How health technology assessment can help to address challenges in drug repurposing: a conceptual framework.

Drug repurposing faces various challenges that can impede its success. We developed a framework outlining key challenges in drug repurposing to explore when and how health technology assessment (HTA) methods can address them. We identified 20 drug-repurposing challenges across the categories of data access, research and development, collaboration, business case, regulatory and legal challenges. Early incorporation of HTA methods, including literature review, empirical research, stakeholder consultation, health economic evaluation and uncertainty assessment, can help to address these challenges. HTA methods canassess the value proposition of repurposed drugs, inform further research and ultimately help to bring cost-effective repurposed drugs to patients.

Care Pathway Analysis to Inform the Earliest Stages of Technology Development: Scoping Oncological Indications in Need of Innovation.

OBJECTIVES: Identifying unmet needs for innovative solutions across disease contexts is challenging but important for directing funding and research efforts and informing early-stage decisions during the innovation process. Our aim was to study the merits of care pathway analysis to scope disease contexts and guide the development of innovative devices. We used oncologic surgery as a case study, for which many intraoperative imaging techniques are under development. METHODS: Care pathway analysis is a mapping process, which produces graphical maps of clinical pathways using important outcomes and subsequent consequences. We performed care pathway analyses for glioblastoma, breast, bladder, prostate, renal, pancreatic, and oral cavity cancer. Differences between a "perfect" care pathway and the current care pathway in terms of percentage of inadequate margins, associated recurrences, quality of life, and 5-year overall survival were calculated to determine unmet needs. Data from The Netherlands Cancer Registry and literature were used. RESULTS: Care pathway analysis showed that highest percentages of inadequate margins were found in oral cavity cancer (72.5%), glioblastoma (48.7%), and pancreatic cancer (43.9%). Inadequate margins showed the strongest increase in recurrences in cancer of oral cavity, and bladder (absolute increases of 43.5% and 41.2%, respectively). Impact on survival was largest for bladder and oral cavity cancer with positive margins. CONCLUSIONS: Care pathway analysis provides overviews of current clinical paths in multiple indications. Disease contexts can be compared via effectiveness gaps that show the potential need for innovative solutions. This information can be used as basis for stakeholder involvement processes to prioritize care pathways in need of innovation.

Dealing With Uncertainty in Early Health Technology Assessment: An Exploration of Methods for Decision Making Under Deep Uncertainty.

OBJECTIVES: In early stages, the consequences of innovations are often unknown or deeply uncertain, which complicates early health economic modeling (EHEM). The field of decision making under deep uncertainty uses exploratory modeling (EM) in situations when the system model, input probabilities/distributions, and consequences are unknown or debated. Our aim was to evaluate the use of EM for early evaluation of health technologies. METHODS: We applied EM and EHEM to an early evaluation of minimally invasive endoscopy-guided surgery (MIS) for acute intracerebral hemorrhage and compared these models to derive differences, merits, and drawbacks of EM. RESULTS: EHEM and EM differ fundamentally in how uncertainty is handled. Where in EHEM the focus is on the value of technology, while accounting for the uncertainty, EM focuses on the uncertainty. EM aims to find robust strategies, which give relatively good outcomes over a wide range of plausible futures. This was reflected in our case study. EHEM provided cost-effectiveness thresholds for MIS effectiveness, assuming fixed MIS costs. EM showed that a policy with a population in which most patients had severe intracerebral hemorrhage was most robust, regardless of MIS effectiveness, complications, and costs. CONCLUSIONS: EHEM and EM were found to complement each other. EM seems most suited in the very early phases of innovation to explore existing uncertainty and many potential strategies. EHEM seems most useful to optimize promising strategies, yet EM methods are complex and might only add value when stakeholders are willing to consider multiple solutions to a problem and adopt flexible research and adoption strategies.

Identifying the Conditions for Cost-Effective Minimally Invasive Neurosurgery in Spontaneous Supratentorial Intracerebral Hemorrhage.

Background: In patients with spontaneous supratentorial intracerebral hemorrhage (ICH), open craniotomy has failed to improve a functional outcome. Innovative minimally invasive neurosurgery (MIS) may improve a health outcome and reduce healthcare costs. Aims: Before starting phase-III trials, we aim to assess conditions that need to be met to reach the potential cost-effectiveness of MIS compared to usual care in patients with spontaneous supratentorial ICH. Methods: We used a state-transition model to determine at what effectiveness and cost MIS would become cost-effective compared to usual care in terms of quality-adjusted life-years (QALYs) and direct healthcare costs. Threshold and two-way sensitivity analyses were used to determine the minimal effectiveness and maximal costs of MIS, and the most cost-effective strategy for each combination of cost and effectiveness. Scenario and probabilistic sensitivity analyses addressed model uncertainty. Results: Given €10,000 of surgical costs, MIS would become cost-effective when at least 0.7-1.3% of patients improve to a modified Rankin Scale (mRS) score of 0-3 compared to usual care. When 11% of patients improve to mRS 0-3, surgical costs may be up to €83,301-€164,382, depending on the population studied. The cost-effectiveness of MIS was mainly determined by its effectiveness. In lower mRS states, MIS needs to be more effective to be cost-effective compared to higher mRS states. Conclusion: MIS has the potential to be cost-effective in patients with spontaneous supratentorial ICH, even with relatively low effectiveness. These results support phase-III trials to investigate the effectiveness of MIS.

Development of a decision analytical framework to prioritise operating room capacity: lessons learnt from an empirical example on delayed elective surgeries during the COVID-19 pandemic in a hospital in the Netherlands.

OBJECTIVE: To develop a prioritisation framework to support priority setting for elective surgeries after COVID-19 based on the impact on patient well-being and cost. DESIGN: We developed decision analytical models to estimate the consequences of delayed elective surgical procedures (eg, total hip replacement, bariatric surgery or septoplasty). SETTING: The framework was applied to a large hospital in the Netherlands. OUTCOME MEASURES: Quality measures impacts on quality of life and costs were taken into account and combined to calculate net monetary losses per week delay, which quantifies the total loss for society expressed in monetary terms. Net monetary losses were weighted by operating times. RESULTS: We studied 13 common elective procedures from four specialties. Highest loss in quality of life due to delayed surgery was found for total hip replacement (utility loss of 0.27, ie, 99 days lost in perfect health); the lowest for arthroscopic partial meniscectomy (utility loss of 0.05, ie, 18 days lost in perfect health). Costs of surgical delay per patient were highest for bariatric surgery (€31/pp per week) and lowest for arthroscopic partial meniscectomy (-€2/pp per week). Weighted by operating room (OR) time bariatric surgery provides most value (€1.19/pp per OR minute) and arthroscopic partial meniscectomy provides the least value (€0.34/pp per OR minute). In a large hospital the net monetary loss due to prolonged waiting times was €700 840 after the first COVID-19 wave, an increase of 506% compared with the year before. CONCLUSIONS: This surgical prioritisation framework can be tailored to specific centres and countries to support priority setting for delayed elective operations during and after the COVID-19 pandemic, both in and between surgical disciplines. In the long-term, the framework can contribute to the efficient distribution of OR time and will therefore add to the discussion on appropriate use of healthcare budgets. The online framework can be accessed via: https://stanwijn.shinyapps.io/priORitize/.

Early Health Economic Modeling of Novel Therapeutics in Age-Related Hearing Loss.

Background: Health systems face challenges to accelerate access to innovations that add value and avoid those unlikely to do so. This is very timely to the field of age-related sensorineural hearing loss (ARHL), where a significant unmet market need has been identified and sizeable investments made to promote the development of novel hearing therapeutics (NT). This study aims to apply health economic modeling to inform the development of cost-effective NT. Methods: We developed a decision-analytic model to assess the potential costs and effects of using regenerative NT in patients ≥50 with ARHL. This was compared to the current standard of care including hearing aids and cochlear implants. Input data was collected from systematic literature searches and expert opinion. A UK NHS healthcare perspective was adopted. Three different but related analyses were performed using probabilistic modeling: (1) headroom analysis, (2) scenario analyses, and (3) threshold analyses. Results: The headroom analysis shows an incremental net monetary benefit (iNMB) of £20,017[£11,299-£28,737] compared to the standard of care due to quality-adjusted life-years (QALY) gains and cost savings. Higher therapeutic efficacy and access for patients with all degrees of hearing loss yields higher iNMBs. Threshold analyses shows that the ceiling price of the therapeutic increases with more severe degrees of hearing loss. Conclusion: NT for ARHL are potentially cost-effective under current willingness-to-pay (WTP) thresholds with considerable room for improvement in the current standard of care pathway. Our model can be used to help decision makers decide which therapeutics represent value for money and are worth commissioning, thereby paving the way for urgently needed NT.

The Use of Decision Analytic Modeling in the Evaluation of Surgical Innovations: A Scoping Review.

OBJECTIVES: The main objective of this review was to map how decision analytic models are used in surgical innovation (in which research phase, with what aim) and to understand how challenges related to the assessment of surgical interventions are incorporated. METHODS: We systematically searched PubMed, Embase, and the Cochrane Library for studies published in 2018. We included original articles using a decision analytic model to compare surgical strategies. We included modeling studies of surgical innovations. General, innovation, and modeling characteristics were extracted, as were outcomes, recommendations, and handling of challenges related to the assessment of surgical interventions (learning curve, incremental innovation, dynamic pricing, quality variation, organizational impact). RESULTS: We included 46 studies. The number of studies increased with each research phase, from 4% (n = 2) in the preclinical phase to 40% (n = 20) in phase 3 studies. Eighty-one studies were excluded because they investigated established surgical procedures, indicating that modeling is predominantly applied after the innovation process. Regardless of the research stage, the aim to determine cost-effectiveness was most frequently identified (n = 40, 87%), whereas exploratory aims (eg, exploring when a strategy becomes cost-effective) were less common (n = 9, 20%). Most challenges related to the assessment of surgical interventions were rarely incorporated in models (eg, learning curve [n = 1, 2%], organizational impact [n = 2, 4%], and incremental innovation [n = 1, 2%]), except for dynamic pricing (n = 10, 22%) and quality variation (n = 6, 13%). CONCLUSIONS: In surgical innovation, modeling is predominantly used in later research stages to assess cost-effectiveness. The exploratory use of modeling seems still largely overlooked in surgery; therefore, the opportunity to inform research and development may not be optimally used.

Novel imaging techniques for intraoperative margin assessment in surgical oncology: A systematic review.

Inadequate margins continue to occur frequently in patients who undergo surgical resection of a tumor, suggesting that current intraoperative methods are not sufficiently reliable in determining the margin status. This clinical demand has inspired the development of many novel imaging techniques that could help surgeons with intraoperative margin assessment. This systematic review provides an overview of novel imaging techniques for intraoperative margin assessment in surgical oncology, and reports on their technical properties, feasibility in clinical practice and diagnostic accuracy. PubMed, Embase, Web of Science and the Cochrane library were systematically searched (2013-2018) for studies reporting on imaging techniques for intraoperative margin assessment. Patient and study characteristics, technical properties, feasibility characteristics and diagnostic accuracy were extracted. This systematic review identified 134 studies that investigated and developed 16 groups of techniques for intraoperative margin assessment: fluorescence, advanced microscopy, ultrasound, specimen radiography, optical coherence tomography, magnetic resonance imaging, elastic scattering spectroscopy, bio-impedance, X-ray computed tomography, mass spectrometry, Raman spectroscopy, nuclear medicine imaging, terahertz imaging, photoacoustic imaging, hyperspectral imaging and pH measurement. Most studies were in early developmental stages (IDEAL 1 or 2a, n = 98); high-quality stage 2b and 3 studies were rare. None of the techniques was found to be clearly superior in demonstrating high feasibility as well as high diagnostic accuracy. In conclusion, the field of imaging techniques for intraoperative margin assessment is highly evolving. This review provides a unique overview of the opportunities and limitations of the currently available imaging techniques.

The Potential Added Value of Novel Hearing Therapeutics: An Early Health Economic Model for Hearing Loss.

OBJECTIVE: To construct an early health economic model to assess the potential added value of novel hearing therapeutics, compared with the current standard of care. We use idiopathic sudden sensorineural hearing loss (ISSNHL) as a case example, because it is a lead indication for several emerging hearing therapeutics. METHODS: A decision analytic model was developed to assess the costs and effects of using novel hearing therapeutics for patients with ISSNHL. This was compared to the current standard of care. Input data were derived from literature searches and expert opinion. The study adopted a healthcare perspective of the UK National Health Service. Four analyses were conducted: 1) headroom, 2) scenario, 3) threshold, 4) sensitivity. RESULTS: The decision analytic model showed that novel therapeutics for ISSNHL have potential value both in terms of improved patient outcomes, as well as incremental net monetary benefit (iNMB). The base case analysis revealed an iNMB of £39,032 for novel therapeutics compared with the current standard of care. Results of the threshold and scenario analysis revealed that age of treatment and severity of ISSNHL are major determinants of iNMB for novel therapeutics. CONCLUSION: This article describes the first health economic model for novel therapeutics for hearing loss; and shows that novel hearing therapeutics can be cost-effective under NICE's cost-effectiveness threshold, with considerable room for improvement in the current standard of care. Our model can be used to inform the development of cost-effective hearing therapeutics; and help decision makers decide which therapeutics represent value for money.

Extent and consequences of lymphadenectomy in oesophageal cancer surgery: case vignette survey.

OBJECTIVES: Lymph node dissection (LND) is part of the standard operating procedure in patients with resectable oesophageal cancer after neoadjuvant chemoradiotherapy regardless of lymph node (LN) status. The aims of this case vignette survey were to acquire expert opinions on the current practice of LND and to determine potential consequences of non-invasive LN staging on the extent of LND and postoperative morbidity. DESIGN: An online survey including five short clinical cases (case vignettes) was sent to 272 oesophageal surgeons worldwide. PARTICIPANTS: 86 oesophageal surgeons (median experience in oesophageal surgery of 15 years) participated in the survey (response rate 32%). MAIN OUTCOME MEASURES: Extent of standard LND, potential changes in LND based on accurate LN staging and consequences for postoperative morbidity were evaluated. RESULTS: Standard LND varied considerably between experts; for example, pulmonary ligament, splenic artery, aortopulmonary window and paratracheal LNs are routinely dissected in less than 60%. The omission of (parts of) LND is expected to decrease the number of chyle leakages, pneumonias, and laryngeal nerve pareses and to reduce operating time. In order to guide surgical treatment decisions, a diagnostic test for LN staging after neoadjuvant therapy requires a minimum sensitivity of 92% and a specificity of 90%. CONCLUSIONS: This expert case vignette survey study shows that there is no consensus on the extent of standard LND. Oesophageal surgeons seem more willing to extend LND rather than omit LND, based on accurate LN staging. The majority of surgeons expect that less extensive LND can reduce postoperative morbidity.

Selecting esophageal cancer patients for lymphadenectomy after neoadjuvant chemoradiotherapy: a modeling study.

OBJECTIVES: Two-thirds of patients do not harbor lymph node (LN) metastases after neoadjuvant chemoradiotherapy (nCRT). Our aim was to explore under which circumstances a selective lymph node dissection (LND) strategy, which selects patients for LND based on the restaging results after nCRT, has added value compared with standard LND in esophageal cancer. DESIGN: A decision tree with state-transition model was developed. Input data on short-term and long-term consequences were derived from literature. Sensitivity analyses were conducted to assess promising scenarios and uncertainty. SETTING: Dutch healthcare system. PARTICIPANTS: Hypothetical cohort of esophageal cancer patients who have already received nCRT and are scheduled for esophagectomy. INTERVENTIONS: A standard LND cohort was compared with a cohort of patients that received selective LND based on the restaging results after nCRT. MAIN OUTCOME MEASURES: Quality-adjusted life years (QALYs), residual LN metastases and LND-related complications. RESULTS: Selective LND could have short-term benefits, that is, a decrease in the number of performed LNDs and LND-related complications. However, this may not outweigh a slight increase in residual LN metastases which negatively impacts QALYs in the long-term. To accomplish equal QALYs as with standard LND, a new surgical strategy should have the same or higher treatment success rate as standard LND, that is, should show equal or less recurrences due to residual LN metastases. CONCLUSIONS: The reduction in LND-related complications that is accomplished by selecting patients for LND based on restaging results after nCRT seems not to outweigh a QALY loss in the long-term due to residual LN metastases. Despite the short-term advantages of selective LND, this strategy can only match long-term QALYs of standard LND when its success rate equals the success rate of standard LND.

Modelling Study with an Interactive Model Assessing the Cost-effectiveness of 68Ga Prostate-specific Membrane Antigen Positron Emission Tomography/Computed Tomography and Nano Magnetic Resonance Imaging for the Detection of Pelvic Lymph Node Metastases in Patients with Primary Prostate Cancer.

BACKGROUND: Outcomes of extended pelvic lymph node dissection (ePLND) show that only 16% of prostate cancer (PCa) patients harbour lymph node (LN) metastases. Ga-68 prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT) and nano magnetic resonance imaging (nano-MRI) might be noninvasive alternatives for ePLND; however, it remains uncertain whether they are cost-effective. OBJECTIVE: To develop an interactive model to determine the cost-effectiveness of 68Ga PSMA PET/CT and nano-MRI as compared with ePLND for the detection of pelvic LN metastases in patients with intermediate- to high-risk PCa. DESIGN, SETTING, AND PARTICIPANTS: Decision tree with state transition model for men with intermediate- to high-risk PCa. Input data was derived from systematic literature searches. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Quality-adjusted life years (QALYs) and healthcare costs were modelled over lifetime. Sensitivity analyses were used to assess uncertainty. RESULTS AND LIMITATIONS: Assuming 100% sensitivity of ePLND, no QALY loss after ePLND, and no treatment improvement due to imaging, the PSMA PET/CT and nano-MRI strategies seem to be less expensive per patient (€3047 and €2738, respectively) and result in loss of QALYs (0.07 and 0.03, respectively) compared with the ePLND strategy. PSMA PET/CT and nano-MRI are both cost saving and more effective when ePLND has a sensitivity of ≤60% and ≤84%, ePLND results in a QALY loss of 0.060 and 0.024 over lifetime, or the imaging techniques reduce recurrences by 26% and 8%, respectively. CONCLUSIONS: PSMA PET/CT and nano-MRI seem to be cost-effective compared with ePLND since they save cost, but at the possible expense of a small QALY loss. Our interactive model provides insight into the influence of important model parameters on the cost effectiveness of 68Ga PSMA PET/CT and nano-MRI, and the opportunity for updating the cost effectiveness when new evidence becomes available. PATIENT SUMMARY: We developed an interactive model that can be used in shared decision making regarding the use of extended pelvic lymph node dissection, 68Ga prostate-specific membrane antigen positron emission tomography/computed tomography, or nano magnetic resonance imaging for lymph node staging in individual patients with intermediate- to high-risk prostate cancer. Owing to remaining uncertainty, we cannot yet give advice about the use of these techniques.

In search of the most cost-effective monitoring strategy for vestibular schwannoma: A decision analytical modelling study.

OBJECTIVES: To assess the cost-effectiveness of frequently used monitoring strategies for vestibular schwannoma (VS). DESIGN: A state transition model was developed to compare six monitoring strategies for patients with VS: lifelong annual monitoring; annual monitoring for the first 10 years after diagnosis; scanning at 1-5, 7, 9, 12, 15 years after diagnosis and subsequently every 5 years; a personalised monitoring strategy for small and large tumours; scanning at 1, 2 and 5 years after diagnosis and no monitoring. Input data were derived from literature and expert opinion. Quality-adjusted life years (QALYs) and healthcare costs of each strategy were modelled over lifetime. Net monetary benefits (NMBs) were calculated to determine which strategy provided most value for money. Sensitivity analyses were performed to address uncertainty. RESULTS: Omitting monitoring is least effective with 18.23 (95% CI 16.84-19.37) QALYs per patient, and lifelong annual monitoring is most effective with 18.66 (95% CI 17.42-19.65) QALYs. Corresponding costs were €6526 (95% CI 5923-7058) and €9429 (95% CI 9197-9643) per patient, respectively. Lifelong annual monitoring provided the best value with a NMB of €363 765 (339 040-383 697), but the overall probability of being most cost-effective compared to the other strategies was still only 23%. Sensitivity analysis shows that there is large uncertainty in the effectiveness of all strategies, with largely overlapping 95% confidence intervals for all strategies. CONCLUSIONS: Due to the largely overlapping 95% confidence intervals of all monitoring strategies for VS, it is unclear which monitoring strategy provides most value for money at this moment.