients currently stable on IFX-O to IFX-B. The ESPGHAN recommend children with sustained remission on a specific medication should not be switched to a biosimilar until clinical trials in IBD are available to support the safety and efficacy of such a change (4).
Only 2 prospective pediatric cohort studies have looked at switching from IFX-O to IFX-B. The first took place across 3 Polish academic centers, and examined the outcomes of 32 pediatric patients with CD and 7 patients with UC. Study authors concluded that switching was safe, with stable remission rates across both groups and no increase in AEs (32).
The second is a single-center prospective observational study in South Korea. Patients with PIBD received either maintenance infliximab RP (originator) (n = 36) or switched to infliximab CT-P13 (biosimilar) (n = 38) (33). At 1 year, remission rates were similar (86.1% in the RP maintenance group vs 92.1% in the CT-P13 switched group, P = 1.0), and there were no significant differences disease activity or AEs between both groups.
The NOR-SWITCH trial demonstrated that IFX-B was non-inferior to continued treatment with IFX-O in 482 adult patients, 51% of whom had IBD, already on stable treatment with IFX-O (34). Frequency for AEs was similar between both groups. Similarly, international data from adult cohorts suggest that on induction and maintenance, switching to biosimilar medication from originator is safe and efficacious (34–38).
This study provides much-needed information related to pre-treatment screening before initiation of biologics, occurrence of AEs, and potential cost savings associated with commencement of IFX-B. The conclusions are significant but have yet to be realized for the majority of pediatric patients treated with anti-TNF therapy. Future prospective cohort studies will evaluate long-term outcomes in these patients, and we hope to continue to work nationally and internationally to add to the growing evidence base on the safety of biosimilars in this group of patients, where a significant cost benefit can be incurred for health care providers.
The authors particularly like to thank all colleagues in our teams who contributed to the data collection for this audit.
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