The Challenge for Orphan Drugs Remains: Three Case Studies Demonstrating the Impact of Changes to NICE Methods and Processes and Alternative Mechanisms to Value Orphan Products.

BACKGROUND: The National Institute for Health and Care Excellence (NICE) is responsible for ensuring that patients in England and Wales can access clinically and cost-effective treatments. However, NICE's processes pose significant reimbursement challenges for treatments for rare diseases. While some orphan medicines have been appraised via the highly specialised technology route, most are appraised via the single technology appraisal programme, a route that is expected to be increasingly used given new more restrictive highly specialised technology criteria. This often results in delays to access owing to differences in applicable thresholds and the single technology appraisal approach being ill-equipped to deal with the inevitable decision uncertainty. NICE recently published their updated methods and process manual, which includes a new severity-of-disease modifier and an instruction to be more flexible when considering uncertainty in rare diseases. However, as the threshold gap between the single technology appraisal and highly specialised technology programmes remains, it is unlikely that these changes alone will address the problem. OBJECTIVE: We explored the potential impact of quality-adjusted life-year weights in decision making. METHODS: We explored the impact of NICE's new severity-of-disease modifier weighting and two alternative methods (the use of alternative quality-adjusted life-year weights and the fair rate of return), using three recent single technology appraisals of orphan medicines (caplacizumab, teduglutide and pirfenidone for mild idiopathic pulmonary fibrosis). RESULTS: Our results suggest NICE's severity-of-disease modifier would not have affected the recommendations. Using alternative methods, based upon achievement of an incremental cost-effectiveness ratio below standard thresholds, patients could have received access to caplacizumab approximately 5 months earlier, and the appraisals for teduglutide and pirfenidone would have resulted in a positive recommendation following appraisal consultation meeting 1 when neither of these products was available over 5 years from the initial submission. CONCLUSION: Ultimately, moving from a restrictive end-of-life modifier to one based on disease severity is a more equitable approach likely to benefit many therapies, including orphan products. However, NICE's single technology appraisal updates are unlikely to result in faster reimbursement of orphan medicines, nor will they address concerns around market access for orphan medicines in the UK.

Targeted therapies for patients with moderate-to-severe psoriasis: a systematic review and network meta-analysis of PASI response at 1 year.

PURPOSE: To compare PASI outcomes of approved biologics and apremilast after 1 year of treatment. METHODS: A systematic review identified RCTs and long-term extensions reporting PASI 75, 90, and 100 responses in adults with moderate-to-severe psoriasis. Data for analysis were modeled using a Bayesian multinomial likelihood model with probit link. RESULTS: Twenty-eight studies reporting PASI responses were included in the network meta-analysis. Differences in study design led to a stepwise approach to synthesis, consisting of two analyses. The primary analysis included nine RCTs investigating comparative efficacy at 1 year. Results indicated risankizumab, brodalumab, and guselkumab were the most effective therapies, followed by ixekizumab and secukinumab; all demonstrated superiority to ustekinumab and etanercept. The secondary analysis extended the primary analysis with 19 further studies comparing active interventions to placebo outcomes extrapolated from induction. The interventions generating the highest PASI response were the same as the primary analysis. These therapies were more effective than apremilast, ustekinumab, adalimumab, certolizumab, etanercept, and infliximab. CONCLUSIONS: This NMA demonstrated that evaluated IL-17 and IL-23 inhibitors outperformed other biological therapies after 1 year. Risankizumab had a higher probability of achieving PASI outcomes than all other biologics, except brodalumab and guselkumab, where no significant difference could be concluded.

Assessing the Quality and Coherence of Network Meta-Analyses of Biologics in Plaque Psoriasis: What Does All This Evidence Synthesis Tell Us?

INTRODUCTION: A range of treatments are available for moderate-to-severe psoriasis; however, there remains a paucity of direct comparisons of these in head-to-head trials. Network meta-analyses (NMA) allow comparisons of these to support clinical decision making. This systematic literature review assesses the methodological quality of NMAs available for moderate-to-severe psoriasis and compares their methods and results. Their validity and applicability for current practice is also assessed. METHODS: A systematic review of published NMAs of at least two biologics for moderate-to-severe psoriasis was undertaken. Embase, MEDLINE, MEDLINE In-Process, and the Cochrane Library were last searched on 19 February 2020. The quality of NMAs was assessed using the International Society of Pharmacoeconomics and Outcomes Research (ISPOR) criteria. NMA methodology, funding, and results were compared and differences in results explored. RESULTS: Twenty-five analyses evaluating up to 19 different treatments at 8-24 weeks, and two analyses at 1 year, were included. Psoriasis Area Severity Index (PASI) response was assessed in 23, facilitating comparisons between NMAs. All NMAs met at least half of the ISPOR criteria. The major limitations were explaining the rationale for methodology, exploring effect modifiers, and consistency between direct and indirect estimates. The analyses differed in model type (Bayesian or frequentist), analysis of PASI response (binomial or multinomial), and analysis of different treatment doses (separate or pooled). PASI results were broadly similar, except for the Cochrane Collaboration NMA which provided lower estimates of treatment efficacy versus placebo. This analysis differed methodologically from others, including pooling data for different doses. CONCLUSIONS: Based on PASI 90 at induction, the majority of recent NMAs came to similar conclusions: interleukin (IL) 17 inhibitors (brodalumab, ixekizumab, secukinumab), IL-23 inhibitors (guselkumab and risankizumab) and infliximab were most efficacious, supporting the validity of NMAs in this clinical area. Decisions should be made using high-quality, up-to-date NMAs with assumptions relevant to clinical practice.

Assessing the relative efficacy of interleukin-17 and interleukin-23 targeted treatments for moderate-to-severe plaque psoriasis: A systematic review and network meta-analysis of PASI response.

INTRODUCTION: New generation biologics, including interleukin (IL)-17 and IL-23 inhibitors, have delivered higher rates of skin clearance than older treatments in head-to-head studies. However, studies comparing these new biologics directly to one another are limited. OBJECTIVES: To compare the short-term efficacy of available (or imminently available) biologic and non-biologic systemic therapies for treating patients with moderate-to-severe plaque psoriasis. METHODS: A systematic review was undertaken to identify randomised controlled trials evaluating biologic treatments, apremilast and dimethyl fumarate. MEDLINE, MEDLINE In-Process, Embase and the Cochrane Library were searched from the 1st January 2000 to 22nd November 2018. A Bayesian network meta-analysis (NMA) using a random-effects multinomial likelihood model with probit link and meta-regression to adjust for cross-trial variation in placebo responses compared the efficacy of interventions at inducing different levels of Psoriasis Area and Severity Index (PASI) response during the induction period. A range of sensitivity analyses was undertaken. RESULTS: Seventy-seven trials (34,816 patients) were included in the NMA. The base-case analysis showed that all active treatments were superior to placebo. IL-17 inhibitors, guselkumab and risankizumab were found to be more efficacious than tildrakizumab, ustekinumab, all TNF inhibitors and non-biologic systemic treatments at inducing all levels of PASI response. In addition, brodalumab, ixekizumab and risankizumab were significantly more efficacious than secukinumab; no significant difference was found in the comparison with guselkumab. The greatest benefit of brodalumab, ixekizumab, guselkumab, and risankizumab was seen for PASI 90 and PASI 100 response. Results were consistent across all analyses. CONCLUSIONS: In the NMA brodalumab, ixekizumab, risankizumab and guselkumab showed the highest levels of short-term efficacy. There were differences in efficacy between treatments within the same class. Longer-term analyses are needed to understand differences between these drugs beyond induction in what is a life-long condition.

The Cancer Drugs Fund in Practice and Under the New Framework.

BACKGROUND: The Cancer Drugs Fund (CDF) was established in 2010 to improve access to treatments not routinely available. Having widely overspent, stricter budgeting rules were introduced in 2016. The CDF can now only include treatments with potential to be cost effective once sufficient data are collected. OBJECTIVES: Our objective was to explore the process and criteria used for consideration of treatments under the new CDF framework and to describe the extent of evidence collection. METHODS: We identified CDF list, UK National Institute for Health and Care Excellence (NICE) and Scottish Medicines Consortium documents (10 May 2018). Data were collected on drugs and indications, reasons for inclusion in the CDF, data collection, incremental cost-effectiveness ratios (ICERs), and corresponding recommendations for Scotland. RESULTS: In total, 12 drugs were listed on the CDF in 17 indications, 12 of which were considered end-of-life care. The most common cancers were non-small-cell lung (n = 4), urothelial (n = 3), lymphocytic leukaemia (n = 2) and multiple myeloma (n = 2). The companies' ICERs were generally lower than those from the committee and the evidence review group. Drugs were included in the CDF for 6-42 months, with the majority included for ≥18 months. Data were frequently collected on overall survival (n = 16) and progression-free survival (n = 5) using NHS systems and, frequently, ongoing trials. CONCLUSIONS: Data collection frequently included overall survival and exceeded the 2 years recommended in the CDF strategy. It appears the CDF is allowing patients access to drugs long before they may become available for routine use. Our results are limited by the availability of published information and the small dataset.

Research methods to change clinical practice for patients with rare cancers.

Rare cancers are a growing group as a result of reclassification of common cancers by molecular markers. There is therefore an increasing need to identify methods to assess interventions that are sufficiently robust to potentially affect clinical practice in this setting. Methods advocated for clinical trials in rare diseases are not necessarily applicable in rare cancers. This Series paper describes research methods that are relevant for rare cancers in relation to the range of incidence levels. Strategies that maximise recruitment, minimise sample size, or maximise the usefulness of the evidence could enable the application of conventional clinical trial design to rare cancer populations. Alternative designs that address specific challenges for rare cancers with the aim of potentially changing clinical practice include Bayesian designs, uncontrolled n-of-1 trials, and umbrella and basket trials. Pragmatic solutions must be sought to enable some level of evidence-based health care for patients with rare cancers.

Problems of variable biomarker evaluation in stratified medicine research--A case study of ERCC1 in non-small-cell lung cancer.

OBJECTIVES: Consistency of procedures for the evaluation of a predictive biomarker (including sample collection, processing, assay and scoring system) based on adequate evidence is necessary to implement research findings in clinical practice. As a case study we evaluated how a particular predictive biomarker, ERCC1, was assessed in research on platinum-based chemotherapy in non-small-cell lung cancer and what motivated the choice of procedure. MATERIALS AND METHODS: A systematic review of studies completed since 2007 and ongoing was undertaken. Questionnaires on details of ERCC1 evaluation procedures and the rationale for their choice were sent to contacts of identified studies. RESULTS: Thirty-three studies of platinum-based chemotherapy in non-small-cell lung cancer using ERCC1 were identified. A reply to the questionnaire was received for 16 studies. Procedures for ERCC1 evaluation varied substantially and included reverse transcriptase quantitative polymerase chain reaction (nine studies), immunohistochemistry (five studies) and other methods (multiple methods-two studies, NER polymorphism-one study). In five studies ERCC1 use was planned, but not undertaken. In nine data was insufficient to identify the procedure. For each assay there was variation across studies in the details of the laboratory techniques, scoring systems and methods for obtaining samples. CONCLUSIONS: We found large variation across studies in ERCC1 evaluation procedures. This will limit the future comparability of results between these different studies. To enable evidence-based clinical practice, consensus is needed on a validated procedure to assess a predictive biomarker in the early phase of research. We believe that ERCC1 is not untypical of biomarkers being investigated for stratified medicine.

Stratified medicine in European Medicines Agency licensing: a systematic review of predictive biomarkers.

OBJECTIVES: Stratified medicine is often heralded as the future of clinical practice. Key part of stratified medicine is the use of predictive biomarkers, which identify patient subgroups most likely to benefit (or least likely to experience harm) from an intervention. We investigated how many and what predictive biomarkers are currently included in European Medicines Agency (EMA) licensing. SETTING: EMA licensing. PARTICIPANTS: Indications and contraindications of all drugs considered by the EMA and published in 883 European Public Assessment Reports and Pending Decisions. PRIMARY AND SECONDARY OUTCOME MEASURES: Data were collected on: the type of the biomarker, whether it selected a subgroup of patients based on efficacy or toxicity, therapeutic area, marketing status, date of licensing decision, date of inclusion of the biomarker in the indication or contraindication and on orphan designation. RESULTS: 49 biomarker-indication-drug (B-I-D) combinations were identified over 16 years, which included 37 biomarkers and 41 different drugs. All identified biomarkers were molecular. Six drugs (relating to 10 B-I-D combinations) had an orphan designation at the time of licensing. The identified B-I-D combinations were mainly used in cancer and HIV treatment, and also in hepatitis C and three other indications (cystic fibrosis, hyperlipoproteinaemia type I and methemoglobinaemia). In 45 B-I-D combinations, biomarkers were used as predictive of drug efficacy and in four of drug toxicity. It appeared that there was an increase in the number of B-I-D combinations introduced each year; however, the numbers were too small to identify any trends. CONCLUSIONS: Given the large body of literature documenting research into potential predictive biomarkers and extensive investment into stratified medicine, we identified relatively few predictive biomarkers included in licensing. These were also limited to a small number of clinical areas. This might suggest a need for improvement in methods of translation from laboratory findings to clinical practice.