REMICADE (infliximab) Remicade in the treatment of ulcerative colitis in England and Wales

Transcription

1 Remicade Schering Plough ltd Page 1 REMICADE (infliximab) Remicade in the treatment of ulcerative colitis in England and Wales A Submission to the National Institute for Health and Clinical Excellence Schering Plough Ltd Date of Report: 8 may 2007 Page 1 of 104

2 Table of Contents 1 Description of technology under assessment Statement of the decision problem Executive summary Context Clinical evidence Cost effectiveness Assessment of factors relevant to the NHS and other parties References Appendices...85 Page 2 of 104

3 Section A 1 Description of technology under assessment 1.1 Give the brand name, approved name and, where appropriate, therapeutic class. For devices please provide details of any different versions of the same device. The brand name is Remicade (infliximab). Therapeutic class: immunologic, immunosuppressant; 1.2 Does the technology have a UK marketing authorisation/ce marking for the indications detailed in this submission? If so, please give the date on which authorisation was received. If not, please state current UK regulatory status, with relevant dates (for example, date of application and/or expected approval dates). February 28 th, What are the (anticipated) indication(s) in the UK? For devices, please provide the (anticipated) CE marking, including the indication for use. Ulcerative colitis: Remicade is indicated for: Treatment of moderately to severely active ulcerative colitis in patients who have had an inadequate response to conventional therapy including corticosteroids and 6 MP or AZA, or who are intolerant to or have medical contraindications for such therapies. Other indications Infliximab is also licensed for treatment of: Rheumatoid Arthritis, Ankylosing Spondylitis, Psoriatic arthritis, Psoriasis, and Crohn s Disease. 1.4 To what extent is the technology currently being used in the NHS for the proposed indication? Include details of use in ongoing clinical trials. If the technology has not been launched, please supply the anticipated date of availability in the UK. 14.5% of Ulcerative Colitis (UC) patients are eligible to receive infliximab treatment. This translates to around 13,500 patients in the UK. Of these patients, 4.1 per cent (550) are currently offered infliximab treatment. (Data on file) 1.5 Does the technology have regulatory approval outside the UK? If so, please provide details. Infliximab has regulatory approval following a positive opinion granted on 28 th February 2006, by the European Unionʹs (EU) Committee for Medicinal Products for Human Use Page 3 of 104

4 (CHMP), for the European Agency for the Evaluation of Medicines Agency (EMEA). The Commission approval results in Marketing Authorisation with unified labelling valid in all EU member states (current 25 members), as well as Iceland and Norway. Infliximab has been approved by US FDA for moderate to severely active UC patients on 15 th September Is the technology subject to any other form of health technology assessment in the UK? If so, what is the timescale for completion? Negative guidance in Scotland due to non submission to SMC. Submission was not made pending outcome of several ongoing studies which have now completed. Submission planned in near future. 1.7 For pharmaceuticals, what formulation(s) (for example, ampoule, vial, sustained release tablet, strength(s) and pack size(s) will be available? 100 mg vial containing powder for concentrate for solution for infusion 1.8 What is the proposed course of treatment? For pharmaceuticals, list the dose, dosing frequency, length of course and anticipated frequency of repeat courses of treatment. 5 mg/kg given as an intravenous infusion over a 2 hour period followed by additional 5 mg/kg infusion doses at 2 and 6 weeks after the first infusion, then every 8 weeks thereafter. Available data suggest that the clinical response is usually achieved within 14 weeks of treatment, i.e. three doses. Continued therapy should be carefully reconsidered in patients who show no evidence of therapeutic benefit within this time period. 1.9 What is the acquisition cost of the technology (excluding VAT)? For devices, provide the list price and average selling price. If the unit cost of the technology is not yet known, please provide details of the anticipated unit cost, including the range of possible unit costs per vial of Remicade 1.10 What is the setting for the use of the technology? Secondary care 1.11 For patients being treated with this technology, are there any other aspects that need to be taken into account? For example, are there additional tests or investigations needed for selection, or particular administration requirements, or is there a need for monitoring of patients over and above usual clinical practice for this condition? What other therapies, if any, are likely to be administered at the same time as the intervention as part of a course of treatment? None Page 4 of 104

5 2 Statement of the decision problem Element Final scope issued by NICE Decision problem addressed in the submission Population Adults with moderately to severely active ulcerative colitis who have had an inadequate response to conventional therapy including corticosteroids and 6 mercaptopurine or azathioprine, or who are intolerant to or have medical contraindications for such therapies. Adults with moderately to severely active ulcerative colitis as per scope Intervention Infliximab In clinical practice infliximab is added to standard care. This approach also was followed in clinical trials where infliximab was added to patients existing therapy. Therefore, the intervention addressed in the submission is addition of infliximab to standard care. Comparator(s) Cyclosporine Surgery Standard care as defined in the scope was used as the comparator for the moderate to severe active UC population. Surgery was used as an outcome measure and not as a comparator, because no relevant data are available to inform this analysis. Standard care which may include conventional therapy with a combination of 5 ASA compounds, corticosteroids and immunomodulators (azathioprine or 6 mercaptopurine) Outcomes Economic Analysis Special considerations and other issues Health related quality of life Survival Measures of disease activity Rates of and duration of response, relapse and remission Rates of hospitalisation Reduction in use of corticosteroids Rates of surgical intervention Adverse effects of treatment. The reference case stipulates that the cost effectiveness of treatments should be expressed in terms of incremental cost per qualityadjusted life year. Time horizon should be long enough to allow reasonable estimation of expected costs (including adverse events if applicable) and benefits for each of the two clinical situations. Costs will be considered from an NHS and Personal Social Services perspective. Where evidence permits, the appraisal of infliximab for moderate to severely active UC should identify patient subgroups for whom the technology is most appropriate. Where evidence permits, the appraisal of infliximab for moderate to severely active UC should consider the length of treatment required, when patients have responded to infliximab.guidance will only be issued in accordance with the SPC. The outcome measures addressed include health related quality of life assessed using EQ 5D or direct TTO method disease activity assessed using Mayo scores rates and duration of response, relapse and remission estimated using RCTs of Infliximab rates of hospitalisation observed in RCTs reduction in use of corticosteroids estimated using RCTs of Infliximab rates of surgical intervention estimated using RCTs of Infliximab adverse effects of treatment estimated using RCTs of Infliximab Cost effectiveness of treatments expressed as incremental cost per quality adjusted life year Time horizon of 10 years Costs considered from NHS and Personal Social Services perspective A single subgroup of moderate/severe patients was addressed. Patients in whom avoiding surgery is desirable either due to patient s preference or due to clinician s opinion. Page 5 of 104

6 Section B 3 Executive summary Ulcerative colitis (UC) is estimated to affect up to 90,000 people in the UK, with an annual incidence of 5,000 10,000 new cases per year (Calculation based on BSG Guidelines). It is a lifelong condition characterised by diffuse inflammation primarily involving the colon mucosa (BSG Guidelines). The primary symptoms of UC are bloody diarrhoea and abdominal pain and other symptoms include anaemia, weight loss, rectal bleeding and skin lesions. Patients with UC often have recurrent flares of the disease resulting in hospitalisation and an increased risk of surgery. It is estimated that 10 20% of all UC patients will have such acute attacks at any given time. For UC patients the goal of treatment is to induce and maintain remission, and to improve quality of life. Current standard care for these patients comprises a combination of 5 aminosalicylate derivatives, oral or IV corticosteroids and immunomodulators such as 6 mercaptopurine (6 MP), azathioprine (AZA) and cyclosporine. However, 15% of all UC patients will stop responding to or are intolerant to standard care during the course of their disease, and will therefore be eligible for treatment with infliximab. The primary treatment option for such moderate/severe UC patients is surgery. However, surgery is associated with important risks in particular patient groups (e.g. women of childbearing age, young males, and patients with co morbid conditions), will lead to significant post surgical complications in a proportion of patients, and may also impact negatively upon quality of life. On account of the various risks and outcomes of surgical intervention, certain patients will be defined unsuitable for surgical intervention, expressed either as a patient preference not to undergo surgery or as a clinical judgement. As a result of the risks and outcomes of surgery and the preference for some patients to avoid surgical intervention, there is a substantial unmet need in this patient population. Alternative treatment options are therefore an important consideration. The biological therapy, infliximab (Remicade ), is an inhibitor of tumour necrosis factor (TNF), a cytokine that plays a major role in the pathogenesis of UC. Infliximab is the only TNF inhibitor licensed for treatment of UC with its primary competitor being standard care. Infliximab received marketing authorisation in the UK in February 2006 for the treatment of moderately or severely active UC patients who have had an inadequate response to standard care. The current evidence indicates that the clinical response is usually achieved after three doses of infliximab i.e. week 0, 2 and 6 (the induction dose). The Summary of Product Characteristics (SPC) recommends that continued therapy should be carefully reconsidered in patients who show no evidence of therapeutic benefit within this time period. The efficacy of infliximab in the treatment of moderate/severe UC patients has been demonstrated in two randomised controlled trials where the drug was added to an existing regimen of standard care. ACT I and ACT II investigated the efficacy of infliximab maintenance treatment (5 mg/kg) in patients with moderate to severe active UC for 54 weeks and 30 weeks, respectively. In both studies infliximab induced higher response rates and subsequently maintained these over the trial period. Infliximab therapy also produced a sustained improvement in health related quality of life (HRQoL) assessed using the EuroQol (EQ 5D) and Inflammatory Bowel Disease Questionnaire (IBDQ), and was well tolerated. Page 6 of 104

7 Infliximab is available in vials containing 100mg powder to be prepared into a solution for infusion. Each vial costs with an estimated average cost of infliximab treatment for an 80 kg patient of 14,196 in the first year (8 infusions, 5mg/kg at weeks 0, 2 and 6 and every 8 weeks thereafter) including the cost of administration. The average annual cost of treatment decreases to 11,534 in subsequent years (6.5 infusions). A Markov model was constructed based on the placebo controlled studies of infliximab in UC. The model structure and design reflected the current treatment pattern in England and Wales. On account of both the chronic nature of UC and the available clinical evidence base, a ten year time horizon was modelled in the base case. Sensitivity analyses were performed using alternative time horizons. In a similar way to its other license indications, the cost effectiveness case for infliximab in ulcerative colitis is dependent upon the selection of appropriate patients for continued treatment after induction therapy. On this basis, two separate treatment strategies were evaluated using the model. Strategy A modelled the continuation of treatment in those patients demonstrating a clinical response to the induction dose of infliximab and achieving and maintaining mild disease or remission. The results of the economic analyses indicated that the incremental cost per quality adjusted life year (QALY) gained associated with this treatment strategy, was estimated to be 33,866. Strategy B modelled the continuation of treatment only in those patients achieving remission following the induction dose and maintaining remission following each subsequent dose. The incremental cost per QALY gained using this second treatment strategy was estimated to be 25,044. As expected, this second treatment strategy, which aims to target infliximab treatment specifically at only those patients who derive the greatest utility gains, appears to represent the best value for money from the NHS perspective. Alongside the conventional estimates of cost effectiveness presented for infliximab in ulcerative colitis, decisions regarding resource allocation should be made with reference to the unmet needs and preferences expressed by patients for alternative treatment options to surgical intervention. These needs and preferences are likely to be a particularly important consideration in certain patient populations, for example women of child bearing age and young men. It is estimated that recommending infliximab therapy to be used in accordance with the proposed strategy A, in England and Wales for patients with moderate/severe UC would cost up to 13.8 million at year 5 following introduction, assuming an 8 week dosing interval, depending on which treatment strategy is adopted. In conclusion, infliximab is a highly effective and well tolerated therapy for the management of moderate/severe UC patients and provides significant clinical benefit over standard care. Economic analyses demonstrate that the incremental costs associated with achieving these clinical benefits are acceptable, and that infliximab is a cost effective treatment option for patients who achieve and sustain an early remission of the disease. Page 7 of 104

8 4 Context 4.1 Please provide a brief overview of the disease/condition for which the technology is being used. Provide details of the treatment pathway and current treatment options at each stage. The disease Ulcerative colitis (UC) is estimated to affect up to 90,000 people in the UK, with an annual incidence of 5,000 10,000 new cases per year (Calculation based on BSG Guidelines). It is a lifelong condition, with the highest incidence observed between the ages of 10 and 40 years (BSG guideline). UC is an irritable bowel disease (IBD) and is characterised by diffuse inflammation primarily involving the colon mucosa (BSG Guidelines). It starts at the rectum and progresses symmetrically and uninterrupted proximally to a variable extent. The disease extent can be split into Distal (limited to below the splenic flexure) and Extensive (extending proximally to the splenic flexure). The aetiology of UC is unknown, but it is believed to be an immune response in genetically susceptible individuals. The clinical course of UC is marked by flares or exacerbations and remissions, with 50% of patients with UC having a relapse in any given year (BSG Guidelines). The primary symptom of UC is bloody diarrhoea and abdominal pain; other symptoms include anaemia, weight loss, rectal bleeding and skin lesions. A number of treatment options exist for UC, depending on the disease activity and extent. In maintenance therapy, drug options include 5 aminosalicylate derivatives of sulphasalazine (5 ASA derivatives) and some immunomodulators such as 6 mercaptopurine (6 MP), azathioprine (AZA), and now infliximab. Short term maintenance or rescue therapies include cyclosporine and corticosteroids either in intravenous (IV), oral or topical form. Surgery is also indicated. About 55% of patients with UC may have chronically active disease, which is subject to repeated flares every few months, monthly or daily (NACC European Survey 2006). The flares often require IV corticosteroids with many unwanted side effects (e.g. cataract, Cushing, osteoporosis, hypertension, hyperglycaemia, etc.). Until now for such patients surgery was the only remaining choice once other therapies were deemed ineffective or inappropriate, although it is not desired by many patients. Drug Therapy Overview The British Society of Gastroenterologists published in 2004 a guideline for the management of inflammatory bowel disease in adults. This guideline sets out recommendations for the diagnosis and monitoring of UC as well as its treatment through drugs. The drugs and their action are outlined below. A tabular summary of the BSG 2004 recommendations for the drug treatment of UC are given in Table 1. Page 8 of 104

9 Aminosalicylates including 5 aminosalicylic acid (5 ASA) These drugs are available in tablet, liquid, suspension, enema or suppository forms, and act in a variety of ways to control the action of epithelial cells in releasing lipid mediators, cytokines and other molecules. Corticosteroids This class of therapy includes a wide range of molecules delivered by a variety of methods including topical suppositories, enemas, oral tablets, and intravenous infusions. Many strategies attempt to maximise topical effects while limiting systemic side effects of steroids. Intravenous corticosteroids are given in the event of UC flares requiring rapid control. They have powerful anti inflammatory effects, but are not recommended as maintenance therapy for UC because of their side effect profile as previously mentioned and potential for dependency. Thiopurines Purine antimetabolites inhibit ribonucleotide synthesis, but the mechanism of immunomodulation is by inducing T cell apoptosis by modulating cell (Rac1) signalling. Azathioprine is metabolised to mercaptopurine and subsequently to 6 thioguanine nucleotides. T(h)ioguanine has been used for treatment of IBD, but caution is appropriate because of potential hepatotoxicity. Thiopurines are effective for both active disease and maintaining remission in UC. Cyclosporine Cyclosporine A (CsA) is an inhibitor of calcineurin, preventing clonal expansion of T cell subsets. It has a rapid onset of action and is effective in the management of severe UC flares. The use of cyclosporine is controversial because of toxicity and long term failure rate; also a Cochrane review has concluded that the majority of scientific evidence has not demonstrated significant efficacy over placebo (Shibolet et al 2005). Infliximab Infliximab, an anti TNF α monoclonal antibody, was approved by the EMEA in 2006 for the treatment of adult patients with moderately to severely active UC, whose response to conventional therapy including corticosteroids and 6 MP or AZA has been inadequate, or who are intolerant to or have medical contraindications for such therapies. Table 1. BSG Recommendations for Drug Treatment of UC Drug Aminosalicylates Corticosteroids BSG recommendation Use in maintenance Use to control symptoms Do not use in maintenance Thiopurines Cyclosporine Infliximab Exercise care to manage dependency Use in active disease flares and in maintenance Use in short term maintenance Do not exceed treatment duration of 1 year No recommendations at present in BSG guideline as UC license was granted after 2004 publication of guideline Surgery Surgery for UC is indicated for the following broad indications: Page 9 of 104

10 Emergency surgery, although infrequent, is undertaken for life threatening complications such as toxic megacolon, colonic perforation and massive haemorrhage. This is emergency surgery. More commonly surgery is undertaken for acute or severe disease characterized by treatment refractoriness; frequent flare ups; extra colonic manifestations; chronic corticosteroid dependence; side effects / intolerance / complications from medications, in particular steroids; or clinician s judgment. Another reason for surgery is related to presence of epithelial dysplasia in biopsies or proven cancer. Whatever the indication the surgery aims to remove the diseased colon completely and reconstruct the remaining bowel. The set of procedures required to treat UC are given in Figure 1. Figure 1. Overview of surgical procedures in management of UC Proctocolectomy is the surgical procedure to remove the colon and rectum. The procedure eliminates all possibly afffected colon from the caecum to the distal rectum and therefore involves a pelvic dissection down to the anus. The intervention is rarely completed in a single operation; it is often a 2 or 3 stage process sometimes taking place over 12 months. The small intestine is formed into a pouch and attached to the anus to reestablish the continuity of the digestive tract. This new pouch, called the ileoanal pouch, serves as a reservoir for waste. Its emptying is controlled by the anal and rectal muscles. Page 10 of 104

11 Since the ileoanal pouch requires more than a month to heal, a temporary ileostomy is formed. The ileostomy is an opening in the abdominal wall, where waste exits the small intestine. The temporary exit is upstream to the newly formed ileoanal pouch. After a couple of months, the patient will return to have the ileostomy reversed. Combined, this procedure is referred to as total proctocolectomy with ileal J pouch anal anastomosis (IPAA). 4.2 What was the rationale for the development of the new technology? Infliximab is an established technology whose efficacy and safety in other indications have already been evaluated in NICE and SMC technology appraisals. Preclinical and clinical data suggest an important role for TNF in the pathogenesis of UC. Patients with UC have demonstrated increased concentrations of serum TNF which vary with disease activity (Murch et al 1991, Schurmann et al 1992, Maeda et al 1992). Rodent models of chronic colitis have shown that compounds, such as anti TNF antibodies, that down regulate the production or activity of these inflammatory cytokines are able to reduce the severity of intestinal inflammation (Powrie et al 1994, Neurath et al 1996). There is a significant unmet need in the therapeutic choices of patients who have chronically active moderate to severe UC, and it was for this indication that the infliximab license was sought. 4.3 What is the principal mechanism of action of the technology? Infliximab is a chimeric murine human immunoglobulin G1 monoclonal antibody. Infliximab is known as Tumour Necrosis Factor Alpha (TNF α) inhibitor because it antagonizes the vital inflammatory cytokine TNF α. Infliximab (REMICADE ) is an anti TNFα monoclonal antibody developed as a therapeutic agent for various diseases in which TNFα is thought to mediate chronic inflammation. This antibody is a recombinant IgG1k, human murine chimeric monoclonal antibody that specifically and potently binds and neutralizes TNFα and its membrane bound precursor. This high affinity binding prevents the interaction of TNFα with its cellular receptors, thus attenuating inflammatory and other deleterious effects secondary to TNFα overproduction. 4.4 What is the suggested place for this technology with respect to treatments currently available for managing the disease/condition? Infliximab is indicated for the treatment of moderately to severely active UC in patients who have had an inadequate response to conventional therapy including corticosteroids and 6 MP or AZA, or who are intolerant to or have medical contraindications for such therapies. Page 11 of 104

12 4.5 Describe any issues relating to current clinical practice, including any variations or uncertainty about best practice. Real life clinical practice Infliximab s indication covers patients with moderately to severely active UC whose response to, or tolerance of, conventional therapy is unsatisfactory. The infliximab license was applied for to address an unmet need in these patients. Previously in these patients the only available treatment option was surgery. Since the granting of infliximab s license, clinicians in current practice routinely prescribe infliximab maintenance therapy to these patients. Infliximab is especially beneficial within those subgroups where surgery is not a preferred option. Some key oppositions to surgery include: Surgery is deemed high risk because of an existing comorbid condition Patient is a woman of child bearing age; concern about infertility as a result of extensive pelvic surgery Patient is a man; concern about impotence, retrograde ejaculation or incontinence as a result of extensive pelvic surgery Perceived impact on body image of a stoma Quality of life after surgery Ina recent survey of 281 UC patients in the UK, over 90% of respondents expressed a preference to try new drug therapy before undertaking surgery (NACC European survey 2006). Clinicians in current practice have also been observed to administer a single dose of infliximab, off label, as rescue therapy in patients with active moderate to severe UC who are admitted to hospital because of an acute severe flare that proves refractory to intravenous corticosteroids. Sequelae of surgery A review by Lichtenstein et al (2005) identified some of the sequelae of surgery which are outlined below. Surgery Quality Presently, surgery in UC has been poorly appraised and there is potential for large variation in the degree of surgery success, due to factors at the patient, operator, and hospital level. There is no Cochrane review directly addressing this variation, although the Lichtenstein et al (2005) review identified published statistics citing overall pouch failure rates of 6.8% after IPAA rising to 8.5% with a follow up longer than 5 years. Pouch failure is characterized as a clinical complication necessitating pouch removal and fitting of an ileostomy or proximal diversion. Despite the evidence of IPAA failure, the published papers investigating the sequelae of surgery do not consistently take account of how well the procedure was executed; rather all studies view the surgery as having been equally successful. Complications IPAA is the most common surgical intervention for UC. It is a complex operation bearing risk of marked complications including bowel obstruction (2% to 13%), anastomotic stricture (9% to 24%), and pouch leakage with pelvic abscess (5% to 18%). Following surgery, pouchitis may develop in 8% to 48% of patients, with chronic pouchitis developing in up to 20% of patients. Irritable pouch syndrome was also identified. Page 12 of 104

13 Mortality Lichtenstein et al (2005) analysed the mortality and morbidity rates from several studies all with n>100. The estimated overall mortality rates between 0% and 1% and overall morbidity rates between 5% to 63%). Quality of Life Here the Lichtenstein review noted that studies in QOL post surgery did not collect data consistently: many studies did not assess QOL pre surgery. Furthermore the studies had conflicting findings, with some reporting an improvement in QOL scores and others reporting a decline. Thus, the authors concluded by accepting the null hypothesis that there was no change in QOL subsequent to surgery. Sexual Function and Fertility The Lichtenstein review also noted sexual dysfunction and fertility problems following surgery. Impotence and retrograde ejaculation were reported in 0% to 3% of men after IPAA. In women after IPAA, significant vaginal discharge was reported in up to 56%, dyspareunia in 38%, decreased vaginal sensitivity in 25%, as well as faecal leakage during intercourse. A recent meta analysis reported a pooled incidence of 3.6% for sexual dysfunction. Fertility in women was also considered, and studies identified which noted significantly lower fertility of women with UC both preoperatively, where women with UC had a birth rate 87% of that expected, as well as postoperatively where this figure declined significantly to 49%. Twenty nine percent of these postoperative births were achieved through in vitro fertilisation. Other studies also identified decreased fecundity in women after surgery. Cyclosporine Cyclosporine is a systemic drug which is often used in ʺrescueʺ therapy. According to expert opinion, the use of cyclosporine in clinical practice is sporadic and declining, with only a few centres regularly using the drug in UC. This low level of use in the NHS is thought to be due to three factors: i. the lack of a license for cyclosporine in UC ii. the lack of compelling efficacy evidence. A Cochrane Review (Shibolet et al 2005) found that cyclosporine did not perform significantly better than placebo in a comprehensive sample of RCTs iii. difficulties with its use, especially around toxicity and side effect profile Accordingly, cyclosporine has not been included as a comparator in this report. 4.6 Provide details of any relevant guidelines or protocols. The British Society of Gastroenterology has published Guidelines for the management of IBD including Crohn s disease and UC. Infliximab is recommended as a treatment option for Crohn s disease in these guidelines, but it is not mentioned as a UC therapy. At the time of the guideline s publication infliximab was not licensed for the treatment of UC. NICE has also produced guidelines for the use of infliximab in the management of Crohn s disease ( Guideline 40). Page 13 of 104

14 5 Clinical evidence 5.1 Identification of studies A Cochrane review of infliximab for UC was conducted by Lawson et al (latest update 2006). The selection criteria in this review defined a very similar field of study to that required for the current submission. Accordingly, references from the Lawson review were taken as a starting point for this section. A confirmatory literature search was subsequently carried out, using slightly broader criteria, to ensure that the list of relevant references from Lawson et al (2006) was comprehensive. Full details of this search are given in the Appendix; no additional papers of relevance to the main efficacy analysis were identified in this search, excepting the two clinical study reports which were retrieved through by way of a request to the manufacturer. 5.2 Study selection Complete list of RCTs Infliximab trials identified The search strategy identified 7 RCTs involving infliximab in ulcerative colitis. All studies had placebo as comparator. Table 2. Complete list of infliximab RCTs Trial ID Reference(s) n Intervention Comparator Primary Endpoints ACT I Rutgeerts et al Infliximab Placebo Remission Response ACT II 364 Infliximab Placebo Remission Response Järnerot et al Infliximab Placebo Remission Response Probert et al Infliximab Placebo Remission Response Sands et al Infliximab Placebo Remission Response Armuzzi Infliximab Methylprednisolone Remission Ochsenkuhn 13 Infliximab Prednisolone Response Corticosteroid dose increase or surgery Remission Inclusion and exclusion criteria RCTs of infliximab efficacy were considered relevant if they were placebo controlled, with randomised allocation to the two arms. All patients with UC were considered, but each paper was required to study patients included in infliximab s license indication. It was also required that the studies had as their primary, or co primary, endpoint a relevant clinical outcome such as remission, response, treatment failure or surgery. Systematic reviews were scanned manually to identify any new RCTs referred therein. Page 14 of 104

15 5.2.3 List of relevant RCTs Five relevant infliximab RCTs were identified, as summarized in Figure 2. The five relevant infliximab RCTs have been written up in peer reviewed journal articles. Two RCTs were manufacturer sponsored (Centocor). Where possible, the published results are given, however it has been necessary to include some commercial in confidence (CiC) information. This has been highlighted as follows: Example Commercial in Confidence. The list of relevant RCTs is given in Table 3. Page 15 of 104

16 Table 3. List of Relevant Infliximab RCTs Trial Name Reference and (ID number) location ACT I Rutgeerts et al 2005 International Design Participants Length Intervention Comparator Primary and Secondary Endpoints Phase III, randomised, multi centre, doubleblind, placebocontrolled trial N = 364 Adults with moderate to severe UC 54 weeks Infliximab 5mg/kg (n=121) 10mg/kg (n=122) Placebo (n=121) % patients achieving clinical response at week 8 (Mayo score definition) Clinical remission (Mayo) and mucosal healing at week 8, 30, 54. Clinical response (Mayo) or remission (Mayo) with discontinuation of steroids at week 30, week 54 ACT II Rutgeerts et al 2005 International Järnerot et al 2005 Sweden Denmark Probert et al 2003 United Kingdom Sands et al 2001 United States Phase III, randomised, multi centre, doubleblind, placebocontrolled trial double placebo Randomised, multicentre, blind, controlled Randomised, multicentre, double blind, placebo controlled trial Randomised, multicentre, double blind, placebo controlled trial UCSS, Ulcerative Colitis Symptoms Score; UC, Ulcerative Colitis N = 364 Adults with moderate to severe UC N = 45 Adults with moderate to severe UC not responding to conventional treatment N = 43 Adults with established UC not responding to glucocorticoids and not in need of urgent colectomy N = 11 Adults with active, severe, steroid refractory UC who were hospitalised for disease management 30 weeks Infliximab 5mg/kg (n=121) 10mg/kg (n=120) 3 months Infliximab (n=24) 4mg/kg or 5mg/kg 6 Weeks Infliximab (n=23) 5mg/kg (Open label infliximab 10mg/kg for patients without wk 6 remission) 12 weeks Infliximab 5mg/kg (n=3) 10mg/kg (n=3) 20mg/kg (n=2) Placebo (n=123) Placebo (n=21) Placebo (n=20) Placebo (n=3) Hospitalisation and Surgery % patients achieving at week 8: Clinical response Clinical remission and mucosal healing at week 8.30 Clinical response or remission with discontinuation of steroids at week 30 Hospitalisation and Surgery % patients at month 3 avoiding death and/or colectomy Clinical and endoscopic remission in patients not undergoing colectomy % patients achieving at week 6: remission as defined by UCSS Change from baseline in: Baron score IBDQ EuroQol % patients week 2 failing therapy, defined by: Lack of response Corticosteroid or cyclosporine booster Non elective colectomy Death Page 16 of 104

17 Figure 2. Selection of Relevant infliximab RCTs References Identified: Embase: 363 Medline: 124 CCTR: 26 (26) Total: 513 Potentially relevant RCTs identified and screened (n=7) Papers excluded with reasons (No new papers identified beyond base list from Lawson et al 2006) Reasons for exclusion: Already included Not UC population Juvenile data Infliximab not a study drug Posters, Talks, Abstracts, Editorials RCTs excluded with reasons Control was not placebo: 2 Relevant RCTs included in discussion: n= List of relevant non randomised controlled trials It was not necessary to seek further information from non randomised trials Ongoing studies The following trials are ongoing in UC infliximab treatment: P04807: Comparison of the efficacy of infliximab / Azathioprine combination therapy and Infliximab monotherapy to azathioprine monotherapy in moderately to severely active UC (part 1) and a follow up safety and efficacy study (part 2) to compare scheduled to episodic infliximab treatment in maintaining remission P04808: Ulcerative Colitis European Registry. A Prospective, Observational, Non Interventional, Post Marketing Safety Surveillance Program. 168T62: A Multicenter International Study of the Long term Safety of Infliximab (REMICADE ) in Ulcerative Colitis Page 17 of 104

18 5.3 Summary of methodology of relevant RCTs Description of Common Outcome Measures The relevant infliximab RCTs assessed clinical remission or clinical response, derived from a variety of disease scales. The scales differ in how they are calculated, but in general, clinical remission is defined as a clearance of symptoms as measured by these scales; and clinical response is defined as a marked reduction in symptoms measured by the scales. An overview of the scales used in the relevant RCTs is found in the Appendix, along with a brief explanation of their use in defining clinical remission and response. Short Overview of All Relevant RCTs ACT I/II Two large, placebo controlled, Phase 3 trials (ACT I and ACT II) were conducted to evaluate the safety and efficacy of infliximab in patients with active UC. Study participants were randomised to receive infliximab 5 mg/kg, infliximab 10 mg/kg, or placebo. Their main efficacy results were written up in the NEJM (Rutgeerts et al 2005). Induction of clinical response, the primary endpoint, was evaluated 8 weeks following the initial infusion. Major secondary endpoints were evaluated at Weeks 8 and 30 (response, remission and mucosal healing), and the ACT I trial assessed these outcomes at week 54 also. Clinical response was defined by a >30% and >3 point reduction in the Mayo score accompanied by a decrease in the rectal bleeding subscore of >1 or a rectal bleeding score of 0 or one. Clinical remission (Mayo score <2, with no individual subscores >1) and mucosal healing (endoscopy subscore of 0 or one) were also evaluated. Concomitant treatment with stable doses of aminosalicylates, corticosteroids and/or immunomodulatory agents was permitted. Corticosteroid taper was permitted after week 8. Sands et al 2001 Sands et al conducted a Phase II trial to evaluate the efficacy, safety, and tolerability of REMICADE in patients with severe UC. This trial was a randomised, multi center, placebocontrolled, double blind study in 11 patients with active UC refractory to intravenous corticosteroid therapy. Patients were randomised to receive a single, intravenous infusion of REMICADE at doses of 5 (n=3), 10 (n=3), or 20 mg/kg (n=2) or placebo (n=3). The primary endpoint for this trial was treatment failure at the 2 week evaluation. Treatment failure was defined as one or more of the following criteria: failure to achieve a clinical response (defined as a modified Truelove and Witts Severity Assessment of <10 and a 5 point reduction from baseline), colectomy, addition of immunosuppressants or an increase in corticosteroids to a dosage above 60 mg/day, and death. Despite initial intentions to enroll 60 patients, slow enrollment required early termination of the study after 11 patients (1 female and 10 males) had been enrolled. At baseline, all patients were receiving concomitant corticosteroids, and most were receiving concomitant 5 ASA or AZA/6 MP. Page 18 of 104

19 Probert et al 2003 Probert et al conducted a double blind, placebo controlled study of REMICADE in the treatment of moderately severe steroid resistant UC. During screening, all patients were required to have received treatment for relapse with at least 30 mg prednisolone (or equivalent) for at least one week. Despite treatment, these patients presented with active UC, defined as an ulcerative colitis symptom score (UCSS) of 6 and a sigmoidoscopy score of >2 on the Baron scale. Forty three patients (mean age years) were randomised to receive either REMICADE 5 mg/kg (n=23) or placebo (n=20) at weeks 0 and 2. The primary endpoint was clinical remission defined as a UCSS of <2 and/or Baron score of 0 at week 6. Secondary endpoints included changes in UCSS, Baron score, disease activity, quality of life (QOL), C Reactive Protein (CRP) levels, change in daily glucocorticoid dose and safety, which were assessed at weeks 0, and 6. Patients who were not in remission at week 6 were offered openlabel REMICADE 10 mg/kg and were assessed 2 weeks later. Järnerot et al 2005 Järnerot et al conducted a randomised, parallel, double blind trial in patients with acute severe or moderately severe UC unresponsive to intensive intravenous corticosteroids (IIVT [betamethasone 4 mg twice daily]). Twenty four patients were randomised to additional treatment with a single dose of REMICADE (5 mg/kg or a dose close to 5 mg/kg) plus IIVT therapy and 21 patients were randomised to placebo plus IIVT therapy. The Seo Index was used to determine entry into the trial. Clinical remission or mild UC was defined as a score <150, moderate severe UC was and severe UC was >220. Patients with a Seo Index >150 were potential candidates for REMICADE if IIVT failed. On day 0, IIVT was initiated. The fuliminant colitis index was calculated on day 4. Patients with a score >8 were subsequently randomised to receive REMICADE or placebo. Furthermore, the Seo Index was calculated on days 6, 7 and 8. Patients with a score >150 on any of these days were also randomised to REMICADE or placebo. Concomitant and/or additional medications were permitted in the study (i.e. mesalamine, azathioporine). Patients were switched to oral prednisone 40mg/day and tapered by 5 mg/day each week. The primary endpoint was colectomy or death within 3 months after randomisation. Secondary endpoints included clinical and endoscopic remission at 1 and 3 months after the infusions. Page 19 of 104

20 5.3.1 Methods Sands 2001 Design This was a multicenter, prospective, randomised, placebo controlled study designed to assess the efficacy, safety, and tolerability of infliximab in the treatment of patients with severe UC. However, the study was terminated due to slow enrollment after the eleventh of 60 planned patients. Dosage Patients who met the eligibility requirements were randomly assigned to receive a single, intravenous infusion of placebo or infliximab at 5, 10, or 20 mg/kg body weight. Procedure The study was conducted in three phases or periods a pre enrollment and screening period, a 2 week blinded treatment and evaluation period, and a 10 week follow up period. Clinical response was assessed prior to the infusion of study medication and at 72 hours and 1, 2, 4, 6, and 12 weeks after infusion, or until treatment failure was observed. Patient weight, a modified Truelove and Witts severity assessment score, and physician and patient global evaluations were obtained at each assessment. Endoscopic and histologic responses were determined by sigmoidoscopy and biopsy within 7 days before the infusion of study medication and at 2 and 6 weeks after infusion. Endoscopic assessment of disease activity was scored as quiescent, mildly active, moderately active, or severe according to the Blackstone classification (20). Laboratory response was evaluated by erythrocyte sedimentation rate (ESR) and serum levels of C reactive protein (CRP) determined immediately before infusion and at 72 hours and 1, 2, 4, 6, and 12 weeks following the infusion. Blood levels of TNF and IL 6 were determined immediately before infusion and at 1 and 24 hours and 2, 4, and 6 weeks following the infusion. All medications administered during the screening period and throughout the 12 week trial were recorded. Patients were permitted to receive sulfasalazine, mesalazine, antibiotics, azathioprine, 6 mercaptopurine, or antidiarrheal drugs at stable doses. The treating physician was allowed to alter medications for the benefit of the patient; however, any changes in medications that met the criteria for treatment failure (addition of cyclosporine or other immunomodulators within 2 weeks of study infusion, or an increase in corticosteroid dosage) were to be considered as treatment failures, even if the patient s clinical status improved. Randomisation and Blinding The randomisation strategy is not given in the paper write up of this study. Safety Probert 2003 Safety evaluations during the study period included measurements of vital signs, hematology and clinical laboratory measurements, and occurrence of adverse experiences. Design In a randomised, double blind, placebo controlled study conducted in four centres in the UK and Germany, we evaluated the role of infliximab in the treatment of patients with moderately severe glucocorticoid resistant ulcerative colitis. Dosage All patients were randomised to receive a blinded infusion of infliximab 5 mg/kg body weight or placebo at week 0 and a second identical infusion at week 2. Procedure Following the initial infusions at weeks 0 and 2, patients were reassessed at week 6 and those who continued to have active ulcerative colitis were offered open label treatment with 10 mg/kg infliximab. The second infusion was given to see whether it offered any additional benefit over the first. The option to receive open label treatment was included to ensure non responders who may have received placebo had the opportunity to have active treatment, in addition to determining whether the third Page 20 of 104

21 dose could bring about remission in those patients who failed to respond to the first two doses. Importantly, at that stage, the investigators remained blinded to the nature of the earlier infusions. Randomisation and Blinding Consecutive patients who met the inclusion and exclusion criteria were recruited. Each centre was allocated a series of patient numbers by Schering Plough. Each number was randomly assigned to either treatment group based on blocks of four within each centre. The local pharmacists and investigators were blinded to the treatment each patient received. Safety Järnerot 2005 Serious adverse events during the study period and the following 30 days were recorded in compliance with good clinical practice. Serious adverse events were defined according to the latest International Committee on Harmonisation. This included patients who underwent colectomy during the study period and the following 30 days. Design This was a randomised double blind trial of infliximab or placebo in severe to moderately severe ulcerative colitis not responding to conventional treatment. All patients received infliximab in addition to a standard betamethasone treatment. There were 9 Swedish centers and 1 Danish center, covering 7 hospital regions, recruiting patients for the study. Dosage On day 0, IIVT with betamethasone 4 mg intravenously twice daily was started. No rectal treatment was given. When a patient was randomised to infliximab/placebo, a dose as close as possible to 5 mg/kg was given as a slow infusion. Procedure The patients were monitored clinically on a daily basis by the gastroenterologist and the surgeon. Decisions about continued medical treatment or emergency colectomy were made on clinical grounds. When switching to oral medication, prednisolone 40 mg daily was given with a dose reduction of 5 mg/day each week. Maintenance treatment with a mesalamine based drug was started or continued. Azathioprine mg/kg body weight could be added according to the individual investigator s judgment. As prophylaxis against opportunistic infections, trimethoprim 160 mg and sulfamethoxazole 800 mg was prescribed daily for 8 weeks. In patients who did not receive surgical therapy, a new endoscopy was performed 10 14, 30, and 90 days after the infliximab/placebo infusion. At the same time, blood tests were taken, and the Seo index was calculated. Randomisation and Blinding In each of the regions, a local randomisation list was placed in 1 pharmacy. Randomisation, which was performed in blocks of 4, was known only by the statistician. Patients to be treated were reported to the pharmacy with their birth number, name, and weight for correct dosing. Preparation of the solution for infusion was performed in the pharmacy and delivered to the ward to blind the investigator. Safety ACT I The study s procedure for tracking monitoring adverse events is not detailed, however the procedure states that all patients were monitored clinically on a daily basis by the gastroenterologist and the surgeon, and that decisions about continued medical treatment or emergency colectomy were made as required. Design This was a randomised, multicentre, placebo controlled, double blind trial to evaluate the safety and efficacy of infliximab in patients with active, severe ulcerative colitis. Approximately 360 subjects were to be enrolled in this study with equal allocation to each of 3 treatment groups: Page 21 of 104

22 Group I Placebo Group II: Infliximab 5 mg/kg Group III: Infliximab 10 mg/kg Dosage Infliximab infusions of 5 mg/kg and 10 mg/kg were chosen based on the pharmacokinetics of infliximab in subjects with Crohn s disease, an inflammatory bowel disease with an etiology thought to be similar to that in ulcerative colitis. Procedure Subjects in all 3 treatment groups were to have induction infusions at Weeks 0, 2, and 6, followed by maintenance infusions every 8 weeks up to Week 46 (ie, Weeks 14, 22, 30, 38, and 46). Primary and secondary efficacy parameters were measured at each interval, to study end at week 54. Randomisation and Blinding Before the first infusion, subjects were randomly assigned in a 1:1:1 ratio to 1 of 3 treatment groups: placebo (Group I; n = 120), 5 mg/kg infliximab (Group II; n = 120), or 10 mg/kg infliximab (Group III; n = 120). Subjects were randomly assigned to 1 of the 3 treatment groups using an adaptive randomisation procedure, with investigative site and corticosteroid refractory status as the stratification factors. Treatment assignment for a given subject was determined by Covance s code protected Interactive Voice Response System (IVRS). The site called the IVRS to randomize a subject, at which point a 6 digit subject number was assigned to the subject. Treatment assignments were stored electronically. After the randomisation call, an automated fax, which contained no information regarding treatment assignment, was sent to the site coordinator confirming the randomisation. A second automated fax confirming the randomisation, which also included the subject s treatment assignment, was sent to the unblinded site pharmacist. Safety At each study visit, subjects were questioned about the occurrence and nature of AEs or symptoms. All AEs occurring after randomisation through the Week 54 visit were to be recorded on the appropriate AE CRF page. Safety evaluations were conducted at each evaluation visit and included the measurement of vital signs, the assessment of adverse events that occurred during and for 1 hour after the completion of the infusion of study medication, and the assessment of any adverse events that may have occurred between evaluation visits. Routine laboratory tests and blood samples for tests, including the determination of infliximab concentrations, the presence of antibodies to infliximab, and the presence of autoantibodies were performed and collected as indicated in the protocol. A physical examination was completed at screening and at Week 54. ACT II Design ACT II was a 30 week randomised, double blind, placebo controlled, multicentre, parallel group study. Approximately 360 subjects were to be enrolled in this study, with equal allocation to each of 3 treatment groups: Group I Placebo Group II: Infliximab 5 mg/kg Group III: Infliximab 10 mg/kg Dosage The infliximab dosing choice was based on the same logic as that in ACT I. Page 22 of 104