The impact of updated NICE guidelines on biologic treatment of ulcerative colitis: reflections on past practices, the changing present and implications for the future

KEYWORDS:

• Adalimumab
• anti-TNF
• golimumab
• infliximab
• NICE
• vedolizumab

1. Introduction

The advent of biologic therapies has led to significant changes in treatment strategies for ulcerative colitis (UC). Over the past decade, large-scale randomized controlled trials (RCTs) have demonstrated the efficacy of the antitumor necrosis factor (anti-TNF) alpha therapies comprising infliximab,[1] adalimumab, [2,3] and golimumab.[4,5] More recently, a selective leukocyte adhesion molecule inhibitor, vedolizumab,[6] has been shown to be effective in the treatment of UC. The approval of these agents by the European Medicines Agency (EMA) and the National Institute for Health and Care Excellence (NICE) has resulted in a paradigm shift in many aspects of UC care. Here, we consider the impact of recent NICE guidance on the use of these agents and changes in the management of UC over time.

2. The past

Prior to biologic therapies, options for treatment of UC primarily consisted of the stepwise use of mesalazine, corticosteroids, and immunomodulators for disease of increasing severity. Mesalazine was used to achieve and maintain remission in mild-to-moderate UC with the addition of corticosteroids for those failing to respond or with more severe disease. Patients with colitis refractory to intravenous (IV) corticosteroids received cyclosporin or underwent colectomy. However, cyclosporin use is limited by toxicity, and alternative strategies, such as white cell apheresis, have not been widely adopted due to insufficient efficacy.[7] Alternate immunosuppressive approaches, such as the use of tacrolimus, have shown promise but have failed to become integrated into common clinical practice due to safety concerns.

Infliximab was granted EMA approval for use in UC in 2006, having previously been approved a year earlier by the US Food and Drug Administration. It had also been licensed for use in Crohn’s disease (CD) since 1999. NICE subsequently carried out their own program of technology appraisals regarding the use of infliximab for subacute manifestations (TA140, published in April 2008) and acute exacerbations of UC (TA163, published in December 2008). The outcome of these appraisals was that infliximab was recommended as an option for the treatment of acute exacerbations of severely active UC, in patients for whom cyclosporin is contraindicated or clinically inappropriate. However, it was not recommended for the treatment of subacute manifestations of UC. It should be noted that NICE use a version of the Truelove and Witts criteria, with subsequent modifications, to stratify disease activity. Based on this index, an ‘exacerbation of severely active UC’ would constitute more than six bowel movements daily in addition to evidence of systemic illness (tachycardia, fever, anemia, or a raised erythrocyte sedimentation rate). Patients fulfilling these criteria normally require hospitalization and emergency care and are more commonly described as having acute severe UC (ASUC). ‘Subacute’ patients, who at that time did not qualify for infliximab treatment, were defined as having more than four bowel movements daily in the absence of systemic illness. Though the choice of disease activity index differs, this latter group of patients would actually fit closely with the moderate-to-severely active patients recruited to the landmark RCTs of infliximab, active ulcerative colitis trials (ACT) 1 and 2.[1]

The guidance issued by NICE in 2008, therefore, generated a great deal of debate and clearly influenced practice patterns over the subsequent 7 years, up to the recent revised guidance. There was a degree of consternation among clinicians and patients alike that access to a potentially life-altering treatment (based on health-related quality-of-life studies [8]) would be restricted to a minority of patients. However, most clinicians did recognize that NICE appraisals employ exhaustive and complex bespoke health economic models and that infliximab is significantly more expensive than conventional therapies for UC. NICE estimates that the total cost of continuing therapy at a standard dosage for a patient weighing 73 kg is approximately £12,584 each year. This figure is in sharp contrast with an annual cost of approximately £65 to treat the same patient with azathioprine. In addition, although for some patients infliximab offered the only alternative to colectomy, the rates of corticosteroid-free remission at 1 year in ACT were modest at approximately 25%, with similar rates of complete mucosal normalization (Mayo 0) at week 8. Nonetheless, in certain ‘subacute’ circumstances, clinicians still felt that infliximab treatment was the correct course of action for their patients, especially when considering that the same patient would qualify for treatment in many European countries as well as in North America. Indeed, NICE guidance was at loggerheads with subsequently published guidance from the European Crohn’s and Colitis Organisation.[9] These conflicting positions resulted in some patients being unnecessarily being admitted to hospital, thus classifying them as having ASUC and qualifying them for rescue infliximab therapy, when, in reality, they could have been treated as outpatients. Following their first dose of ‘rescue’ therapy, patients then qualified for two subsequent doses (at weeks 2 and 6) to complete their induction therapy but could not be commenced on maintenance therapy thereafter. Although this process could be repeated as necessary, it had been known since 2004 (albeit from trials in CD, rather than UC) that episodic therapy with infliximab was less effective than scheduled treatment.[10] Moreover, subsequent direct evidence of anti-TNF withdrawal (in this case golimumab) after induction therapy in UC has shown it to be less effective than proceeding to maintenance therapy.[5] Accordingly, in an attempt to avoid colectomy, infliximab was being used in a suboptimal way. In some cases, access to infliximab or adalimumab was sought on a named-patient basis using an individual funding request, stating the ‘exceptional circumstance’ of the case. However, this frequently resulted in lengthy delays (in some cases many months) in crucial treatment decisions and often ended in the treatment being denied as the circumstances were, in reality, not exceptional.

Despite gaining approval for moderate-to-severe UC by the EMA and US Food and Drug Administration (FDA) in 2012, adalimumab was not fully considered by NICE until 2015. Their technology appraisal of adalimumab for the treatment of moderate-to-severe ulcerative colitis (TA262) was terminated in 2013 as ‘no evidence submission was provided by the manufacturer’. The EMA and FDA had based their approvals on results generated in ulcerative colitis long-term remission and maintenance with adalimumab (ULTRA) 1 and 2. The efficacy of induction therapy was demonstrated in ULTRA 1,[2] a phase III, randomized, double-blind, placebo-controlled study conducted across 94 European and North American centers. The value of maintenance therapy was subsequently demonstrated in ULTRA 2,[3] with the combined trial program including over 900 patients. However, due to the lack of NICE approval, adalimumab was not made available for use in UC in the UK. Furthermore, as there was no evidence for its effectiveness in ASUC, it was not available as a rescue therapy.

3. The present

In February 2015, NICE issued updated guidance based on a renewed multiple technology appraisal (TA329) of anti-TNF agents available to treat UC, comprising infliximab, adalimumab, and golimumab. Shortly after, in June 2015, their single technology appraisal (TA342) of vedolizumab (a selective leukocyte adhesion molecule inhibitor) was published. These appraisals have proved to be a pivotal moment in the treatment of UC as approval was granted for the use of all four agents in moderate-to-severe disease UC, after the failure of conventional therapy, or where it is inappropriate.

Approval of the three anti-TNF agents was based upon a comprehensive (70,000-word) technology assessment report commissioned by the National Institute for Health Research and carried out by the School of Health and Related Research (ScHARR) Technology Assessment Group. ScHARR is a division of the University of Sheffield and specializes in the synthesis of research regarding the clinical effectiveness and cost-effectiveness of health-care interventions. They considered evidence from 10 RCTs identified in a systematic review (five relating to infliximab, [1,11-13] three adalimumab, [2,3,14] and two golimumab [4,5]). All were placebo controlled, with the exception of UC SUCCESS,[11] which demonstrated that infliximab in combination with azathioprine was superior to either therapy alone.

The evidence considered by NICE regarding vedolizumab was generated by GEMINI 1,[6] a multinational, double-blind, placebo-controlled RCT. They employed a similar cost-effectiveness model to that used for anti-TNF therapy and in June 2015 their technology appraisal (TA342) recommended the use of vedolizumab in moderate-to-severely active UC, failing conventional therapy.

4. The future

These approvals have resulted in a step change in the management of patients with UC and have already been widely adopted into treatment algorithms. They have allowed clinicians and patients to choose the most appropriate treatment on an individual basis, based on factors such as preferred route of administration (IV or subcutaneous), previous treatment exposure (anti-TNF failure), and risks of systemic immunosuppression (mechanistically, less concerning with vedolizumab). Moreover, they have allowed these decisions to be actioned in a timely manner. The updated guidance has also resulted in a meaningful change to patients’ lives, both judged anecdotally and based on extrapolation from trial data.[8] In addition, they have resulted in a more rewarding pattern of practice for clinicians and allied health professionals, such as clinical nurse specialists and pharmacists. However, many questions remain regarding the best use of these agents, which are not fully addressed by NICE guidance. For example: which mechanism of action should be used first (and does it matter)? Which anti-TNF should be used first? When should treatment be withdrawn and in whom? Although NICE suggest that patients in complete remission after 1 year of treatment should be considered for withdrawal, evidence to support this strategy is lacking. Indeed, a retrospective UK-wide study explored the outcome of anti-TNF withdrawal in inflammatory bowel disease and found that 35% of UC patients had relapsed within a year of cessation.[15] In addition, treatment withdrawal may not be the preferred option for many patients[16] or clinicians.

The optimal use of biologic therapy is likely to involve therapeutic drug monitoring with trial evidence demonstrating an exposure–response relationship for each agent. This issue, along with the aforementioned unresolved questions, will require dedicated prospective studies to generate the necessary data for evidence-based answers. These are likely to involve both observational studies [17] specifically aimed at elucidating the exposure–response relationship and interventional clinical trials exploring the effectiveness of utilizing it in practice.

5. Expert opinion

The recent changes to NICE guidance have already had a meaningful impact on the treatment of patients with UC. This benefit is likely to continue to grow as treatment algorithms evolve to reflect the improved access to a range of effective medications. Some clinicians may consider these changes overdue, but few would argue with the rigor with which NICE evaluations are conducted. Most importantly, we believe all would agree that the changes offer us a precious opportunity to improve outcomes in this difficult-to-treat group. The significant challenge that we now face moving forward is the how to use these agents most effectively. The importance of therapeutic drug monitoring is becoming increasingly appreciated and is likely to offer the best route to maximize the benefit biologic drugs can offer in UC. Detailed pharmacokinetic and pharmacodynamics studies are necessary to better understand the factors that determine treatment success and failure. Currently, the evidence for therapeutic drug monitoring is largely derived from retrospective, post hoc analysis. Therefore, large-scale, prospective studies using therapeutic drug monitoring to drive dosing (compared with empirical dosing) are required to demonstrate the validity of this type of approach.

Declaration of interest

Mark A Samaan has received advisory fees from Hospiraand lecture fees from Hospira, Takeda and MSD. Peter M Irving has received lecture fees from Abbvie, Warner Chilcott, Ferring, Falk Pharma, Takeda, MSD, Johnson and Johnson and Shire, financial support for research from MSD and Takeda, advisory fees from Abbvie, Warner Chilcott, Takeda, MSD, Vifor Pharma, Pharmacosmos, Topivert, Genentech, Hospira and Samsung Bioepis. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.