Innovative regenerative medicines in the EU: a better future in evidence?

BACKGROUND: Despite a steady stream of headlines suggesting they will transform the future of healthcare, high-tech regenerative medicines have, to date, been quite inaccessible to patients, with only eight having been granted an EU marketing licence in the last 7 years. Here, we outline some of the historical reasons for this paucity of licensed innovative regenerative medicines. We discuss the challenges to be overcome to expedite the development of this complex and rapidly changing area of medicine, together with possible reasons to be more optimistic for the future. DISCUSSION: Several factors have contributed to the scarcity of cutting-edge regenerative medicines in clinical practice. These include the great expense and difficulties involved in planning how individual therapies will be developed, manufactured to commercial levels and ultimately successfully delivered to patients. Specific challenges also exist when evaluating the safety, efficacy and cost-effectiveness of these therapies. Furthermore, many treatments are used without a licence from the European Medicines Agency, under "Hospital Exemption" from the EC legislation. For products which are licensed, alternative financing approaches by healthcare providers may be needed, since many therapies will have significant up-front costs but uncertain benefits and harms in the long-term. However, increasing political interest and more flexible mechanisms for licensing and financing of therapies are now evident; these could be key to the future growth and development of regenerative medicine in clinical practice. CONCLUSIONS: Recent developments in regulatory processes, coupled with increasing political interest, may offer some hope for improvements to the long and often difficult routes from laboratory to marketplace for leading-edge cell or tissue therapies. Collaboration between publicly-funded researchers and the pharmaceutical industry could be key to the future development of regenerative medicine in clinical practice; such collaborations might also offer a possible antidote to the innovation crisis in the pharmaceutical industry.

The Type and Impact of Evidence Review Group Exploratory Analyses in the NICE Single Technology Appraisal Process.

BACKGROUND: As part of the UK National Institute for Health and Care Excellence (NICE) single technology appraisal process, independent evidence review groups (ERGs) critically appraise a company's submission relating to a specific technology and indication. OBJECTIVES: To explore the type of additional exploratory analyses conducted by ERGs and their impact on the recommendations made by NICE. METHODS: The 100 most recently completed single technology appraisals with published guidance were selected for inclusion. A content analysis of relevant documents was undertaken to identify and extract relevant data, and narrative synthesis was used to rationalize and present these data. RESULTS: The types of exploratory analysis conducted in relation to companies' models were fixing errors, addressing violations, addressing matters of judgment, and the provision of a new, ERG-preferred base case. Ninety-three of the 100 ERG reports contained at least one of these analyses. The most frequently reported type of analysis in these 93 ERG reports related to the category "Matters of judgment," which was reported in 83 reports (89%). At least one of the exploratory analyses conducted and reported by an ERG is mentioned in 97% of NICE appraisal consultation documents and 94% of NICE final appraisal determinations, and had a clear influence on recommendations in 72% of appraisal consultation documents and 47% of final appraisal determinations. CONCLUSIONS: These results suggest that the additional analyses undertaken by ERGs in the appraisal of company submissions are highly influential in the policy-making and decision-making process.

Systematic review of patient preference and adherence to the correct use of graduated compression stockings to prevent deep vein thrombosis in surgical patients.

AIM: The aim of this study was to explore patient preference and adherence to thigh and knee length graduated compression stockings for the prevention of deep vein thrombosis in surgical patients. BACKGROUND: Hospitalised patients are at risk of developing deep vein thrombosis. Mechanical methods of prophylaxis include compression stockings, available as knee or thigh length. Patient adherence to correct stocking use is of critical importance to their effectiveness. DESIGN: Systematic review of quantitative evidence. DATA SOURCES: Eleven databases were searched from inception to 2013 for systematic reviews of compression stockings. Reviews were screened for relevant primary studies and update searches of eight electronic sources were undertaken (2010-2014). REVIEW METHODS: Randomised controlled trials and observational studies of surgical patients using compression stockings were quality assessed and data were extracted on patient adherence and preference. A narrative summary is presented. RESULTS: Nine randomised controlled trials and seven observational studies were included in the systematic review. There was substantial variation between studies in terms of patient characteristics, interventions and methods of outcome assessment. CONCLUSION: Patient adherence was generally higher with knee length than thigh length stockings. However, the studies reflect patient adherence in a hospital setting only, where patients are observed by healthcare professionals; it is likely that adherence reduces once patients have been discharged from hospital. Patients preferred knee length stockings over thigh length stockings. In many clinical settings, any difference in efficacy between thigh length and knee length stockings may be rendered irrelevant by patient preference for and likely better adherence to knee length stockings.

A systematic review of the clinical effectiveness of EOS 2D/3D X-ray imaging system.

PURPOSE: To evaluate the available evidence for the clinical effectiveness of the EOS(®) 2D/3D X-ray imaging system for the evaluation and monitoring of scoliosis and other relevant orthopaedic conditions. METHODS: A systematic review of studies of EOS(®), compared with standard X-ray film, computed radiography or digital radiography, of patients with orthopaedic conditions was undertaken. Ten electronic databases were searched. The quality of the included studies was assessed and a narrative synthesis undertaken. RESULTS: Three small, limited quality studies, primarily of children with scoliosis, were identified. No patient health outcomes were reported. Spinal image quality was comparable or better overall with EOS(®). Radiation dose was considerably lower with EOS(®) than X-ray film or computed radiography; the mean entrance surface dose was over five times lower with EOS(®) for the posteroanterior spine radiograph and over six times lower for the lateral spine radiograph. CONCLUSIONS: The available clinical evidence for EOS(®) is limited to establishing its basic technical ability. The technical advancements associated with EOS(®) (the ability to generate a full body scan and to construct a three-dimensional model from synchronously acquired lateral and posteroanterior images) have not been evaluated in terms of their ability to improve patient outcomes. Whilst radiation dose is a concern for orthopaedic patients who require repeated imaging, it is difficult to quantify the reductions in radiation dose seen with EOS(®) in terms of patient health benefits. Clinical studies that investigate the impact of EOS(®) on patient management are required.

The use and reporting of WOMAC in the assessment of the benefit of physical therapies for the pain of osteoarthritis of the knee: findings from a systematic review of clinical trials.

OBJECTIVE: For the purposes of meta-analysis and network meta-analysis, the use of standard outcome measures is ideal. In OA research, the WOMAC was developed as an OA-specific measure of disability. It includes a pain subscale. In 1994 a consensus meeting recommended the use of WOMAC as a primary measure of efficacy in OA. In the context of a review of the efficacy of physical interventions for the relief of the pain of OA of the knee, we investigated the use of WOMAC. METHODS: A systematic review (December 2009-January 2010) identified trials that used the WOMAC outcome. These were investigated for correct use and clear reporting of the WOMAC pain subscale and the WOMAC index. RESULTS: The WOMAC pain subscale was used in 45% of the 134 trials. Reporting of the exact method of administering the WOMAC pain subscale was poor in many cases: in 53% of trials the reporting of the type of WOMAC scale used was inadequate; the score range was reported ambiguously in 38% of trials, with a further 10% being completely unclear. Similar less than optimal reporting of the WOMAC index was found. CONCLUSION: Poor reporting of both the WOMAC pain subscale and the WOMAC index resulted in significant uncertainty in the interpretation of the results of individual trials and limited their contribution to evidence synthesis. Improved adherence with the standard use of the WOMAC scoring system, with clear reporting of it in trials of OA of the knee should be encouraged.

Dilemmas in the interpretation of diagnostic accuracy studies on presurgical workup for epilepsy surgery.

We conducted a systematic review to determine which noninvasive technologies should be used in the workup for epilepsy surgery to identify structural or functional abnormalities to help locate the site of seizure onset. The review focused on patients where there was insufficient confidence, in either the decision to go to surgery or the site at which surgery should be conducted, after the initial clinical examination. The majority of the studies identified were single-gate diagnostic accuracy studies; none were randomized controlled trials, and only one reported the effect of the test results on the decision making process. It became apparent that the data derived from diagnostic accuracy studies could not be used to answer the review question. This article focuses on the methods used to extract data from the diagnostic accuracy studies, the difficulties interpreting the resulting data, why such studies are not an appropriate study design in this setting, and how the evidence-base can be improved.

Cost-effectiveness of aldosterone antagonists for the treatment of post-myocardial infarction heart failure.

OBJECTIVE: To assess the cost-effectiveness of eplerenone versus spironolactone as an adjunctive therapy to standard care in patients with heart failure (HF) following a myocardial infarction (post-MI) from the perspective of the National Health Service in the United Kingdom. METHODS: A systematic review was conducted, and a Bayesian meta-regression approach was used to establish the relative effectiveness of eplerenone and spironolactone by using evidence from randomized controlled trials. A decision analytic model was developed to assess the costs and consequences associated with the primary outcome of the trials over a lifetime time horizon. RESULTS: The incremental cost-effectiveness ratio of eplerenone compared with that of standard care alone was £ 4457 and £ 7893 for each additional quality-adjusted life-year when 2-year and lifetime treatment duration was assumed, respectively. In both scenarios, spironolactone did not appear cost-effective compared with eplerenone. The results were sensitive to the higher relative effectiveness estimated for eplerenone compared with spironolactone from the meta-regression. When a class effect was assumed for the effect on mortality and hospitalizations, spironolactone emerged as the most cost-effective treatment. CONCLUSIONS: Eplerenone appears more cost-effective than spironolactone for the treatment of post-MI HF. These findings, however, remain subject to important uncertainties regarding the effects of treatment on major clinical events. An adequately powered, well-conducted randomized controlled trial that directly compares spironolactone and eplerenone may be required to provide more robust evidence on the optimal management of post-MI HF. Despite these uncertainties, the use of an aldosterone antagonist was consistently demonstrated to be a highly cost-effective strategy for the management of post-MI HF in the National Health Service.

Modelling the cost-effectiveness of biologic treatments for psoriatic arthritis.

OBJECTIVES: A probabilistic model was developed to determine the cost-effectiveness of three biologics, etanercept, infliximab and adalimumab, compared with palliative care for the treatment of active and progressive PsA in patients who have an inadequate response to standard treatment (including DMARDs). METHODS: A previous model was revised to evaluate the impact of biologics on both skin and joint disease and to include new evidence from the clinical review and evidence synthesis. Initial response to biologics was determined using the PsA response criteria. The impact of biologics on the arthritis component of the disease is then modelled via a change in the HAQ and the impact of the psoriasis component measured using the Psoriasis Area and Severity Index. RESULTS: For PsA patients with mild to moderate skin disease, the incremental cost-effectiveness ratio (ICER) for etanercept vs palliative care is around £18 000, and the ICER for infliximab vs etanercept is around £44 000 per quality-adjusted life year (QALY). Adalimumab is extendedly dominated. The probability that etanercept is cost effective is 0.436 at a threshold of £20 000 per QALY. Etanercept is also likely to be cost effective for patients with moderate to severe psoriasis or negligible skin involvement. CONCLUSIONS: Further investigation is required to reduce uncertainties around a number of model parameters, in particular the length of time over which biologics are assumed to be effective and the progression of HAQ on and off treatment.

Are adverse effects incorporated in economic models? A survey of current practice.

BACKGROUND: Clearly the benefits of a treatment must not be outweighed by the adverse effects. If researchers fail to incorporate adverse effects adequately in models, this could limit the validity of the results obtained. In the worst case, interventions that are cost-effective may be shown not to be. The aim of this research was to review current practice when incorporating adverse effects in economic models. METHODS: A survey of HTA reports commissioned by the National Institute for Health Research (NIHR) Health Technology Assessment programme, published between 2004 and 2007 was conducted. All reports which investigated the clinical and cost-effectiveness of a health technology using a systematic review and an economic model framework were included. RESULTS: A total of eighty reports met the inclusion criteria. Of the models including adverse effects (43/80), 67 percent used a clinical adverse effects parameter, 79 percent a cost of adverse effects parameter, 86 percent used one of these, and 60 percent used both. Of the thirty-seven models that did not include adverse effects, eighteen justified this omission, most commonly lack of data; nineteen appeared to make no explicit consideration of adverse effects in the model. CONCLUSIONS: In many cases, poor reporting made it difficult to ascertain if there had been any consideration of adverse effects. We suggest that the findings of this survey support a call for much clearer and explicit reporting of adverse effects, or their exclusion, in decision models and for explicit recognition in future guidelines that "all relevant outcomes" should include some consideration of adverse events.

Cost-effectiveness of enhanced external counterpulsation (EECP) for the treatment of stable angina in the United Kingdom.

OBJECTIVES: The objective of this study is to assess the cost-effectiveness of enhanced external counterpulsation (EECP) compared with no treatment as additional therapy to usual care for the treatment of chronic stable angina from the perspective of the UK National Health Service. METHODS: The study design was a systematic review of published evidence, use of expert clinical opinion, and decision analytic cost-effectiveness model. The systematic review was conducted and statistical methods used to synthesize the effectiveness evidence from randomized control trials. Formal methods were used to elicit opinion from clinical experts where no evidence was available. These provide informed "priors" on key model parameters. A decision analytic model was developed to assess the costs and health consequences associated with the primary outcome of the trials over a lifetime time horizon. The main outcome measures were costs from a health service perspective and outcomes measured as quality-adjusted life-years (QALYs). RESULTS: The incremental cost-effectiveness ratio of EECP was 18,643 pound sterling for each additional QALY, with a probability of being cost-effective of 0.44 and 0.70 at cost-effectiveness thresholds of 20,000 pound sterling and 30,000 pound sterling per QALY gained, respectively. Results were sensitive to the duration of health-related quality of life (HRQoL) benefits from treatment. CONCLUSIONS: The long-term maintenance of HRQoL benefits of EECP is central to the estimate of cost-effectiveness. The results from a single randomized control trial do not provide firm evidence of the clinical or cost-effectiveness of EECP in stable angina. Long-term follow-up trials assessing quality of life from EECP are required.

Strimvelis® for Treating Severe Combined Immunodeficiency Caused by Adenosine Deaminase Deficiency: An Evidence Review Group Perspective of a NICE Highly Specialised Technology Evaluation.

The Centre for Reviews and Dissemination and Centre for Health Economics Technology Assessment Group at the University of York was commissioned by the National Institute for Health and Care Excellence (NICE) Highly Specialised Technologies (HST) programme to act as the independent Evidence Review Group (ERG) for an appraisal of Strimvelis®, a gene therapy treatment for adenosine deaminase deficiency-severe combined immunodeficiency (ADA-SCID). This paper describes the manufacturing company's submission of clinical and economic evidence, the ERG's review and the resulting NICE guidance. For Strimvelis® compared with haematopoietic stem cell transplant (HSCT) from a matched unrelated donor (MUD) and HSCT from a haploidentical donor, the company base-case deterministic incremental cost-effectiveness ratios (ICERs) were £36,360 and £14,645 per quality-adjusted life-year (QALY) gained, respectively (using a discount rate of 1.5%). Although overall survival in patients receiving Strimvelis® was substantially higher than historical comparator data on HSCT from a MUD or haploidentical donor, the ERG was concerned that the estimated treatment benefit remained highly uncertain. The ERG critiqued some assumptions in the cost-effectiveness model, including that all patients return to general population mortality and morbidity after a successful procedure; that all patients receive a matched sibling donor following an unsuccessful engraftment; and that differences in wait times exist between the treatments. Incorporating a number of changes to the model, the ERG's base-case ICERs were £86,815 per QALY gained for Strimvelis® compared with HSCT from a MUD and £16,704 per QALY gained compared with HSCT from a haploidentical donor (using a discount rate of 1.5%). The ICER for Strimvelis® compared with HSCT from a MUD was highly sensitive to the difference in procedural mortality and could exceed NICE's £100,000 per QALY gained threshold for HSTs, if HSCT survival rates have improved since the most recent data. The evaluation committee concluded that the most plausible ICERs were lower than £100,000 per QALY gained and that Strimvelis® should be recommended for treatment of ADA-SCID where a matched related donor is unavailable.

Hyperhidrosis quality of life measures: review and patient perspective.

PURPOSE: To identify the tools that have been used to measure quality of life in hyperhidrosis research and obtain patient insight on commonly used tools. METHODS: Twelve databases were searched to identify studies that reported measuring quality of life or described a quality of life tool in the context of hyperhidrosis. Data on the use of the tools were tabulated and hyperhidrosis-specific and dermatology-specific measures were summarized. A workshop was held to obtain the patients' perspective on the most commonly used tools and the newly developed HidroQoL tool. RESULTS: One hundred and eighty-two studies were included in the review. Twenty-two quality of life tools were identified; two or more tools were often used in combination. The most commonly used tools were the Hyperhidrosis Disease Severity Scale, the Dermatology Quality of Life Index and the Hyperhidrosis Quality-of-Life Questionnaire. Patient advisors preferred the new HidroQoL tool, which was considered to be easy to complete and most relevant to hyperhidrosis patients. CONCLUSIONS: There are several tools available for assessing quality of life in hyperhidrosis patients; disease specific measures are widely used and appear suitable. It is unclear which tool is the most reliable, although the HidroQoL tool was preferred by a small group of patient advisors.

Correction to: Ceritinib for Untreated Anaplastic Lymphoma Kinase-Positive Advanced Non-Small-Cell Lung: An Evidence Review Group Evaluation of a NICE Single Technology Appraisal.

The title of the article should read.

Ceritinib for Untreated Anaplastic Lymphoma Kinase-Positive Advanced Non-Small-Cell Lung Cancer: An Evidence Review Group Evaluation of a NICE Single Technology Appraisal.

The National Institute for Health and Care Excellence (NICE) invited the company that manufactures ceritinib (Zykadia®, Novartis) to submit evidence on the clinical and cost effectiveness of the drug, as a first-line treatment for adults with anaplastic lymphoma kinase (ALK)-positive (+) advanced non-small-cell lung cancer (NSCLC), as part of the Institute's single technology appraisal (STA) process. The CRD (Centre for Reviews and Dissemination) and CHE (Centre for Health Economics) Technology Assessment Group at the University of York was commissioned to act as the Evidence Review Group (ERG). This paper describes the Company's submission (CS), the ERG review and NICE's subsequent decisions. The evidence submitted in support of ceritinib, as the first-line treatment in ALK+ advanced NSCLC, was a phase III, international, multicentre, open-label randomised controlled trial (RCT) comparing ceritinib with pemetrexed/cisplatin plus pemetrexed maintenance therapy (chemotherapy [CT] group). The results indicated that ceritinib prolonged progression-free survival (PFS) compared with CT. The only comparator considered in the CS was crizotinib. The evidence selected in support of crizotinib was PROFILE 1014, an open-label RCT of crizotinib, compared with pemetrexed/cisplatin CT (without maintenance therapy), in previously untreated advanced or metastatic ALK+ NSCLC. The design and population of PROFILE 1014 was similar to that of ASCEND-4, though there were some differences between the trials. The Company considered it not possible to perform an 'anchor-based' analysis of first-line ceritinib and crizotinib, and presented a Matching-Adjusted Indirect Comparison (MAIC) of ceritinib and crizotinib using only the ALK inhibitor arm of ASCEND-4 and PROFILE 1014. The indirect comparison suggests that ceritinib may be more effective in prolonging PFS than crizotinib. The ERG agreed that an indirect comparison using only the ALK inhibitor arm of the trials was the only option available in the present assessment; however, a number of limitations and potential bias were identified in this analysis. The Company's model estimated that ceritinib was cost effective when compared with crizotinib. However, the ERG highlighted several concerns with the Company's analysis; the ERG's preferred base case estimated an incremental cost-effectiveness ratio of £69,255 per quality-adjusted life-year (no patient access scheme [PAS] included). The ERG considered the economic analysis to be sensitive to changes in assumption used, partly due to the due to the immaturity of the overall survival data from trials, which leads to uncertainty around the extrapolation used. The NICE Appraisal Committee concluded that ceritinib is recommended, within its marketing authorisation, as an option for untreated ALK+ advanced NSCLC in adults, if the Company provides it with the discount agreed in the PAS.

Ustekinumab for Treating Moderately to Severely Active Crohn's Disease after Prior Therapy: An Evidence Review Group Perspective of a NICE Single Technology Appraisal.

As part of the single technology appraisal (STA) process, the National Institute for Health and Care Excellence (NICE) invited Janssen to submit evidence on the clinical and cost effectiveness of their drug ustekinumab, an interleukin-12/23 inhibitor, for treating moderate-to-severe active Crohn's disease (CD). The Centre for Reviews and Dissemination (CRD) and Centre for Health Economics (CHE) Technology Appraisal Group at the University of York was commissioned to act as the independent Evidence Review Group (ERG). This article provides a description of the Company's submission, the ERG's critical review of submitted evidence, and the resulting NICE guidance. The main supporting clinical evidence was derived from four well conducted, randomised controlled trials, comparing ustekinumab with placebo in two sub-populations (conventional care failure and anti-TNFα failure patients) of adults with moderate-to-severe CD. Three trials assessed treatment induction over 8 weeks, while the fourth recruited successfully induced patients into a maintenance trial for 1 year. These trials showed ustekinumab to be more effective than placebo in terms of its ability to induce and maintain clinical response and remission. In the absence of any direct head-to-head data, the Company conducted a network meta-analysis (NMA), which synthesised induction trial data on ustekinumab and relevant comparators (vedolizumab, adalimumab and infliximab) using placebo data as a common comparator. This analysis found ustekinumab to be of comparable efficacy to previously approved biologics in treatment induction. A 'treatment sequence analysis' compared long-term treatment efficacy, finding ustekinumab to be comparable in maintaining treatment response and remission to the three other biologic therapies. However, the ERG had identified many limitations and potential bias in this analysis, and urged caution when interpreting the results. The Company's economic model estimated ustekinumab to be dominant in both sub-populations compared with conventional care; however, the ERG's preferred base-case estimated an incremental cost-effectiveness ratio of £109,279 in the conventional care failure sub-population, and £110,967 in the anti-TNFα failure sub-population when compared with conventional care. However, the ERG identified significant failings in both the model structure and data inputs, which could not be addressed without complete restructuring. The ERG considered that the economic analysis presented by the Company failed to adequately address the decision problem specified in NICE's scope. The NICE Appraisal Committee recommended ustekinumab within its market authorisation, on the grounds of sufficiently similar efficacy and costs to previously recommended biologic therapies. However, the ERG's analyses demonstrated that all currently recommended biologics are unlikely to be cost effective relative to conventional care, raising broader questions regarding the appropriateness of cost-comparison exercises for decision making.

Brain and spinal stimulation therapies for phantom limb pain: a systematic review.

BACKGROUND: Although many treatments exist for phantom limb pain (PLP), the evidence supporting them is limited and there are no guidelines for PLP management. Brain and spinal cord neurostimulation therapies are targeted at patients with chronic PLP but have yet to be systematically reviewed. OBJECTIVE: To determine which types of brain and spinal stimulation therapy appear to be the best for treating chronic PLP. DESIGN: Systematic reviews of effectiveness and epidemiology studies, and a survey of NHS practice. POPULATION: All patients with PLP. INTERVENTIONS: Invasive interventions - deep brain stimulation (DBS), motor cortex stimulation (MCS), spinal cord stimulation (SCS) and dorsal root ganglion (DRG) stimulation. Non-invasive interventions - repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS). MAIN OUTCOME MEASURES: Phantom limb pain and quality of life. DATA SOURCES: Twelve databases (including MEDLINE and EMBASE) and clinical trial registries were searched in May 2017, with no date limits applied. REVIEW METHODS: Two reviewers screened titles and abstracts and full texts. Data extraction and quality assessments were undertaken by one reviewer and checked by another. A questionnaire was distributed to clinicians via established e-mail lists of two relevant clinical societies. All results were presented narratively with accompanying tables. RESULTS: Seven randomised controlled trials (RCTs), 30 non-comparative group studies, 18 case reports and 21 epidemiology studies were included. Results from a good-quality RCT suggested short-term benefits of rTMS in reducing PLP, but not in reducing anxiety or depression. Small randomised trials of tDCS suggested the possibility of modest, short-term reductions in PLP. No RCTs of invasive therapies were identified. Results from small, non-comparative group studies suggested that, although many patients benefited from short-term pain reduction, far fewer maintained their benefits. Most studies had important methodological or reporting limitations and few studies reported quality-of-life data. The evidence on prognostic factors for the development of chronic PLP from the longitudinal studies also had important limitations. The results from these studies suggested that pre-amputation pain and early PLP intensity are good predictors of chronic PLP. Results from the cross-sectional studies suggested that the proportion of patients with severe chronic PLP is between around 30% and 40% of the chronic PLP population, and that around one-quarter of chronic PLP patients find their PLP to be either moderately or severely limiting or bothersome. There were 37 responses to the questionnaire distributed to clinicians. SCS and DRG stimulation are frequently used in the NHS but the prevalence of use of DBS and MCS was low. Most responders considered SCS and DRG stimulation to be at least sometimes effective. Neurosurgeons had mixed views on DBS, but most considered MCS to rarely be effective. Most clinicians thought that a randomised trial design could be successfully used to study neurostimulation therapies. LIMITATION: There was a lack of robust research studies. CONCLUSIONS: Currently available studies of the efficacy, effectiveness and safety of neurostimulation treatments do not provide robust, reliable results. Therefore, it is uncertain which treatments are best for chronic PLP. FUTURE WORK: Randomised crossover trials, randomised N-of-1 trials and prospective registry trials are viable study designs for future research. STUDY REGISTRATION: The study is registered as PROSPERO CRD42017065387. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Methodological challenges for the evaluation of clinical effectiveness in the context of accelerated regulatory approval: an overview.

BACKGROUND: Regulatory authorities are approving innovative therapies with limited evidence. Although this level of data is sufficient for the regulator to establish an acceptable risk-benefit balance, it is problematic for downstream health technology assessment, where assessment of cost-effectiveness requires reliable estimates of effectiveness relative to existing clinical practice. Some key issues associated with a limited evidence base include using data, from nonrandomized studies, from small single-arm trials, or from single-center trials; and using surrogate end points. METHODS: We examined these methodological challenges through a pragmatic review of the available literature. RESULTS: Methods to adjust nonrandomized studies for confounding are imperfect. The relative treatment effect generated from single-arm trials is uncertain and may be optimistic. Single-center trial results may not be generalizable. Surrogate end points, on average, overestimate treatment effects. Current methods for analyzing such data are limited, and effectiveness claims based on these suboptimal forms of evidence are likely to be subject to significant uncertainty. CONCLUSION: Assessments of cost-effectiveness, based on the modeling of such data, are likely to be subject to considerable uncertainty. This uncertainty must not be underestimated by decision makers: methods for its quantification are required and schemes to protect payers from the cost of uncertainty should be implemented.

A Review of Ruxolitinib for the Treatment of Myelofibrosis: A Critique of the Evidence.

As part of the National Institute for Health and Care Excellence's (NICE) Single Technology Appraisal (STA) process, ruxolitinib was assessed to determine the clinical and cost effectiveness of its use in the treatment of disease-related splenomegaly or symptoms in adults with myelofibrosis. Ruxolitinib had previously been assessed as part of the STA process and was not recommended in NICE guidance issued in June 2013 (TA289). A review of TA289 was commissioned following the availability of new longer-term survival data; a price discount patient access scheme (PAS) was also introduced. The Centre for Reviews and Dissemination (CRD) and Centre for Health Economics (CHE) Technology Appraisal Group at the University of York was commissioned to act as the independent Evidence Review Group (ERG). This article provides a summary of the manufacturer or sponsor of the technology's (referred to as the company) submission, the ERG review and the resulting NICE guidance issued in March 2016. The main clinical effectiveness data were derived from two good-quality multicentre randomised controlled trials (RCTs): COMFORT-II compared ruxolitinib with best available therapy (BAT) and COMFORT-I compared ruxolitinib with placebo. Both RCTs demonstrated a statistically significant reduction in splenomegaly and its associated symptoms in intermediate-2 and high-risk myelofibrosis patients. Overall survival was statistically significantly improved with ruxolitinib compared with BAT at 3.5 years of follow-up in the COMFORT-II trial (hazard ratio 0.58, 95 % CI 0.36-0.93). Grade 3-4 adverse events were more frequent in the ruxolitinib group than in the BAT group; 42 % compared with 25 %. Evidence relating to patients with lower-risk disease or low platelet counts (50-100 × 109/L) was less robust. The company's economic model was well-presented and had an appropriate model structure. The base-case incremental cost-effectiveness ratio (ICER) was estimated to be around £45,000 per quality-adjusted life-year (QALY) gained (including the PAS discount). Extensive sensitivity and scenario analyses were presented, demonstrating that the estimated ICER was robust to a range of input values and assumptions made in the model. Alternative scenarios presented by the ERG showed only modest increases in the estimated ICER, primarily as a result of including an element of drug wastage within the model. Alternative scenarios resulted in estimated ICERs ranging from around £45,000 to £49,000 per QALY gained (including the PAS discount). At the first appraisal meeting, the NICE Appraisal Committee concluded that ruxolitinib was clinically effective and was a cost effective use of National Health Service (NHS) resources for patients with high-risk myelofibrosis who meet NICE's end-of-life criteria. Following the consultation, the company offered a revised PAS, resulting in a revised base-case ICER of £31,229 per QALY gained. The company also presented new evidence on the cost effectiveness of ruxolitinib in intermediate-2 and high-risk subgroups and a revised version of the model. The NICE Appraisal Committee considered the new evidence and recommended ruxolitinib for the treatment of patients with intermediate-2-risk disease as well as patients with high-risk disease, based on International Prognostic Scoring System (IPSS) prognostic factors.

Crizotinib for Untreated Anaplastic Lymphoma Kinase-Positive Non-Small-Cell Lung Cancer: An Evidence Review Group Perspective of a NICE Single Technology Appraisal.

As part of the National Institute for Health and Care Excellence (NICE) single technology appraisal process, the manufacturer of crizotinib submitted evidence on the clinical and cost effectiveness of crizotinib in untreated anaplastic lymphoma kinase-positive (ALK-positive) non-small-cell lung cancer (NSCLC). Crizotinib has previously been assessed by NICE for patients with previously treated ALK-positive NSCLC (TA 296). It was not approved in this previous appraisal, but had been made available through the cancer drugs fund. As part of this new appraisal, the company included a price discount patient access scheme (PAS). The Centre for Reviews and Dissemination and Centre for Health Economics Technology Appraisal Group at the University of York was commissioned to act as the independent Evidence Review Group (ERG). This article provides a description of the company's submission and the ERG's review and summarises the resulting NICE guidance issued in August 2016. The main clinical-effectiveness data were derived from a multicentre randomised controlled trial-PROFILE 1014-that compared crizotinib with pemetrexed chemotherapy in combination with carboplatin or cisplatin in patients with untreated non-squamous ALK-positive NSCLC. In the trial, crizotinib demonstrated improvements in progression-free survival (PFS) and overall survival (OS). The company's economic model was a three-state 'area under the curve' Markov model. The base-case incremental cost-effectiveness ratio (ICER) was estimated to be greater than £50,000 per quality-adjusted life-year (QALY) gained (excluding the PAS discount). The ERG assessment of the evidence submitted by the company raised a number of concerns. In terms of the clinical evidence, the OS benefit was highly uncertain due to the cross-over permitted in the trial and the immaturity of the data; only 26% of events had occurred by the data cut-off point. In the economic modelling, the most significant concerns related to the analysis of OS and assumptions made regarding the duration of therapy. The ERG exploratory re-analysis of the OS data relaxed the assumption of proportional hazards made in the company submission, which demonstrated significant uncertainty regarding the OS gains from crizotinib. The ERG reconfigured the economic model so that duration of therapy was based on the area under the curve analysis of the PROFILE 1014 trial, dramatically increasing the cost associated with implementing crizotinib and consequently, substantially increasing the ICER. At the first appraisal meeting, the NICE Appraisal Committee concluded that crizotinib, while clinically effective, was not sufficiently cost effective for use in the UK NHS. Following the consultation, the company offered a revised PAS and conducted extensive re-analysis, resulting in a revised base-case ICER of £47,291 per QALY gained. The NICE Appraisal Committee concluded that crizotinib was likely to be a cost-effective use of NHS resources, despite the uncertainty that persisted around a number of factors, namely the long-term survival benefit of crizotinib. Crizotinib was therefore recommended as an option for untreated ALK-positive advanced NSCLC in adults.

The assessment and appraisal of regenerative medicines and cell therapy products: an exploration of methods for review, economic evaluation and appraisal.

BACKGROUND: The National Institute for Health and Care Excellence (NICE) commissioned a 'mock technology appraisal' to assess whether changes to its methods and processes are needed. This report presents the findings of independent research commissioned to inform this appraisal and the deliberations of a panel convened by NICE to evaluate the mock appraisal. METHODS: Our research included reviews to identify issues, analysis methods and conceptual differences and the relevance of alternative decision frameworks, alongside the development of an exemplar case study of chimeric antigen receptor (CAR) T-cell therapy for treating acute lymphoblastic leukaemia. RESULTS: An assessment of previous evaluations of regenerative medicines found that, although there were a number of evidential challenges, none was unique to regenerative medicines or was beyond the scope of existing methods used to conceptualise decision uncertainty. Regarding the clinical evidence for regenerative medicines, the issues were those associated with a limited evidence base but were not unique to regenerative medicines: small non-randomised studies, high variation in response and the intervention subject to continuing development. The relative treatment effects generated from single-arm trials are likely to be optimistic unless it is certain that the historical data have accurately estimated the efficacy of the control agent. Pivotal trials may use surrogate end points, which, on average, overestimate treatment effects. To reduce overall uncertainty, multivariate meta-analysis of all available data should be considered. Incorporating indirectly relevant but more reliable (more mature) data into the analysis can also be considered; such data may become available as a result of the evolving regulatory pathways being developed by the European Medicines Agency. For the exemplar case of CAR T-cell therapy, target product profiles (TPPs) were developed, which considered the 'curative' and 'bridging to stem-cell transplantation' treatment approaches separately. Within each TPP, three 'hypothetical' evidence sets (minimum, intermediate and mature) were generated to simulate the impact of alternative levels of precision and maturity in the clinical evidence. Subsequent assessments of cost-effectiveness were undertaken, employing the existing NICE reference case alongside additional analyses suggested within alternative frameworks. The additional exploratory analyses were undertaken to demonstrate how assessments of cost-effectiveness and uncertainty could be impacted by alternative managed entry agreements (MEAs), including price discounts, performance-related schemes and technology leasing. The panel deliberated on the range of TPPs, evidence sets and MEAs, commenting on the likely recommendations for each scenario. The panel discussed the challenges associated with the exemplar and regenerative medicines more broadly, focusing on the need for a robust quantification of the level of uncertainty in the cost-effective estimates and the potential value of MEAs in limiting the exposure of the NHS to high upfront costs and loss associated with a wrong decision. CONCLUSIONS: It is to be expected that there will be a significant level of uncertainty in determining the clinical effectiveness of regenerative medicines and their long-term costs and benefits, but the existing methods available to estimate the implications of this uncertainty are sufficient. The use of risk sharing and MEAs between the NHS and manufacturers of regenerative medicines should be investigated further. FUNDING: The National Institute for Health Research Health Technology Assessment programme.