bluuebunny/crossref_metadata_2025_split huggingface dataset:
OP73 Navigating The Advanced Therapy Medicinal Products (ATMPs) Conundrum: Insights From ATMPs Withdrawn In The European Market
Authors: Leong Katherine , Macaulay Richard 
Published: January 2025

IntroductionAdvanced therapy medicinal product (ATMP) is a classification used by the European Medicines Agency (EMA) for cell-, gene-, and tissue-engineered therapies. Since the first ATMP received market authorization in 2009, a substantial proportion of these highly innovative therapies have been withdrawn from the European market. This research investigates the key reasons underlying these withdrawals.Methods
ATMPs with withdrawn EMA marketing authorizations were identified from the EMA website. A targeted review of relevant company press releases was undertaken and key information extracted. Health technology assessment (HTA) outcomes in France, Germany, and England were extracted from their respective websites (1 Sep 2023).Results
Thirty-two ATMPs have received EMA marketing authorizations, with 22 percent (7/32) withdrawn. One of these seven withdrawals was driven by unfavorable clinical results versus six out of seven due to commercial reasons. Of the six withdrawals driven by commercial reasons, four were associated with negative HTA and/or reimbursement issues (Chondro-Celect, Glybera, and Zalmoxis’s Service Médical Rendu (SMR, actual medical benefit) insufficient, driven by data-related issues in France; Glybera’s challenge to obtain reimbursement by insurance funds with only one sale reported, and Zynteglo’s price agreement not reached in Germany). One of the six withdrawals (Chondro-Celect) was also associated with hospital exemption (continued production without marketing authorization). One of six (Provenge) was also associated with chemistry-, manufacturing-, and controls (CMC)-related issues.ConclusionsThe ATMP landscape has rapidly evolved in the past decade. While ATMPs offer the promise of long-term benefits, the unique manufacturing, clinical, and especially the reimbursement challenges they face can lead to commercial failure. To ensure ATMP patient access and commercial success, manufacturers should engage early with payers, understand potential reimbursement challenges, and proactively plan to mitigate these.
OP75 Pharmaceutical Innovativeness Index: Evaluation Of Pharmaceutical Innovation In Lung Cancer Treatment Drugs Approved Between 2011 And 2021
Authors: Freitas Isabela , Gargano Ludmila , André Ariane , de Assis Acurcio Francisco , Alvares-Teodoro Juliana , Guerra Augusto 
Published: January 2025

IntroductionLung cancer (LC) ranks second globally in neoplasia diagnoses and exhibits the highest oncological mortality rate. Oncology has seen a marked increase in U.S. Food and Drug Administration (FDA) approvals for novel drugs, notably in the case of LC. This study aims to assess the innovativeness of recently FDA-approved LC treatments compared to existing options, spanning the 2011 to 2021 period.MethodsThe innovativeness of drugs was assessed through the Pharmaceutical Innovativeness Index (PII). The methodology considers population health needs and aggregated clinical benefits, while weighing methodological quality and the adequacy of available evidence. New drugs are analyzed considering available therapeutic alternatives. The assessment assigns an innovativeness score to the drugs, with 1.0 representing the highest degree of innovation. PII was applied to all drugs with their first FDA indication for LC treatment. The evaluation considered specific clinical indications (e.g., treatment of ALK-positive LC), and data from FDA clinical review reports and pivotal clinical trials were considered.ResultsEighteen new drugs were identified during the period. The drugs were evaluated with a mean PII of 0.615, ranging from 0.474 to 0.811. No discernible trends in innovativeness were observed within specific indications. Overall, the evaluations indicated that these medications were approved to address significant therapeutic needs. However, the added therapeutic value ranged from absent to moderate. Most supporting evidence for these approvals was derived from clinical studies with low risk of bias. Nevertheless, these studies often featured inadequate designs due to the absence of a comparator arm, limiting the assessment of added therapeutic value.ConclusionsPharmaceutical innovations in recent years for LC treatment have demonstrated limited clinical benefits when compared to existing alternatives, highlighting a substantial therapeutic need. The application of the PII can assist in healthcare decision-making, guide investments and research efforts, as well as inform pricing and reimbursement of new technologies, thereby contributing to the sustainability of healthcare systems.
OD05 Frameworks For Synthesizing Qualitative Evidence In Health Technology Assessment: A Scoping Review
Authors: de Almeida Cardoso Marilia Mastrocolla , Marques Raphael Thomaz , Machado-Rugolo Juliana , Thabane Lehana , Püschel Vilanice , Theresa Weber Silke Anna , Duque Graciela Paula , Almeida Rosimary Terezinha , Rodrigue Clarice , Guimarães Drumond Sybelle Luzia , De Paula Cristiane , Lopes Luciane , Gabriel Mariana , Vanston Meredith 
Published: January 2025

IntroductionHealth technology assessment (HTA) agencies and researchers recognize the necessity of evidence-based methodologies beyond quantitative data to assess feasibility, appropriateness, meaningfulness, patient values, preferences, acceptability, and equity. Despite existing guidelines for synthesizing qualitative data, the HTA framework requires clarification. This review aims to describe the frameworks, tools, and processes used to synthesize qualitative evidence and assess the quality of HTA.MethodsUsing the JBI methodology, the authors accessed databases such as MEDLINE, LILACS, CINAHL, Embase, Web of Science, Scopus, PsycINFO, Cochrane Library, JBI Database, and ScienceDirect. Grey literature searches included ProQuest, OpenGrey, CADTH’s Grey Matters, Google Scholar, and HTA agencies’ websites. Inclusion criteria focused on synthesizing qualitative evidence frameworks, methods for evidence synthesis, and quality rating. The review had a global scope, without specific population and time restrictions. Data, encompassing fundamental concepts, frameworks, methods, subjects, and objectives, were presented in tables and figures.ResultsOut of 2,054 articles, 31 were included, mainly from Europe, with a predominant “guide” authored by an HTA agency and university. The majority of documents did not originate from agencies. Only three agencies developed specific documents. A surge in publications occurred in 2018/2019. Qualitative data in HTA were justified for opinions, acceptability, feasibility, and equity. SPICE was the most cited acronym; RETREAT was the preferred framework. Thematic synthesis was the most cited method, CASP for quality assessment. GRADE-CERQual graded evidence quality, and ENTREQ was cited for reporting qualitative research. The GRADE EtD framework was the sole tool mentioned for recommendations.Conclusions
This review highlights a growing trend in including qualitative evidence in HTA. While various proposals suggest instruments and methods, few documents cover all necessary steps, resulting in diverse recommendations. Standardizing processes can improve decision-making by guiding the integration of qualitative evidence, potentially enhancing recommendation quality. This ensures evidence on feasibility, appropriateness, significance, patient values, preferences, acceptability, and equity are considered.
OD07 Disaggregation Of The Costs Of Pharmaceutical Research And Development
Authors: Fabian Daniel , Wild Claudia 
Published: January 2025

IntroductionCosts for pharmaceutical products are increasing. Pharmaceutical companies claim that high research and development (R&D) costs are the reason for the steep price increase of new products. However, there exists little data to support such claims; there is a lack of transparency in R&D cost reporting. This research intends to analyze and to disaggregate the costs of pharmaceutical R&D.MethodsStudies on the costs of introducing new medications to the market can differ substantially in their methodology, their origin of data, and their results. A scoping review was conducted on costs of R&D for pharmaceutical products using Embase, PubMed, and EconLit, using a combination of the terms “drug research and development” and “costs” or “drug research and development” and “expenditure.” Additionally, semi structured interviews with 16 experts from non-governmental organizations (NGOs), pharmaceutical companies, academic researchers, and not-for-profit pharmaceutical companies were conducted to identify the main driving factors for rising costs of new drugs.ResultsOut of 24 studies that analyzed mixed therapeutic fields, the five highest cost estimates had affiliations with industry or received funding from pharmaceutical companies. Non-affiliated researchers are unable to reproduce studies that use confidential data and therefore cannot check the validity of the results. Additionally, different definitions for R&D make analyzing costs challenging. The interviewees emphasized that driving factors influencing costs for pharmaceutical R&D are therapeutic indication, drug complexity, number of patients in clinical trials, length of the development process, and attrition rates.ConclusionsDue to the diverse nature of drug development and the confidential information held by pharmaceutical companies, it is a challenge to provide an exact assessment of the average costs of pharmaceutical R&D. Transparency policies with well-defined definitions for R&D are necessary to level the information asymmetries between the private and the public at price negotiations.
OD17 Future Health And Economic Burden Of Cardiovascular Disease In Type 2 Diabetes In Australia From 2021 To 2031
Authors: Abushanab Dina , Marquina Clara , Morton Jedidiah I , Al-Badriyeh Daoud , Lloyd Melanie , Magliano Dianna J , Liew Danny , Ademi Zanfina 
Published: January 2025

IntroductionDiabetes is a key risk factor for cardiovascular disease (CVD), with a two-to-four-times higher risk than that in non-diabetes. The health burden associated with CVD imposes a major economic concern on healthcare systems and on society. We sought to estimate the future burden of CVD in terms of health and economic outcomes in type 2 diabetes (T2D) from 2022 to 2031.MethodsFrom Australian public healthcare and societal perspectives over the next decade, two dynamic models with annual cycles were designed to predict myocardial infarction (MI) and stroke in patients aged 40 to 90 years. First events at risk of CVD people were estimated using the 2013 pooled cohort equation, while recurrent events in existing CVD were acquired from the global Reduction of Atherothrombosis for Continued Health registry. Costs and utilities were obtained using public sources. Outcomes were fatal and non-fatal MI and stroke, years of life lived, quality-adjusted life years (QALYs), total direct and indirect costs. An annual discount rate of 5 percent was used.ResultsOver the next 10 years, the model projected a total of 83,618 non-fatal MIs (95% confidence interval [CI]: 83,170, 84,053) and 58,774 non-fatal strokes (95% CI: 58,458, 59,013). In terms of health outcomes, total years of life lived and QALYs were 9,549,487 (95% CI: 9,416,423, 9,654,043) and 6,632,897 (95% CI: 5,065,606, 7,591,679), respectively. In terms of economic outcomes, total direct and indirect were AUD9.59 billion (USD6.38 billion) (95% CI: AUD1.90 billion [USD1.26 billion], AUD30.45 billion [USD20.26 billion]) and AUD9.07 billion (USD6.03 billion) (95% CI: AUD663.53 million [USD441.61 million], AUD33.19 billion [USD21.96 billion]), respectively. The chronic costs of CVD contributed most of the total direct cost, while morbidity contributed most of the total indirect costs.ConclusionsOur study shows that from 2022 to 2031, CVD as a complication from T2D will cause a significant impact on the Australian healthcare system and society. These estimates can be used to explore different strategies to optimize the control of risk factors for the prevention and management of CVD in T2D in Australia.
OD22 Innovating Patient Involvement In Health Technology Assessments To Enable More Sustainable Involvement From Patient Stakeholders
Authors: Livingstone Heidi , Fitzpatrick Ella , Tonkinson Mandy , Crosbie Helen , Rasburn Mark , Taylor Sally , Wigmore Janine 
Published: January 2025

IntroductionThe National Institute for Health and Care Excellence (NICE) heard from small organizations how resource intensive and difficult it is for them participate in medicines health technology assessments (HTA) since the COVID-19 pandemic. To provide additional support for these organizations or to provide alternative patient input, NICE explored implementing surveys directly with patients to share with patient stakeholder organizations and NICE’s HTA medicines committees.Methods
Patient organizations and colleagues at NICE were included in the background investigation. Informal interviews were conducted with the HTA bodies in Wales and health technology colleagues in NICE about their experience of this method of patient input.Two approaches were piloted:(i) Developing the online questionnaire using the Summary of Information for Patients.(ii) Developing a jointly branded questionnaire collaboratively with the patient organization and implementing a data-sharing agreement to share the raw data.The survey was distributed by the patient organization, analyzed by NICE, and shared with the patient organization to inform their submission to NICE.ResultsThe results of the background investigation showed that the option to include this additional method of input could provide valuable support for patient organizations and has the potential to increase the amount and quality of patient input to an HTA committee.Both pilots were successful in:•Supporting patient organizations’ input into a medicines HTA•Reducing the resources required from patient organizations.

The second pilot added more value due to:

•Collaboration, relationship, and building trust•Joint development of the survey•Data sharing and potential to add to patient evidence about a disease and treatments.

ConclusionsSurveys conducted directly with patients can help patient organizations participate in medicines HTAs, but they are only one element of developing more innovative and sustainable patient involvement in the process. HTA bodies need to innovate and work collaboratively with patient stakeholders to produce a menu of options for involvement so that it can be tailored to stakeholders’ resources.
OD26 Comparing Health Technology Developers’ Proposed Indication To An Estimated Indication Generated By An International Horizon Scanning Database
Authors: Harte Marie , Choitir Caitríona Ní , Eames Heather , Adams Roisin , McCullagh Laura , Tilson Lesley , Duell Daisy , Odnoletkova Irina , Christensen Anna Bergkvist , Persson Marie , Bräuner Helle , Guardian Marcus , Tuckova Alzbeta Alzbeta , Wilkinson Brian , Kuzmak Beth , Shaw John , Boyce Craig , Palakollu Prashanth , Erinoff Eileen 
Published: January 2025

IntroductionDetail on a technology’s projected therapeutic use is required for horizon scanning. The International Horizon Scanning Initiative (IHSI) database will utilize natural language processing (NLP) augmented by human curation to generate an estimated indication for technologies in development. We compared the estimated indication, generated as a test-set for NLP, with health technology developers’ (HTDs) proposed indications identified from Ireland’s horizon scanning system (HSS).MethodsEight oncology technologies common to both Ireland’s HSS and the IHSI database were analyzed. The analysis included unlicensed technologies in late-stage development that have not submitted a European marketing authorization application. Ireland’s HSS receives data on proposed indications for technologies from HTDs. IHSI database curators extract and convert terms from clinical trials into structured inputs (condition, combination therapy, stage of disease, place in treatment, patient/disease-specific subgroups) to produce an estimated indication for a technology. We sought to identify, by structured input, the degree of alignment between HTDs’ proposed indications with the IHSI database’s estimated indication.ResultsThere was 100 percent alignment between the HTD’s proposed indication and the estimated indication generated in the IHSI database for five of the eight included technology records. There was 83 percent alignment for two records and 67 percent alignment for one record. Across all records there was full alignment on condition, combination therapy details, patient-specific subgroup, disease-specific subgroup, and place in treatment. Stage of disease was the only element where data was either not generated for the IHSI database’s estimated indication, not aligned with the HTD’s proposed indication, or reported in an incorrect field.ConclusionsThere is a high degree of alignment between an HTD-proposed indication and the IHSI-estimated indication. The processes for generating an estimated indication will involve both NLP-generation and human co-curation. The current (curator-selected) elements are being used to train the NLP engine. Thereafter, the engine will process clinical trial data to surface tags for human selection to generate the structured inputs.
OD27 Estimating The Causal Effect Of Adaptive Treatment Strategies Using Longitudinal Observational Data
Authors: Zhang Yingying , Kreif Noemi , Bennett Alastair , Manca Andrea 
Published: January 2025

IntroductionReal-world data can help inform policymaking in health care by facilitating the evaluation of realistic treatment protocols. To generate robust evidence, analysts must address time-dependent confounders—variables influenced by past treatment decisions and affecting future treatment. Double-robust methods can help in eliminating bias by modeling both the treatment and the outcome mechanisms, using machine learning to improve model specification.MethodsLongitudinal targeted minimum loss-based estimation (LTMLE) is a double-robust method that handles time-varying confounding, currently with only a few applications on real-world data. We demonstrate the use of LTMLE to evaluate realistic treatment protocols by applying it on longitudinal registry data to compare various treatment protocols that involve the use of erythropoiesis-stimulating agents (ESA) for myelodysplastic syndromes patients. We define dynamic regimes that trigger initiating ESA when relevant criteria (e.g., low hemoglobin levels) are met and require continuing/stopping ESA based on the response to treatment. We estimate the effect of these protocols on survival and EuroQol 5-dimension questionnaire (EQ-5D) scores.ResultsWe study static treatment regimes where we compare patients always on treatment with patients always not on treatment, and we find the average effects of always administering ESA versus never administering it are positive but not significant on patients’ EQ-5D scores or on survival probabilities across all treatment time periods. We also study dynamic treatment regimes where decisions to initiate and continue/discontinue treatment over time depend on changing patient characteristics and responses to treatment. We find that patients following dynamic treatment regimes are predicted to score higher in EQ-5D and have longer survival probabilities than patients under static treatment regimes.ConclusionsThe paper provides a tutorial and case study demonstration of the LTMLE model that can evaluate realistic treatment protocols using longitudinal observational data. It accounts for time-varying confounding in estimating treatment effects and can incorporate machine learning in improving accuracy of outcome prediction. The model has been applied in the setting of long follow-up times and gradually reduced sample size.
OD38 Real-World Analysis Of First-Line Maintenance Treatment For Patients With Nonsquamous Advanced/Metastatic Non-Small-Cell Lung Cancer
Authors: Tapan Umit , Bell Kelly F. , Aziez Amine , Sun Jiaqian , Du Mandy , Du Ella Xiaoyan , Hua Qi , Yang Hongbo , Shah Manasee 
Published: January 2025

IntroductionPemetrexed and immunotherapies (e.g., pembrolizumab) are approved for first-line maintenance (1LM) treatment of nonsquamous advanced/metastatic non-small-cell lung cancer (NSCLC), but real-world data on their use are limited. The objective of this study was to assess 1LM clinical outcomes, safety, and treatment patterns of immunotherapy versus immunotherapy+pemetrexed among patients with advanced/metastatic NSCLC from the EU4 (France, Germany, Italy, Spain)+UK.MethodsData from patients in the US, Canada, and EU4+UK with nonsquamous advanced/metastatic NSCLC without targetable mutations were collected via electronic case report form. Physician-identified patients (≥18 y) in the EU4+UK were eligible for this subgroup analysis if they achieved stable disease or complete or partial response with first-line platinum-based chemotherapy+immunotherapy (January 2019 to March 2021) and received 1LM immunotherapy or immunotherapy+pemetrexed. Patients were followed from index (1LM initiation) until last physician contact or death. Outcomes were overall survival (OS), progression-free survival (PFS), treatment patterns and duration, and adverse events.ResultsAmong the selected 367 patients (male, 71.9%; mean±StDev age, 63.4±7.2 y; current/former smokers, 85.8%), 203 (55.3%) received immunotherapies, most commonly pembrolizumab (n=173; 85.2%), and 164 (44.7%) received immunotherapy+pemetrexed. Patients receiving immunotherapy had longer median adjusted OS and PFS compared to those receiving immunotherapy+pemetrexed (OS hazard ratio [HR]: 0.63; 95% confidence interval [CI]: 0.36, 0.90; PFS HR: 0.58; 95% CI: 0.38, 0.79). Patients receiving immunotherapy versus patients receiving immunotherapy+pemetrexed had longer median treatment duration (14.0 vs 10.3 mo; p<0.001) and were less likely to experience anemia (19.7% vs 33.5%; p<0.01). Results were similar in the overall study population.ConclusionsIn this real-world study, among the selected patients with nonsquamous advanced/metastatic NSCLC who achieved stable disease or complete or partial response with first-line therapy, the addition of pemetrexed to immunotherapy in 1LM did not appear to confer a clinical benefit. Identifying treatments that can improve clinical outcomes for these patients remains an area of unmet need.