Submission Of Evidence Research Articles

PMU88 WHAT IS THE ROLE OF THE COMPANY EVIDENCE SUBMISSION IN NATIONAL INSTITUTE FOR HEALTH AND CARE EXCELLENCE (NICE) MULTIPLE TECHNOLOGY APPRAISALS?

NICE’s multiple technology appraisal (MTA) process evaluates the clinical and cost-effectiveness of multiple health technologies or a single technology for multiple indications. In MTA, reviews of clinical and economic evidence and de novo economic modelling are done by an independent Assessment Group (AG). Companies may provide evidence submissions in addition to the AG, but this is not an essential requirement and no template is provided. This review examines the type of evidence submitted by companies in recent MTAs, as the role of the company submission is unclear. Published NICE MTAs (excluding withdrawn/terminated and reappraisals) from the last 10 years were reviewed on the NICE website up to May 2019. Key data were extracted, including number and type of technologies appraised, final recommendations, and type of evidence included in the company submission (submissions from biosimilar/generics companies were excluded). Descriptive statistics relating to possible sources of variability were calculated. From May 2009 to May 2019, 49 MTAs were published, providing 144 recommendations on drugs and devices. Interim analyses show the proportion of positive recommendations was high, with 47% recommended, 26% optimised, 1% in research, and 26% not recommended. A total of 134 originator technologies were reviewed; 81% of companies provided an evidence submission, while 19% did not submit any evidence. Of the companies that submitted evidence, the type of evidence varied: 87% provided a full submission including an economic model and 13% submitted partial dossiers of clinical evidence only. The lack of requirement for a company submission in the MTA process does not preclude companies from submitting their own evidence, with a high proportion submitting a full or partial dossier for consideration. The influence of this evidence is unclear, as 19% of companies did not submit any evidence, yet 54% of these companies gained a positive/optimised NICE recommendation.

Shedding light on the HTA consultancy market: Insights from Poland

Research on health technology assessment (HTA) from a policy perspective typically examines public HTA bodies, with little attention devoted to how manufacturers develop their evidence submissions. Taking Poland as a crucial case, we explored the market of HTA consultancy firms which assist drug manufacturers in developing these submissions, called HTA reports. We reviewed 318 HTA reports from 2012 to 2015, data from the Polish National Company Registry, the content of HTA consulting firms’ websites, and appraisal reports developed by the Polish HTA body. We identified HTA consultancy firms which developed 96–98% HTA reports. We found that the transparency of information about the authors of HTA reports provided by the HTA body had improved between 2012 and 2015. Six companies with market shares from 10 to 30% dominated the market. The market size was estimated to be 5–6 million EUR annually. HTA consultancies had a broad service portfolio related to preparation of HTA reports. Over 90% of HTA reports did not meet the official minimum quality requirements, and only half of the resubmissions took into account remarks made by the HTA body. Our study provides insights into the structure, evolution and role of the for-profit HTA consultancy market as a crucial part of the public HTA system. This raises important policy points about transparency and regulation at the intersection of public and private sectors in HTA.

A Blockchain-Based Nonrepudiation Network Computing Service Scheme for Industrial IoT

Emerging network computing technologies extend the functionalities of industrial IoT (IIoT) terminals. However, this promising service-provisioning scheme encounters problems in untrusted and distributed IIoT scenarios because malicious service providers or clients may deny service provisions or usage for their own interests. Traditional nonrepudiation solutions fade in IIoT environments due to requirements of trusted third parties or unacceptable overheads. Fortunately, the blockchain revolution facilitates innovative solutions. In this paper, we propose a blockchain-based fair nonrepudiation service provisioning scheme for IIoT scenarios in which the blockchain is used as a service publisher and an evidence recorder. Each service is separately delivered via on-chain and off-chain channels with mandatory evidence submissions for nonrepudiation purpose. Moreover, a homomorphic-hash-based service verification method is designed that can function with mere on-chain evidence. And an impartial smart contract is implemented to resolve disputes. The security analysis demonstrates the dependability, and the evaluations reveal the effectiveness and efficiency.

Tisagenlecleucel for the Treatment of Relapsed or Refractory B-cell Acute Lymphoblastic Leukaemia in People Aged up to 25Years: An Evidence Review Group Perspective of a NICE Single Technology Appraisal.

As part of the National Institute for Health and Care Excellence's (NICE's) Single Technology Appraisal (STA) process, Novartis submitted evidence on the clinical effectiveness and cost-effectiveness of tisagenlecleucel for treating paediatric and young adult patients (under the age of 25years) with relapsed or refractory (r/r) B-cell acute lymphoblastic leukaemia (ALL). This article presents a summary of the Evidence Review Group's (ERG's) independent review of the evidence submission, the committee's deliberations, and the subsequent development of NICE guidance for the use of tisagenlecleucel on the National Health Service (NHS) in England. Tisagenlecleucel is a chimeric antigen receptor-modified T-cell (CAR-T) product, the first of this emerging therapeutic class to be considered by NICE in this indication. The company's evidence submission was based upon three single-arm, phase II studies: ELIANA, ENSIGN, and B2101J. These trials demonstrated a beneficial effect of tisagenlecleucel, with significant extensions in event-free survival (EFS) and overall survival (OS) compared to historical control datasets on blinatumomab and salvage chemotherapy. Adverse events were common; 77% of patients suffered from cytokine release syndrome (CRS), 56% of whom required intensive care unit-level care. The ERG did not consider clofarabine monotherapy an appropriate proxy for salvage chemotherapy. The company presented a hybrid cost-effectiveness model, combining a decision tree and three-state partitioned survival model structure. The majority of quality-adjusted life-years (QALYs) gained were generated through additional life-years in the extrapolated 'long-term survival' phase of the model, where patients were assumed to be 'cured'. The ERG considered the results to be subject to substantial uncertainty, due in part to immature trial data, unresolved long-term treatment effects, and a lack of appropriate comparator data. The ERG implemented a number of changes to the company's model in an alternative base case, producing deterministic incremental cost-effectiveness ratios (ICERs) of £45,397 per QALY gained versus salvage chemotherapy, and £27,732 versus blinatumomab. The probabilistic model produced ICERs of £48,265 per QALY gained versus salvage chemotherapy, and £29,501 versus blinatumomab. The committee considered the ERG's analysis to be most closely aligned with their preferred assumptions, and did not consider tisagenlecleucel to meet both of the end-of-life (EoL) criteria. In recognition of the innovative nature of tisagenlecleucel, and the present immaturity of ongoing clinical trials, the committee considered further data collection would be valuable in resolving uncertainties around OS, the technology's novel mechanism of action, and the management of CRS and B-cell aplasia. The committee therefore recommended tisagenlecleucel for use in the Cancer Drugs Fund (CDF) until the conclusion of the ELIANA study (June 2023). This appraisal highlighted the difficulty of interpreting EoL criteria in the context of curative therapies and the valuation of cure versus extension of life. Further clarification of NICE's position in these situations may be necessary to ensure consistency and equity in their decision-making.

Block-DEF: A secure digital evidence framework using blockchain

A secure digital evidence system should ensure that evidence cannot be tampered with and that private information cannot be leaked. Blockchain, a distributed tamper-resistant and privacy-preserving ledger, provides a promising solution for decentralized secure digital evidence systems. However, due to the huge number of digital evidences and the contradiction between the traceability and the privacy of evidence, blockchain faces big data and privacy challenges. To solve the above issues, we propose a secure digital evidence framework using blockchain (Block-DEF) with a loose coupling structure in which the evidence and the evidence information are maintained separately. Only the evidence information is stored in the blockchain, and the evidence is stored on a trusted storage platform. To avoid blockchain bloat, a lightweight blockchain combining a mixed block structure with an optimized name-based practical byzantine fault tolerance consensus mechanism is proposed. To support the traceability and the privacy of evidence, the multi-signature technique is adopted for evidence submission and retrieval. The analytical and experimental results show that Block-DEF is a scalable framework, it guarantees the integrity and validity of evidence, and balances privacy and traceability well.

Do evidence submission forms expose latent print examiners to task-irrelevant information?

Emerging research documents the ways in which task-irrelevant contextual information may influence the opinions and decisions that forensic analysts reach regarding evidence (e.g., Dror and Cole, 2010; National Academy of Sciences, 2009; President’s Council of Advisors on Science and Technology, 2016). Consequently, authorities have called for forensic analysts to rely solely on task-relevant information—and to actively avoid task-irrelevant information—when conducting analyses (National Commission on Forensic Science, 2015). In this study, we examined 97 evidence submission forms, used by 148 accredited crime laboratories across the United States, to determine what types of information laboratories solicit when performing latent print analyses. Results indicate that many laboratories request information with no direct relevance to the specific task of latent print comparison. More concerning, approximately one in six forms (16.5%) request information that appears to have a high potential for bias without any discernible relevance to latent print comparison. Solicitations for task-irrelevant information may carry meaningful consequences and current findings inform strategies to reduce the potential for cognitive bias.

ReCell® Spray-On Skin System for Treating Skin Loss, Scarring and Depigmentation after Burn Injury: A NICE Medical Technology Guidance.

The gold standard treatment for deep burns is an autologous skin graft; in larger burns this may be meshed to increase the area covered. However, long-term aesthetic and functional outcomes of graft scars may be poor. ReCell® is a medical device that processes skin samples in the operating theatre into a cell suspension to be sprayed or dripped onto a wound. It is claimed to improve healing and scar appearance. This device was evaluated by the National Institute for Health and Care Excellence (NICE) Medical Technologies Evaluation Programme. Two groups were defined: ReCell compared to conventional dressings in shallower burns, and meshed grafts plus ReCell compared to meshed grafts alone in larger deeper burns. The manufacturer's clinical evidence submission included three papers and eight conference abstracts. The External Assessment Centre (EAC) excluded two of these and added seven abstracts. In general, the evidence did not fit the defined groups, but suggested that ReCell was clinically comparable to skin grafts for partial thickness burns; however, ReCell is not used in this way in the UK. The manufacturer submitted an economic model in which ReCell treatment of partial thickness burns reduced the requirement for later skin grafts. This indicated that ReCell alone was cost saving in comparison to conventional dressings. The EAC indicated that this model was clinically inappropriate, but data were not available to populate a new model. NICE Medical Technologies Guidance 21 recommended that additional research was needed to address the uncertainties regarding the potential benefits of ReCell.

A Review of Issues Affecting the Efficiency of Decision Making in the NICE Single Technology Appraisal Process.

BackgroundEscalating demands upon the National Institute for Health and Care Excellence’s (NICE’s) Single Technology Appraisal (STA) programme require a 2.5-times increase upon 2015 capacity by 2020. This additional strain on committee resources threatens to compromise the rigour of the STA process. In 2018, NICE introduced changes to the appraisal process, aiming to expedite final decisions, including consultation opportunities prior to the company’s evidence submission, a ‘Technical Engagement’ stage prior to the first committee meeting, and powers for committee chairs to recommend technologies without a second formal meeting.ObjectiveThis study reviews recent STAs and aims to understand why appraisals require multiple meetings, and whether recent reforms can address the underlying issues.MethodsNICE STAs published between January 2010 and January 2018 were reviewed, excluding updates or re-considerations. Data on cost, clinical, and decision-making outcomes from 146 appraisals were extracted and analysed thematically.ResultsDrugs for advanced cancers were least likely to be recommended (28/43 [65.1%] vs 71/74 [96%] for non-cancer) and took longer (2.36 meetings for a final decision vs 1.97 for non-cancer). The academic review increased upon the company’s base-case incremental cost-effectiveness ratio by a median of 32.7%. Eighty-four technologies (57.5%) received a negative preliminary recommendation, deferring a final decision by an average of 142 days. Of these, 85.1% were not considered cost-effective. Uncertainty in economic (34.3%) and clinical (22.3%) data also prevented a positive decision. The majority (72.6% [61/84]) of negative preliminary decisions were overturned following further committee discussion; important considerations were Patient Access Schemes, decision optimisation, and the Cancer Drugs Fund.ConclusionsValue considerations are the primary driver of negative preliminary recommendations. It is unclear if new opportunities for additional interaction between NICE, review groups, and manufacturers will meaningfully improve the efficiency of the appraisal process, particularly given the proportion of technologies requiring further committee discussion for decision optimisation or admission into the CDF. Electronic supplementary materialThe online version of this article (10.1007/s41669-018-0113-0) contains supplementary material, which is available to authorized users.

VP23 Assessing The Effectiveness Of A Medical Device With Limited Evidence

IntroductionSecurAcath (Interrad Medical), a catheter securement device designed for central venous catheters, was assessed by the National Institute for Health and Care Excellence (NICE) in 2017 resulting in Medical Technology Guidance 34 (MTG34). Due to the limited number and quality of published evidence, novel methods were used to deliver a report that allowed a recommendation on adoption to be made.MethodsKiTEC, an external assessment centre for NICE, independently evaluated the manufacturers submission of clinical and economic evidence. The submission was characterised by a lack of strong clinical evidence, comprising just one randomized clinical trial (RCT) and a small number of non-comparative observational studies, some of which were available as conference abstracts or poster presentations. KiTEC ran a meta-analysis of these studies along with data on the comparators, securement with sutures and securement with StatLock (Bard Access Systems). Due to the lack of comparative studies, KiTEC pooled data on five outcomes (migration, dislodgement, catheter-related infection, CRBSI, unplanned removals/reinsertions) and calculated relative risks for each. KiTEC revised the manufacturer's cost model, changing a number of parameters and assumptions. The decision to recommend SecurAcath for use in the National Health Service (NHS) was also supported by qualitative evidence from expert clinicians who had used the SecurAcath in practice.ResultsKiTEC's meta-analysis showed non-inferiority for SecurAcath over the comparators. The limited information in the studies made it impossible to ascertain study heterogeneity in the meta-analysis. KiTEC's economic analyses showed that SecurAcath could be cost saving in some scenarios, but not for short indwell times (≤5 days). However, clinical expert opinion was overwhelmingly positive and this qualitative evidence was viewed alongside the less conclusive clinical and cost-effectiveness evidence. SecurAcath was recommended to be used in the NHS, with annual savings estimated to be a minimum of GBP 4.2m.ConclusionsIn cases where there is a lack of published evidence, unpublished material and expert clinical opinion can be used to bolster the case for the adoption of medical devices.

Assessing the Quality of Evidence Presented at Annual General Meetings: A 5-Year Retrospective Study.

Health care professionals rely on annual general meetings (AGMs) to obtain up-to-date information and practice guidelines relevant to their specialty. The majority of such information at meetings is presented through abstract sessions. However, the quality of the evidence presented during such abstract sessions is unclear. Standardized measures were applied to assess the quality of evidence of abstracts presented at the Canadian Society of Nephrology AGM over a 5-year period. Two authors independently reviewed all CSN AGM abstracts presented from 2012 to 2016. Using a schema published in 2011 by the Oxford Centre for Evidence-Based Medicine (OCEBM), each abstract was subsequently ranked based on the quality of evidence. Schema categories ranged from level I, representing the highest evidence quality, to level V, representing the lowest. The number of authors and the authors' institution affiliations were also collected from the abstracts, where available, or if affiliations were unclear, an internet search of the author was performed. Six hundred forty-two articles were screened. In total, 70% (n = 450) met the inclusion criteria. When assessed, 15% of articles were level I (highest quality), 17% level II, 53% level III, 12% level IV, and 3% level V (lowest quality). A Jonckheere-Terpstra test demonstrated a significant trend of increasing quality of evidence (P < .05) and collaboration (P < .005) over the 5-year study period. There was a significant correlation between level of evidence and collaboration across years reviewed in the study, rs(98) = -0.226, P < .001. The results indicate a consistent increase in quality of evidence and collaborative submissions over time. To the authors' knowledge, this is the first assessment and analysis of AGM presentation quality within internal medicine and its subspecialties. Documenting and monitoring changes in the quality of evidence with a standardized framework may offer valuable insight pertaining to the medical field and the research community.

Role of economic evidence in coverage decision-making in South Korea

ObjectivesThe South Korean government required the submission of economic evidence when it implemented the Positive-List System in December 2006. This study investigates the key factors that influenced actual public insurance reimbursement decisions, including the role of economic evidence, after 10 years of decision practice under compulsory health technology assessment (HTA) for new drugs.MethodLogistic regression analysis was used to estimate the impact of the variables involved, including cost-effectiveness ratio as a key variable, on reimbursement decisions. The latter were defined as “yes” or “no” at a submitted price and indication. Only cases (n = 91) that present a cost-effectiveness ratio, and that have been reviewed based on this ratio from January 2007 to December 2016, were included in the analysis.ResultsCases with higher cost-effectiveness ratios were less likely to be accepted. In addition, drugs that were used to treat severe diseases and drugs with no substitute were more likely to be recommended. The probability of acceptance declined along with the level of uncertainty in the submitted evidence. The acceptance rate for severe-disease drugs has increased since 2013, when the government introduced several policies that lowered the existing barriers to positive reimbursement. However, such an increase was not statistically significant.ConclusionsCost-effectiveness is one of the most influential factors in drug-reimbursement decisions. However, inclusion of other explanatory variables, in addition to the cost-effectiveness ratio, predicted the results of decisions more accurately.

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.

Cladribine Tablets for the First-Line Treatment of Relapsing-Remitting Multiple Sclerosis: An Evidence Review Group Perspective of a NICE Single Technology Appraisal.

As part of the single technology appraisal process, the National Institute for Health and Care Excellence invited Merck to submit evidence for the clinical and cost effectiveness of cladribine tablets (cladribine) for the treatment of relapsing-remitting multiple sclerosis (RRMS). Rapidly evolving severe (RES) and sub-optimally treated (SOT) RRMS were specified by the National Institute for Health and Care Excellence as subgroups of interest. The Liverpool Reviews and Implementation Group at the University of Liverpool was the Evidence Review Group. This article summarises the Evidence Review Group’s review of the company’s evidence submission for cladribine and the Appraisal Committee’s final decision. The final scope issued by the National Institute for Health and Care Excellence listed the following disease-modifying treatments as comparators: alemtuzumab, daclizumab, fingolimod and natalizumab. At the time of the company submission, a licence was anticipated for low-dose cladribine. The main clinical evidence (the CLARITY trial) in the company submission focused on the efficacy of low-dose cladribine vs. placebo. The CLARITY trial showed a statistically significant reduction in relapse rate for cladribine in the RES-RRMS subgroup (n = 50) but not in the SOT-RRMS subgroup (n = 19). Cladribine showed a numerical, but not a statistically significant, advantage in delaying disability progression at 6 months in the RES-RRMS subgroup. Disability progression benefits could not be estimated for those in the SOT-RRMS subgroup because of few events. The Evidence Review Group’s main concern regarding the clinical evidence was the small sample size of the subgroups. To compare the effectiveness of cladribine to other disease-modifying treatments, the company conducted network meta-analyses, which showed cladribine and its comparators to be equally effective. The Evidence Review Group considered the results of the disease-modifying treatments to be unreliable because few trials were in the network. The company’s cost-effectiveness evidence showed cladribine to be cheaper and more effective than other disease-modifying treatments in the RES-RRMS arm and the SOT-RRMS arm. The results were most sensitive to treatment effect on disability progression at 6 months. The Evidence Review Group was concerned that there was insufficient evidence to conclude that cladribine was superior to placebo in delaying disability progression. The Evidence Review Group amended the company’s economic model to allow alternative estimates for the treatment effect of cladribine and its comparators on relapse rate and disability progression at 6 months. The Evidence Review Group made other changes to the company model. After implementing all the amendments, cladribine remained cost effective in the RES-RRMS and SOT-RRMS subgroups. The Appraisal Committee recognised the uncertainty in the available data but concluded that cladribine could be considered a cost-effective use of National Health Service resources.

PHP279 - ASSESSMENT OF THE NICE FAST-TRACK APPRAISAL (FTA) PROCESS

NICE introduced the fast-track appraisal (FTA) process in April 2017 to allow less-resource intensive assessment of treatments with an expected base-case ICER below £10,000 per QALY gained or that show similar costs and benefits to NICE-recommended treatments. This study describes the FTA process, and reviews the outcomes and time taken to publication of FTA guidance. FTAs were identified by review of technology appraisal guidance on the NICE website (1st April 2017-13th June 2018). Final FTA guidance was identified for three technologies; aflibercept for choroidal neovascularisation (TA486), golimumab for non-radiographic axial spondyloarthritis (TA497), and guselkumab for plaque psoriasis (TA521). Publication of FTA guidance is intended 24 weeks after evidence submission, compared with 35 weeks for single technology appraisals (STAs). Aflibercept, golimumab, and guselkumab were recommended for routine use with recommendations published 26 (TA486), 31 (TA497), and 33 (TA521) weeks after evidence submission, slightly longer than the FTA process timetable but more rapid than STAs. For FTAs, cost-utility or cost-comparison analysis can be performed. A positive cost-comparison must demonstrate similar/ greater health benefits, and similar/ lower total costs compared with relevant comparators. Clinical outcomes and key drivers of cost-effectiveness must reflect the outcomes and drivers identified for NICE-recommended comparators. In the three completed FTAs, cost-comparison analysis was performed, and clinical-effectiveness data were taken from phase III randomised controlled trials. The first three treatments to undergo NICE FTA were recommended within 33 weeks of evidence submission, a more rapid recommendation than would have been likely through standard technology appraisal processes. The NICE FTA process provides an efficient opportunity for technologies to be recommended for use by NHS England and should be considered by manufacturers of technologies that offer exceptional value for money or that have similar/ lower costs and similar/ greater benefits launching in indications with NICE-recommended comparators.

PHP275 - ORPHAN MEDICINAL PRODUCTS GIVEN AN INITIAL NEGATIVE RECOMMENDATION BY NICE'S STA PROCESS BUT APPROVED FOLLOWING RE-EVALUATION IN ENGLAND

OMPs present a challenge to HTA bodies in that there may be high levels of uncertainty in their clinical and economic data due to the inherent limitations in their trial size. This study assessed the factors that influence overturning initial negative recommendations for OMPs assessed through STA. Products for evaluation through STA between 2011 and 2017 were identified through STA topics published on NICE’s website, and filtered for topics that had not been recommended. The list of topics that had received a negative recommendation was then cross referenced with products and indications that were granted Orphan status by the EMA. The published guidance for each OMP granted a positive recommendation following a re-review were analysed to assess the changes to the submission that may have influenced the change in recommendation, either submission of new evidence, provision of a Patient Access Scheme, or definition of a new patient population. Of the 254 technologies considered between 2011 and 2017, 38 topics were granted an initial negative recommendation, as the technology was not considered to be an appropriate use of NHS resources based on the data available. Of the 38 topics 6 were OMPs, and 4 were recommended following re-review and updated guidance. In two of the re-evaluations additional data was provided by the company, Patient Access Schemes were applied in all 4 cases, and narrowing of the patient population was applied in all 4 cases. This study provides evidence of the measures that have been taken to overturn a negative STA recommendation for OMPs reviewed through STA process in England. Where clinical evidence is scarce due to the nature of the therapy, companies must accept discounts and subgroups in the patient population in order to be given a positive recommendation in the event of a re-review.

Etelcalcetide for Treating Secondary Hyperparathyroidism: An Evidence Review Group Evaluation of a NICE Single Technology Appraisal.

The manufacturer of the calcimimetic drug etelcalcetide was invited to make an evidence submission as part of the National Institute for Health and Care Excellence (NICE) Single Technology Appraisal (STA) programme. Within this submission, they reported evidence on the clinical and cost effectiveness of etelcalcetide for the treatment of secondary hyperparathyroidism (SHPT) in patients with chronic kidney disease (CKD) on haemodialysis. The Southampton Health Technology Assessments Centre (SHTAC), part of the Wessex Institute at the University of Southampton, was the independent Evidence Review Group (ERG) commissioned to appraise the company's submission. This article describes the ERG's review and critique of the company's submission and summarises the NICE Appraisal Committee's subsequent guidance (issued in June 2017). The clinical-effectiveness evidence submitted by the company consisted of two double-blind, randomised controlled trials (RCTs) comparing etelcalcetide with placebo, one RCT comparing etelcalcetide with cinacalcet, two single-arm extension studies of the above trials, and one single-arm study evaluating the effect of switching from cinacalcet to etelcalcetide. No study specifically examined the population specified in the NICE appraisal scope: patients refractory to standard therapy with phosphate binders and vitamin D (PBVD). None of these trials were designed to collect long-term efficacy data for outcomes such as mortality, bone fractures, cardiovascular events, or parathyroidectomies. Instead, biomarker data from the trials were mapped to long-term outcomes by an assumed linear relationship between the trial outcome, reduction of parathyroid hormone (PTH) by > 30%, and the log-hazard ratios for the occurrence of clinical events derived from a large, long-term RCT of cinacalcet (the EVOLVE trial). After submission of a confidential Patient Access Scheme (PAS) discount reducing etelcalcetide drug costs, the incremental cost-effectiveness ratio (ICER) for etelcalcetide versus cinacalcet was £14,778 per quality-adjusted life-year (QALY) gained in the company's base case. While this value is lower than the NICE threshold range of £20,000 and £30,000 per QALY gained, it was the opinion of the ERG that the ICER was highly uncertain due to efficacy data limitations for etelcalcetide, inadequate synthesis of clinical-effectiveness evidence, and strong assumptions connecting short-term biomarker data with long-term clinical outcomes. The ERG produced an alternative base case for etelcalcetide versus cinacalcet, with an ICER of £22,400 per QALY gained, also subject to uncertainty. The NICE Appraisal Committee recommended etelcalcetide as an option for the treatment of SHPT in adults with CKD only if treatment with a calcimimetic is indicated and cinacalcet is not suitable, subject to the company's provision of the agreed PAS discount.

Development of a new understanding of the basic properties of evidence and other provisions of the procedure for dealing with them and their sources in criminal proceedings

In the article new edition of the norm CPC of Ukraine on the understanding of the essence of evidence and their basic legal properties, sources, subjects, order and exhaustive list of actions for their receipt and forms of operating such information in criminal proceedings is proposed. The essence of the evidence and of each their primary and additional basic legal properties is disclosed. The variant of the decision of a problem of subjects of reception of proofs and participation of other persons in the given procedure is offered. Outlined an exhaustive list of those receiving investigative and judicial actions, as well as forms of submission, evaluation and use of evidence in criminal proceedings.

The Use of Real World Data for Nice Decision-Making: A Review of Submissions To Three Treatment Effectiveness Evaluation Programmes In 2015 And 2016

Randomised controlled trials (RCTs) are traditionally the ‘gold-standard’ data source for National Institute for Care and Health Excellence (NICE) evidence appraisals, although real world data (RWD) is gradually being accepted alongside RCTs or sometimes as a distinct evidence source. Guidance regarding the appropriate use of RWD is limited and varies across programmes. This audit aimed to quantify the extent to which RWD was considered in submissions and reviews for three NICE evaluation programmes in the previous two years. A systematic review of NICE guidance published by the NICE Technology Appraisal (TA), Diagnostic Assessment (DA) and Medical Technologies Evaluation (MTE) programmes in 2015-16 was conducted in May 2017. Key information, including a description of evidence considered, committee comments and recommendations made was extracted and recorded in an electronic database. References to RWD (i.e. data generated from non-comparative, observational studies) were noted. In 2015-16, 91 TA, 9 DA and 9 MTE submissions were appraised by NICE. Of TA evidence submissions, 10% (9/91) included RWD, compared with 67% (6/9) DA and 89% (8/9) MTE submissions. The reviewing committee identified aspects of real-world study methods or reporting requiring improvement for 56% (5/9) TA, 50% (3/6) DA and 44% (4/9) MTE appraisals involving RWD: key areas of focus included sample size, generalisability to wider population, and potential confounders. Guidance included specific recommendations for further RWD collection for 5% TA, 100% DA and 56% MTE submissions. The relatively low proportion of RWD in TA submissions suggests a slower uptake for medicine appraisals compared with diagnostics and other technologies. Nevertheless, the thorough evaluations of real-world evidence by NICE, and trend towards specific recommendations for further RWD, indicate increasing prominence of RWD for NICE decision-making. Detailed guidance and collaboration across NICE programmes is needed to enable robust design and consistent critique of real-world studies.

The Role of Noncomparative Evidence in Health Technology Assessment Decisions

BackgroundMany health technology assessment (HTA) agencies express a preference for randomized controlled trial evidence when appraising health technologies; nevertheless, it is not always feasible or ethical to conduct such comparative trials. ObjectivesTo assess the role of noncomparative evidence in HTA decision making. MethodsThe Web sites of the National Institute for Health and Care Excellence (NICE) in the United Kingdom, the Canadian Agency for Drugs and Technologies in Health (CADTH) in Canada, and the Institute for Quality and Efficiency in Health Care (Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen [IQWiG]) in Germany were searched for single HTA reports (published between January 2010 and December 2015). The product, indication, outcome, and clinical evidence presented (comparative/noncomparative) were double-extracted, with any discrepancies reconciled. A noncomparative study was defined as any study not presenting results against another treatment (including placebo or best supportive care), regardless of phase or setting, including dose-ranging studies. ResultsA total of 549 appraisals were extracted. Noncomparative evidence was considered in 38% (45 of 118) of NICE submissions, 13% (34 of 262) of CADTH submissions, and 12% (20 of 169) of IQWiG submissions. Evidence submissions based exclusively on noncomparative evidence were presented in only 4% (5 of 118) of NICE appraisals, 6% (16 of 262) of CADTH appraisals, and 4% (6 of 169) of IQWiG appraisals. Most drugs appraised solely on the basis of noncomparative evidence were indicated for cancer or hepatitis C. Positive outcome rates (encompassing recommended/restricted/added-benefit decisions) for submissions presenting only noncomparative evidence were similar to overall recommendation rates for CADTH (69% vs. 68%, respectively), but were numerically lower for NICE (60% vs. 84%, respectively) and IQWiG (17% vs. 38%, respectively) (P > 0.05 for all). ConclusionsNoncomparative studies can be viewed as acceptable clinical evidence by HTA agencies when these study designs are justifiable and when treatment effect can be convincingly demonstrated, but their use is currently limited.

اليمين المتممة وأهميتها في الاثبات المدني [دراسة تحليلية مقارنة في الاثبات المدني

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