Reimbursement Submissions Research Articles

Composite event-free-survival as an endpoint in oncology drug evaluation: Review and guidance perspectives from the Haute Autorité de Santé (HAS)

BackgroundThe use of right-censored composite endpoints, such as progression-free survival, has been questioned in haemato-oncology trials due to potential bias in estimated treatment effect. This may impact the accuracy of health technology evaluations. We hypothesized that there is heterogeneity and potential sources of bias in the reporting of composite endpoints to health technology assessment (HTA) bodies. MethodsWe reviewed the submissions for reimbursement of oncology drugs in 2021 and 2022 that used a composite endpoint in the pivotal trial, after appraisal by the French HTA body. The retrieved information included the clinical study report, protocol, and statistical analysis plan submitted by the industry. All events of the composite endpoint and all causes of censored observations were measured. The design characteristics and treatment effect estimates were recorded. FindingsSeventy-six submissions were selected, including seven without a right-censored endpoint and four evaluating associations, resulting in 65 analysed records: 17 for haematological and 48 for solid tumours. Out these 65 submissions, 47 (72·3%) used a randomized controlled design, and 18 (27·7%) a non-comparative design. The most frequently used composite endpoint was progression-free survival, used in 54 (83·1%) of the submissions. Censoring was possibly informative in 51 (92·7%) cases, mostly due to the onset of new treatment (44/51, 86·3%) and/or discontinuation of follow-up (33/51, 64·7%). In contrast, 38 (58·5%) trials reported a quantification of censored observations, with only 12/51 (23·5%) quantifying the informative ones. The estimated treatment effect on the composite outcome increased with the amount of censoring, suggesting a higher benefit of the drug, but remained below that on survival with poor evidence of surrogacy (R-squared=0·23). InterpretationClinical study reports should be improved in terms of reporting censoring, while stakeholders should be aware of this potential source of bias. At a minimum, sensitivity analysis that ignores intercurrent events should be requested.

The Checklist for Standard Methodological Requirements and Reporting of Economic Evaluation of Medicines in Slovakia

ObjectivesWe have developed a scientifically well-grounded, methodological, and reporting checklist for economic evaluation (EE) of medicines in the Slovak health technology assessment process, which serves as a supplement to the Slovak pharmacoeconomic guidelines. MethodsThe checklist was developed using an iterative process in which items were generated and gradually added to the baseline checklist based on shortcomings identified in an analysis of Slovak EEs, using relevant published checklists, and Slovak, as well as international, methodological guidance that was identified in the systematic literature review. The selection of checklist recommendations, their clarity, and relevance to the Slovak setting were validated in the online survey. ResultsFrom the sample of 151 price and reimbursement submissions published between January 2018 and July 2021, almost half of them (n = 73) received at least 1 request from the Ministry of Healthcare to justify or modify the methodology used in the EE; and in 18 proceedings, a negative opinion was issued because of shortcomings identified in the EE. The 25-items preliminary checklist, resulting from an iterative working process, has been validated in an online survey conducted among members of ISPOR Chapter Slovakia. After incorporating relevant comments, the final proposal for the Slovak checklist consists of 55 recommendations. ConclusionsThe research represented the first attempt to create a Slovak EE checklist, which serves as a part of ISPOR Slovakia pharmacoeconomic guidelines. Implementation of the checklist allows checking whether EE meets legislative and methodological requirements and thus helps in improving the appropriateness and standardization of EEs in Slovakia.

EE262 Use of Single-Arm Trials in Cadth Reviews of Oncology Drugs

Single-arm trials (SAT) have been increasingly used to support oncology reimbursement submissions worldwide. In a previous study, the authors assessed the use of SAT-based oncology technical appraisals by the National Institute for Health and Care Excellence (NICE) from 2017 to 2022, approach to generate comparative evidence, and recommendations from committee reviews. The objective of this study was to assess the use of SATs in Canadian Agency for Drugs and Technologies in Health (CADTH) reviews of oncology drugs.

HTA66 Modified Delphi Research to Seek Consensus on dRTA Disease Model, Treatment, and Management

To seek insight and validation on the treatment and management of dRTA for the purpose of supporting reimbursement submissions.

EE511 Modeling Approaches in the Cost-Effectiveness Analysis of Cancer Treatments: A Review of Submissions Made to the Canadian Agency for Drugs and Technologies in Health

Partitioned Survival Model (PSM) and State Transition Models are the most frequently used approaches to estimate the cost-effectiveness of treatments. However, each of these approaches have their own limitations in their application in oncology. Our objective was to review the reimbursement submissions of oncology treatments made to Canadian Agency for Drugs and Technologies in Health (CADTH) between 2018 and 2022 to examine the modeling approaches considered by manufacturers.

Reimbursement Application Using Rest API Methods and Android-Based Flutter Framework (Case Study: PT. Protonema)

PT. Protonema is a company engaged in the field of information technology, namely as a consulting partner in Jakarta. This company has provided various kinds of facilities to employees to support their work and simultaneously to improve their quality of life who are concerned about the importance of self-development and provide health insurance. Employees can submit claims to obtain these facilities by attaching receipts as further evidence that the company reimburses the costs that have been incurred, this is often referred to as reimbursement. Submission of reimbursement by employees based on the current process has problems, such as the absence of notification of claims submitted by employees whether the claim is accepted or rejected and still using Microsoft Word which is eventually printed into this archive, it is feared that it will be lost or forgot to save it because scattered archives. The purpose of writing this research is to produce an Android-based reimbursement submission application at PT. Protonema with the REST (Representational state transfer) API (Application Programming Interface) method as a data exchange medium and supported by MySQL so that data processing is precise and safe because it is stored in a database and other supports, namely the Flutter framework, are used to design Android applications. In making this software using the waterfall model and data collection techniques, namely observation, interviews and literature study. From this research, it can be concluded that an Android-based reimbursement application using the REST API method and supported by MySQL can help PT. Protonema in managing employee reimbursement applications more efficiently and effectively. By using this application, employees can submit reimbursement requests easily and quickly via their cellphones, and the data obtained will be recorded correctly and safely in the database. The use of the Flutter framework also helps in designing the appearance and functionality of applications that are easier to use and accessible to employees. Therefore, this application can be an effective solution to increase the efficiency and effectiveness of employee reimbursement management at PT. Protonema.

HPR202 Use of Real-World Data in Regulatory and Reimbursement Submissions for Personalized Medicines in Europe

HPR202 Use of Real-World Data in Regulatory and Reimbursement Submissions for Personalized Medicines in Europe

PD25 Use Of Real-World Evidence In The Reimbursement Assessment Of Medical Devices

IntroductionRandomized controlled trials (RCTs) are typically considered the gold standard source of clinical evidence for reimbursement submissions, but they can often be resource-intensive, expensive, and may not always be appropriate. For example, it may be unethical to assign patients to an untreated or undiagnosed control group, or blinding may not be feasible when assessing medical devices. Evidence for medical devices is therefore often limited to nonrandomized studies. We explored the use and value of real-world evidence (RWE) in the reimbursement of medical devices across several health technology assessment (HTA) agencies.MethodsA narrative review was completed to compare the acceptability of RWE for the HTA evaluation of medical devices across a convenience sample of countries. English-language published guidance documents were reviewed, and study design preferences extracted.ResultsIn Australia, France, Germany, Ireland, Norway, and Scotland, HTA agencies prefer RCT evidence but accept RWE as supporting data. In England, there is no preferred study design, with directly observed clinical outcomes, evidence syntheses, nonclinical, and modelling studies accepted. Notably, methods and processes for HTA programs are being reviewed and are expected to place a greater emphasis on RWE. In Australia, pseudo-randomized trials, comparative cohort studies, case series, and other study designs are permitted. In France, nonrandomized or nonblinded trials, patient preference cohorts, prospective comparative observational studies, and propensity score matched cohorts are permitted, accompanied by justification. In Scotland, lived experiences, RWE, and systematic reviews are accepted. In Germany, nonrandomized studies are deemed to provide “minimum”, “very low” or “low” certainty of results. In Norway, RWE may be accepted if no RCT data are available, or to support RCTs.ConclusionsIn the assessment of medical devices, where RCTs are unsuitable, RWE can form a feasible alternative. Real-world evidence is increasingly being recognized as a valuable source of evidence for medical interventions and is accepted by a number of HTA agencies. No funding was received for this study.

HPR37 Comparing Reimbursement of New Drugs During the COVID-19 Pandemic in Ireland and Scotland

Following the onset of the COVID-19 pandemic, the Scottish Medicines Consortium (SMC) suspended monthly meetings from April to August 2020, to support the National Health Service (NHS) Scotland in maintaining essential work. Following the return of meetings, a fast-track process was introduced to expedite reimbursement for certain medicines. Conversely, the Irish health technology assessment (HTA) agency, the National Centre for Pharmacoeconomics (NCPE), continued to assess new reimbursement applications throughout this period, using the two-stage process of a rapid review (RR), followed by full HTA for some medicines. This research explores how these different approaches impacted reimbursement submissions and recommendations during this time. A database was developed using published data (from 01/03/2020 to 01/03/2022) on the NCPE, SMC and Irish Health Service Executive (HSE) websites, including; • Breakdown of submissions received • Assessment outcomes • Breakdown of reimbursement recommendations Data was extracted into Excel® and analysed using summary and descriptive statistics. SMC advice for 169 medicines were identified (n=89 full submissions; n=36 abbreviated submissions; n=28 non-submissions; n=13 resubmissions; n=3 ultra-orphan assessments). Positive reimbursement recommendations were made for 136 of these medicines (n=68 accepted for use, n=58 accepted for restricted use, n=7 accepted on interim basis, n=3 available under ultra-orphan assessment), with 48 recommendations made using the fast-track process. Contrastingly, the NCPE published 148 RR outcomes and 61 HTA outcomes, with 70 reimbursement recommendations published by the HSE (n=38 positive recommendations, n=11 restricted reimbursement, n=21 reimbursement not recommended). While a similar number of submissions were assessed by the Irish and Scottish HTA agencies during the COViD-19 period, there was a significantly higher number of positive reimbursement recommendations from the SMC, which may be explained by the SMC fast-track process. This research further explores the reimbursement recommendations for each category of submission and compares the reimbursement timelines for each jurisdiction.

HPR30 Too Ultra-Rare for Care? Orphan Drug Availability for People Living With Ultra-Rare Respiratory Diseases in the Pre, Present and Post Pandemic Worlds

To compare the current and potential availability of treatments for seven index ultra-rare respiratory diseases before and after the peak of the COVID-19 pandemic. At the 2019 ISPOR EU Conference, a landscape review of available treatments for ultra-rare respiratory diseases was presented. Therefore, 3 years on, we sought to explore if treatment access has improved for ultra-rare respiratory diseases. A landscape review was undertaken to seek evidence of treatment developments for ataxia telangiectasia (AT), lymphangiomatosis (LYMF), pulmonary alveolar proteinosis (PAP), pleuroparenchymal fibroelastosis (PPFE), pulmonary alveolar microlithiasis (PAM), pulmonary dendriform ossification (PDO), and light chain deposition disorders (LCDD). Information from clinicaltrials.gov, orpha.net, the EMA and FDA archives and websites of five health technology assessment (HTA) bodies was narratively synthesised. The 2019 clinicaltrials.gov search identified 24 studies and the 2022 search 25 studies at various stages of the clinical trial process. They concerned PAP (2019/2022: 11/10), AT (6/10), LCDD (5/4), LYMF (1/0) and PPFE (1/1). No studies were identified for PAM or PDO. The 2019 review found treatments for AT and PAP were granted orphan status by the EMA and the FDA, and in 2021 the FDA granted orphan status to another AT treatment. Neither search found reimbursement submissions for any of the ultra-rare respiratory disease. There still remains an obvious lack of proven and available treatments for ultra-rare respiratory diseases. Over the past 3 years, only 1 new treatment has been granted regulatory approval and no treatments have yet to result in therapies that are licensed or approved by HTA bodies. It is our hope that as we enter the post-pandemic world, we as industry professionals and researchers start to adequately address the treatment needs of people living with these debilitating conditions.

Economic Evaluation of a Tumour-Agnostic Therapy: Dutch Economic Value of Larotrectinib in TRK Fusion-Positive Cancers.

BackgroundLarotrectinib is the first tumour-agnostic therapy that has been approved by the European Medicines Agency. Tumour-agnostic therapies are indicated for a multitude of tumour types. The economic models supporting reimbursement submissions of tumour-agnostic therapies are complex because of the multitude of indications per model.ObjectiveThe objective of this paper was to evaluate the cost effectiveness of larotrectinib compared with standard of care in patients with cancer with tropomyosin receptor kinase fusion-positive tumour types in the Netherlands.MethodsA previously constructed cost-effectiveness model with a partitioned survival approach was adapted to the Dutch setting, simulating costs and effects of treatment in patients with tropomyosin receptor kinase fusion-positive cancer. The cost-effectiveness model conducts a naïve comparison of larotrectinib to a weighted comparator standard-of-care arm. Dutch specific resource use and costs were implemented and inflated to reflect 2019 euros. The analysis includes a lifetime horizon and a societal perspective.ResultsLarotrectinib versus Dutch standard of care resulted in 5.61 incremental (QALYs) and €232,260 incremental costs, leading to an incremental cost-effectivenes ratio of €41,424/QALY. The probabilistic sensitivity analysis reveals a 88% chance of larotrectinib being cost effective compared with the pooled comparator standard-of-care arm at the applicable €80,000/QALY willingness-to-pay threshold in the Netherlands.ConclusionsThe incremental cost-effectivenes ratio was well below the applicable threshold for diseases with a high burden of disease in the Netherlands (€80,000). At this threshold, larotrectinib was estimated to be a cost-effective treatment for patients with tropomyosin receptor kinase fusion-positive cancer compared with current standard of care in the Netherlands.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40258-022-00740-1.

A critical assessment framework to identify, quantify and interpret the sources of uncertainty in cost-effectiveness analyses

BackgroundUsing a standardized approach to describe the sources of uncertainty in cost-effectiveness analyses might bring added value to the local critical assessment procedure of reimbursement submissions in Hungary. The aim of this research is to present a procedural framework to identify, quantify and interpret sources of uncertainty, using the reimbursement dossier of darolutamide as an illustrative example.MethodsIn the procedural framework designed for the critical assessment of cost-effectiveness analyses, the quantifiability of an identified source of uncertainty is assessed through the input parameters of the originally submitted model, which is followed by the interpretation of its impact on estimates of costs and outcomes compared to the base case cost-effectiveness conclusion.ResultsBased on our experiences with the recent reimbursement dossier of darolutamide, the significant and quantifiable sources of uncertainty were the time horizon of the economic analysis; the restriction of the efficacy analysis population; long-term relative effectiveness of darolutamide; price discount on subsequent therapies. We identified resource use patterns for comparator and subsequent therapies as a quantifiable, yet non-significant source of uncertainty. The EQ-5D value set used to estimate utility values was identified as a non-quantifiable and potentially not significant source of uncertainty.ConclusionsThe procedural framework, demonstrated with an example, was sufficiently flexible and coherent to document and structure the sources of uncertainty in cost-effectiveness analyses. The full-scale use of this framework is desirable during the decision-making process for reimbursement in Hungary. The further formalization of identifying sources of uncertainty is a possible subject of methodological development.

Assessing the Value of Nusinersen for Spinal Muscular Atrophy: A Comparative Analysis of Reimbursement Submission and Appraisal in European Countries.

Background: Nusinersen is an orphan drug intended for the treatment of spinal muscular atrophy (SMA), a severe genetic neuromuscular disorder. Considering the very high costs of orphan drugs and the expected market entry of cell and gene therapies, there is increased interest in the use of health technology assessment (HTA) for orphan drugs. This study explores the role of the economic evaluation and budget impact analysis on the reimbursement of nusinersen. Methods: Appraisal reports for nusinersen were retrieved from reimbursement and HTA agencies in Belgium, Canada, France, England and Wales, Germany, Italy, Ireland, Scotland, Sweden, the Netherlands, and the United States. Detailed information was extracted on the economic evaluation, the budget impact, the overall reimbursement decision, and the managed entry agreement (MEA). Costs were adjusted for inflation and currency. Results: Overall, the reports included limited data on budget impact, excluding information on the sources of data for cost and patient estimates. Only three jurisdictions reported on total budget impact, estimated between 30 and 40 million euros per year. For early-onset SMA, the incremental cost-effectiveness threshold (ICER) ranged from €464,891 to €6,399,097 per quality-adjusted life year (QALY) gained for nusinersen versus standard of care. For later-onset SMA, the ICER varied from €493,756 to €10,611,936 per QALY. Although none of the jurisdictions found nusinersen to be cost-effective, reimbursement was granted in each jurisdiction. Remarkably, only four reports included arguments in favor of reimbursement. However, the majority of the jurisdictions set up an MEA, which may have promoted a positive reimbursement decision. Conclusion: There is a need for more transparency on the appraisal process and conditions included in the MEA. Additionally, by considering all relevant criteria explicitly during the appraisal process, decision-makers are in a better position to justify their allocation of funds among the rising number of orphan drugs that are coming to the market in the near future.

Current Issues in Health Technology Assessment of Cancer Therapies: A Survey of Stakeholders and Opinion Leaders in Australia.

The aim of this study was to find ways of bridging the gap in opinions concerning health technology assessment (HTA) in reimbursement submission between manufacturers and payers to avoid access delays for patients of vital medicines such as oncology drugs. This was done by investigating differences and similarities of opinion among key stakeholders in Australia. The survey comprised of nine sections: background demographics, general statements on HTA, clinical claim, extrapolations, quality of life, costs and health resource utilization, agreements, decision making, and capability/capacity. Responses to each question were summarized using descriptive statistics and comparisons were made using chi-square statistics. There were ninety-seven respondents in total, thirty-seven from the public sector (academia/government) and sixty from the private sector (industry/consultancies). Private and public sector respondents had similar views on clinical claims. They were divided when it came to extrapolation of survival data and costs and health resource utilization. However, they generally agreed that rebates are useful, outcomes-based agreements are difficult to implement, managed entry schemes are required when data are limited, and willingness to pay is higher in cancer compared to other therapeutic areas. They also agreed that training mostly takes place through on the job training and that guideline updates were a least favored opportunity for continued training. Private sector respondents favor methods that reduce the incremental cost-effectiveness ratio when compared to the public sector respondents. There still exist a number of challenges for HTA in oncology and many research opportunities as a result of this study.

POSA252 Assessing the Value of Nusinersen for SMA: A Comparative Analysis of Reimbursement Submission and Appraisal in European Countries

Nusinersen is an orphan drug intended for the treatment of spinal muscular athrophy (SMA), a severe neuromuscular disorder. Considering the very high costs of orphan drugs and the expected market entry of cell and gene therapies, there is increased interest in the use of health technology assessment (HTA) for orphan drugs. This study explores the role of the economic evaluation and budget impact analysis on the reimbursement of nusinersen.

POSB284 The Impact of Burden of Diseases on the Rate of Innovation in Portugal

Currently Portugal is still on the EU ending tale of access to innovative medicines, with an average time to availability of 641 days as per the WAIT report, published by EFPIA. With 255 reimbursement submissions reviewed from 2017 to 31st of May 2021, distributed by different therapeutic areas, the objective of this study is to analyze the impact of burden these diseases have to the rate of innovation in each therapeutic area (number of approvals and the average time to approval).

New Orthosis: The Thoracic Lumbar Sacral–Hip Spica Orthotic Sitting Frame

ABSTRACT Introduction This article describes the benefit of combining a thoracic lumbar sacral orthosis (TLSO) and a hip spica orthosis (HSO) to create a sitting frame for children with emerging neck and trunk control who cannot sit by themselves. Materials and Methods A child with motor disabilities who cannot sit independently benefits from a custom floor sitting frame. The sitting frame's thoracic lumbar sacral orthosis and hip spica orthosis are separate entities but are used together to allow a child to sit on the floor independently. Although the presented child does not need added head support, the TLSO-HSO sitting frame can be fabricated with cervical support. This sitting frame has a versatile joint allowing for movement between upright sitting and sitting with upper-limb weight bearing. The frame's hip joint can also be locked in different degrees of tilt. The described child uses the frame in a locked 90° upright position. Evaluation, fitting, fabrication, and reimbursement submission is explained. Conclusions Floor sitting is an important developmental milestone. Available equipment, such as floor sitters and compression garments intended to support a child in sitting, fail to sufficiently support all children with significant motor disabilities who have floor sitting goals. The TLSO-HSO sitting frame is a custom-made floor sitter that may give children with significant motor disabilities who have emerging neck and trunk control the support they need to independently sit on the floor. This orthosis has the potential to improve the lives of many children and their families as it can be used in both home and classroom settings and can give children with significant motor disabilities the opportunity to use their hands freely to play and to interact with peers during floor play time. Clinical Relevance Some children with severe motor disabilities cannot floor sit independently. The present study describes a new floor sitting frame that closes the gap between available products designed as these products do not meet the needs of all children with severe motor disabilities who have emerging neck and trunk control.

Health-related quality of life data collected in chimeric antigen receptor T-cell (CAR-T) therapy clinical trials

IntroductionChimeric antigen receptor T-cell (CAR-T) therapy represents a novel approach to cancer treatment, particularly advanced cancer. Much of the current evidence for the effectiveness of these therapies is associated with considerable uncertainty. This uncertainty poses a challenge for decision-makers and health systems responsible for granting patients access to these therapies. While the stage of development of the technology is a component of this uncertainty, it can be reduced with relevant data collection alongside clinical trials that is meaningful to patients and decision-makers. The objective of this research was to investigate the frequency with which HRQoL data is collected in currently registered clinical trials investigating CAR-T cancer treatment. MethodsWe searched for current CAR-T clinical trials at a registry compiled at United States National Institutes of Health National Library of Medicine (NLM) database. Trials were required to be active, recruiting, or completed. Trials were required to be phase I-IV, listed as ‘interventional’, and specific to cancer treatment. ResultsThere were 424 clinical trials that were included in our analysis. The majority of these trials (76 %) were investigating CAR-T therapy in haematological malignancies. Of the included studies, only 29 (6.8 %) included HRQoL as a primary or secondary outcome measure. Only 25 (5.9 %) trials reported collecting data on overall survival. ConclusionsThis investigation into clinical trials for CAR-T therapies has shown a failure to collect valuable HRQoL data. Sponsors of clinical trials need to appreciate that clinical trials for novel therapies need to collect relevant data that is paramount to informing decision-making and providing access to patients. Policy statementThe effectiveness of innovative cancer therapies, such as CAR-T, remains associated with considerable uncertainty. This uncertainty can be reduced for decision-makers via the collection of critical HRQoL data. Sponsors of clinical trials should be incentivized to collect these data, particularly where the intention is to use that trial for a reimbursement submission and decision..

Early-phase trials used in reimbursement submissions in Canada

Early-phase trials used in reimbursement submissions in Canada

Lessons learned from the reimbursement policy for immune checkpoint inhibitors and real-world data collection in Taiwan.

This paper describes the reimbursement policy for immune checkpoint inhibitors in Taiwan and provides a perspective to improve the quality, consistency, and transparency of decision making. Global trends for cancer treatment have shifted from chemotherapies to targeted therapies and immuno-oncology (IO) medicine, leading to significant increases in treatment costs. To enhance the accessibility of advanced therapy, the Taiwan National Health Insurance Administration announced two pathways for high-cost medicine: the managed entry agreement and a set of general rules of reimbursement submission for high-cost drugs. To further manage the financial burden on Taiwan's national health insurance system, the policy makers introduced novel inhibitory drugs for cancer immune checkpoints, subject to a maximum annual budget of NT$800 million (≈US$26.7 million). In April 2019, a national registry was established for patients undergoing cancer immunotherapy. Clinical characteristics, treatment duration, toxicity, and the outcome of the postcheckpoint inhibitor treatments were recorded. By analyzing real-world data, we assess the therapeutic effect of IO treatment in Taiwanese patients, thereby enabling payers to adjust payment regulations and rules for reimbursement. The Health Technology Assessment Team plays an important role in drawing upon the evidence to support policy making. Under an implemented cost-management mechanism, Taiwan's high-cost drug policy has enabled patients to access new medicines and maximized patient benefits.