How to foster new treatment development in ultra-rare tumours? Joint EMA-EORTC multi-stakeholder workshops on ultra-rare sarcomas as a model for rare cancers.

PSY130 - THE RELATIONSHIP BETWEEN DISEASE TYPE AND CONDITIONAL OR EXCEPTIONAL APPROVAL BY EMA FOR ORPHAN DRUGS IN 2017

ObjectiveTo compare review outcome alignment between European Medicines Agency (EMA) and US Food and Drug Administration (FDA) for medicines approved by both agencies in the time period 2014–2016.DesignUsing publicly available...

6090 Background: Over the last three decades health-related quality of life (HRQOL) has become an important part of the randomised controlled trials (RCTs) conducted by the European Organisation for Research and Treatment of Cancer (EORTC). This review aims to undertake a descriptive database evaluation of all the HRQOL studies conducted in EORTC since 1980. Methods: The EORTC protocol database (n=785) was reviewed, restricting the search to between 1980 and 2011 (n=735). We investigated the number of HRQOL studies conducted in EORTC trials, the RCTs’ status and the use of HRQOL tools since 1980. Results: 157 protocols with HRQOL assessment were identified involving 70,903 patients. 73 studies ended as defined in the protocol; 27 studies closed early due to poor accrual; 17 are at the final analysis of the primary end point stage; 14 studies are still open to recruitment; 11 are closed to patient entry; and 15 new RCTs are pending activation with HRQOL. The majority of phase III (n=135) and phase II/III (n=9) RCTs have HRQOL as secondary endpoint. EORTC also conducted a number of large scale field studies (n=11), where HRQOL was the primary endpoint. During the early period of 1980 to 1989 HRQOL was assessed in 12 EORTC RCTs by using a small number of HRQOL items, but from 1990 to 2000, HRQOL was assessed in 97 RCTs using more comprehensive HRQOL tools. Between 2001 and 2011 the number of RCTs with HRQOL was 48. The EORTC clinical groups with the most RCTs containing HRQOL were Radiation Oncology (n=22), Genito-Urinary (n=20), Gynaecological (n=16), Breast Cancer (n=16), Lung (n=13), Gastrointestinal, (n=13) and Brain (n=10). The EORTC HRQOL tools were used in 90% of the trials, with other validated tools being used when required. Conclusions: Our review of EORTC RCTs has shown how patient perspective has been constantly considered of major importance in oncology during the last three decades. The inclusion of patient perspective in drug development shows that a more comprehensive HRQOL assessment has taken place over time as better instruments have become available. As the positive value of patient perspective grows to clinicians, regulatory bodies and industry, we expect that EORTC will continue its support by including HRQOL endpoints where appropriate.

BackgroundThe present study aims to assess clinical and regulatory variables that would influence pricing and reimbursement (P&R) decisions for Orphan Drugs (ODs) in Spain. ODs approved by the European Commission (EC) between 2006 and 2021 were classified according to their P&R status in Spain: approved, undergoing decision and rejected. A statistical analysis was carried out to assess the potential association between clinical and regulatory variables and P&R decision of ODs in Spain: therapeutic area, rarity of disease, existence of alternative therapies, availability of survival-related outcomes, safety profile, type of population, conditional approval status granted by the European Medicines Agency (EMA) and a positive Therapeutic Positioning Report (TPR) opinion.Results111 ODs have been approved by the EC and have obtained marketing authorisation in Spain between 2006 and 2021. Out of the 111 ODs, 57 (51.4%) were reimbursed, 24 (21.6%) were undergoing decision and 30 (27%) were rejected. According to the statistical analysis, ODs with a positive TPR conclusion (p-value < 0.01), not subject to a conditional approval by the EMA (p-value < 0.05) and approved without the obligation to conduct a post-authorisation safety study (PASS) (p-value < 0.05), were statistically significant, and therefore, would be more likely to obtain P&R approval in Spain.ConclusionsThis study shows that the TPR plays a key role in the P&R process in Spain and highlights that traditional evaluation tools, such us safety and efficacy, were the main drivers of P&R decisions for ODs. A positive conclusion of the TPR, non-conditional approval by the EMA and no obligation for a PASS seems to favourably affect P&R decisions in Spain.

Background Cancer and its related treatments have a huge impact on a patient's quality of life (QOL). To measure such QOL in cancer patients, the European Organization for Research and Treatment of Cancer (EORTC) has introduced various scales/questionnaires for various cancers. In the present study, we aimed to translate and validate high-grade Non-Hodgkin's lymphoma (NHL-HG) English questionnaire (EORTC QLQ-NHL-HG29) into Hindi and Marathi (two of the most popular Indian language) to make it available for patients and the scientific community. Materials and methods The EORTC QLQ-NHL-HG29 was translated into Hindi and Marathi languages as per EORTC guidelines. The translated questionnaire was pilot-tested in a sample of 20 patients (10 for each translation) with NHL-HG. Results After procuring required approvals from EORTC, the existing QLQ-NHL-HG29 English questionnaire was translated (forward and backward) into vernacular languages (Hindi and Marathi). Later, the translations were sent to EORTC for evaluation and all the queries raised by EORTC toward translations were discussed and included in the final questionnaires as per EORTC guidelines. On receiving approval from EORTC translation coordinator, pilot study was conducted in 20 patients. In the pilot study, 10 patients were given the Hindi questionnaire and other 10 patients were given the Marathi questionnaire. Based on the pilot testing interpretations or suggestions from the patients, all the necessary modifications were incorporated in the questionnaires and sent to EORTC for validation and approval. Conclusion Both the translations (Hindi and Marathi) submitted to the EORTC have now been approved (QLQ-NHL-HG29) by the EORTC-QOL unit and after procuring necessary permissions from the EORTC both of these translations can be used reliably in clinical practice and clinical trials to assess QOL in patients suffering from NHL-HG.

Health-related quality of life (HRQOL) is a critical aspect to consider when making treatment decisions for patients with non-Hodgkin-lymphoma (NHL). This international study by the European Organisation for Research and Treatment of Cancer (EORTC) tested the psychometric properties of two newly developed measures for patients with high-grade (HG)- and low-grade (LG)-NHL: the EORTC QLQ-NHL-HG29 and the EORTC QLQ-NHL-LG20 to supplement the core questionnaire (EORTC QLQ-C30). Overall, 768 patients with HG-NHL (N=423) and LG-NHL (N=345) from 12 countries completed the QLQ-C30, QLQ-NHL-HG29/QLQ-NHL-LG20 and a debriefing questionnaire at baseline, and a subset at follow-up for either retest (N=125/124) or responsiveness to change (RCA; N=98/49). Confirmatory factor analysis showed an acceptable to good fit of the 29 items of the QLQ-NHL-HG29 on its five scales (symptom burden [SB], neuropathy, physical condition/fatigue [PF], emotional impact [EI], and worries about health/functioning [WH]), and of the 20 items of the QLQ-NHL-LG20 on its four scales (SB, PF, EI, and WH). Completion took on average 10minutes. Test-retest reliability, convergent validity, known-group comparisons, and RCA find satisfactory results of both measures. A total of 31%-78% of patients with HG-NHL and 22%-73% of patients with LG-NHL reported symptoms and/or worries (e.g., tingling in hands/feet, lack of energy, and worries about recurrence). Patients reporting symptoms/worries had substantially lower HRQOL compared to those without. The use of the EORTC QLQ-NHL-HG29 and QLQ-NHL-LG20 questionnaires in clinical research and practice will provide clinically relevant data to better inform treatment decision-making. The European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Group developed two questionnaires. These questionnaires measure health-related quality of life. The questionnaires are for patients with high-grade or low-grade non-Hodgkin lymphoma. They are called the EORTC QLQ-NHL-HG29 and QLQ-NHL-LG20. The questionnaires are now internationally validated. This study demonstrates that the questionnaires are reliably and valid, which are important aspects of a questionnaire. The questionnaires can now be used in clinical trials and practice. With the information gathered from the questionnaires, patients and clinicians can better evaluate treatments and discuss the best choice for a patient.

The European Organization for Research and Treatment of Cancer (EORTC) is a pan‐European nonprofit cancer research organization that develops conducts, coordinates, and stimulates high‐quality translational and clinical research to improve the standards of cancer care. Founded in 1962, the EORTC has since developed into a vast network of cancer research expertise and infrastructure with more than 2500 scientists and clinicians who collaborate across over 200 affiliated institutions and academic centers in 30 countries. Cancer clinical trial research carried out by the EORTC has contributed to improvements in the quality of life and survival of cancer patients, extended the definition of standards for cancer patient care, advanced the practice of organ preservation as well as minimal and nonmutilating cancer surgery, and established diagnostic and treatment guidelines that aid clinicians in the treatment decision‐making process. The EORTC has also contributed to the advancement of cancer research through its educational programs and activities for scientists, clinicians, young researchers, patients, and the public. The EORTC has undertaken organizational and strategic initiatives throughout the years and continues to adopt novel strategic approaches to meet the challenges of the rapidly changing cancer research environment. Additional breakthroughs in the prevention, diagnosis, and treatment of cancer in the current era of molecular biology will be accomplished primarily through translational research projects, efficient drug development, and the conduct of translational research‐guided large prospective randomized multicenter clinical trials. The EORTC has been a leader in cancer research for over 45 years and will continue to devote its energy and expertise to high‐quality clinical cancer research throughout the twenty‐first century to improve the standards of cancer care, advance the scientific understanding of cancer as a disease, and address pivotal strategic therapeutic questions.

Objective:The aim of the present study was to evaluate the response to treatment by histopathologic type in patients with lung cancer and under follow-up with 18F-fluoro-2deoxy-glucose-positron emission tomography/computed tomography (18F-FDG PET/CT) imaging by using Response Evaluation Criteria in Solid Tumors (RECIST) and European Organisation for Research and Treatment of Cancer (EORTC) criteria that evaluate morphologic and metabolic parameters.Methods:On two separate (pre- and post-treatment) 18F-FDG PET/CT images, the longest dimension of primary tumor as well as of secondary lesions were measured and sum of these two measurements was recorded as the total dimension in 40 patients. PET parameters such as standardized uptake value (SUVmax), metabolic volume and total lesion glycolysis (TLG) were also recorded for these target lesions on two separate 18F-FDG PET/CT images. The percent (%) change was calculated for all these parameters. Morphologic evaluation was based on RECIST 1.1 and the metabolic evaluation was based on EORTC.Results:When evaluated before and after treatment, in spite of the statistically significant change (p<0.05) in SUVmax, the change was not significant in TLG, in the longest total size and in the longest size (p>0.05). In histopathologic typing, when we compare the post-treatment phase change with the treatment responses of RECIST 1.1 and EORTC criteria; for RECIST 1.1 in squamous cell lung cancer group, progression was observed in sixteen patients (57%), stability in seven patients (25%), partial response in five patients (18%); and for EORTC progression was detected in four patients (14%), stability in thirteen patients (47%), partial response in eleven patients (39%), in 12 of these patients an increase in stage (43%), in 4 of them a decrease in stage (14%), and in 12 of them stability in stage (43%) were determined. But in adenocancer patients (n=7), for RECIST 1.1, progression was determined in four patients (57%), stability in two patients (29%), partial response in one patient (14%); for EORTC, progression in one patient (14%), stability in four patients (57%), partial response in two patients (29%) were observed and in these patients, an increase in stage was detected in 3 of them (43%), while 4 of them remained stable. According to histopathologic diagnosis, between squamous cell cancer and adenocancer cases, no significant difference was determined in terms of SUVmax (p>0.05). Post-treatment SUVmax was significantly different in primary tumor but was not significantly different in nodal involvement and metastatic lesions for squamous cell carcinoma patients as compared to the pre-treatment SUVmax measurements. Similarly, there was no significant difference between primary tumor and nodal involvement for adenocarcinoma patients.Conclusion:Whether metabolic or morphologic changes are more accurate in evaluating treatment response in lung cancer remains unknown, and there is no gold standard diagnostic method on this issue yet. The most reliable results can only be achieved by survival curve parameters. However, we believe SUVmax seems to provide more easy and practical data for the evaluation of treatment response.

Quality assurance in surgical oncology (QASO) within the European Organization for Research and Treatment of Cancer (EORTC): current status and future prospects

Objective: To assess shares of reimbursed orphan drugs and agreement in reimbursement decision-making in different European Union member states as well as to define odds for reimbursement influenced by the presence of conditional approval or exceptional circumstances granted by the European Medicines Agency (EMA) or by type of the disease.Methods: The list of authorized drugs with current orphan designations was collected from the website of the EMA. For each drug, the information regarding conditional approval or approval under exceptional circumstances was collected. The reimbursement statuses were available on national reimbursement or HTA agencies websites. The agreement for reimbursement decisions between selected countries was assessed using the κ coefficient for the measurement of agreement. The impact of the EMA's conditional approval as well as approval under exceptional circumstances was assessed using the logistic regression and presented as odds ratio.Results: The percentage of reimbursed orphan drugs varied significantly from 27% in Poland to 88% in Denmark, with an average value of 51% (p < 0.0001). Regarding the reimbursement status, the highest, substantial agreement was observed between Spain and Italy, and the lowest agreement was observed between Germany and England, with κ of 0.64 and 0.01, respectively. Conditional approval status significantly decreased the chance for reimbursement in France, Italy, and Spain by 77–80%; however, approval granted under exceptional circumstances had significant impact only in Germany with 85% decrease in chances for reimbursement. The type of the disease (oncology or metabolic) was significantly associated with both conditional approval (p of 0.03—oncology drugs were more likely to be conditionally approved then the rest of analyzed drugs) and exceptional circumstances (p of 0.02—drugs for metabolic diseases were more likely to be approved under exceptional circumstances).Conclusions: Access to reimbursed orphan drugs varies significantly across EU countries. The highest, substantial agreement in reimbursement decisions was observed between Italy and Spain and the lowest between Germany and England. Conditional approval and approval under exceptional circumstances were significant negative predictors of reimbursement in some countries and they were significantly associated with the type of the disease (oncology or metabolic).

In the last decades, the development of drugs for rare diseases has been supported by regulatory and financial incentives. On the other hand, public health policies have increasingly taken into account the person affected by a rare disease in their strategies. In this perspective, we examined the relation between the regulatory framework on rare diseases and the regulatory framework on drug approval. Technical proposals have been brought forward to protect the needs of individuals. The legislative framework on rare diseases has developed both at a European and national level with the aim to strengthen the network of centers for diagnosis and care by increasing the degree of social and health protection, as well as to accelerate the assessment, approval and access to new drugs. Since 2000, 210 orphan drugs have been approved by the European Medicines Agency (EMA) (compared to an estimated 7-8,000 rare diseases). Of the 118 orphan drugs active in the community register as of 2020, 97 (82.2%) were available in Italy: 17 (17.5%) in class A; 58 (59.8%) in class H; 12 (12.4%) in class C; 10 (10.3%) in class C-nn. In 2020, expenditure on drugs with an orphan indication accounted for 6% of the total pharmaceutical expenditure (+47% since 2016). These drugs have benefited from incentives at both European and national levels, as well as inclusion in national early access programs. However, the average duration of the assessment process is above the 100-day limit set by law. The legislation on rare diseases has developed in different directions, and drug legislation has undoubtedly played a major role in terms of the results achieved. However, orphan drugs enter the market with a high price, which increasingly represents a problem of sustainability for health systems but notwithstanding Italy shows a high ratio between the level of social protection and access times. In this perspective, it is necessary to be provided with tools for a better system balance with a view to optimize these timeframes. Introducing in Italy a system for tracking the negotiation process that considers the clock stops as the EMA does, would allow to know at what point the negotiation process is. In addition, once the 100-day period is over (net of any clock stops) and in case of failure to reach a negotiation agreement, a second 60-day negotiation round could be proposed and so on. In this way, all the parts involved the system would have a clear scope of action to conclude the process in a flexible but certain timeframe. In this regard, the joint clinical assessments foreseen by the new HTA Regulations provide an additional opportunity to harmonize central decisions with national requirements.

Introduction: Comprehensive outcome assessments after breast reconstruction (BRR) require surgery- specific Patient Reported Outcomes Measures (PROMS). Completion of early Phases I-II development resulted in a 31-item questionnaire comprising 5 hypothesised scales and (numbers of items) : Treatment /surgery related symptoms (4), body image (3), sexuality (4), cosmetic outcomes (breast, n = 7, donor site, n = 5, nipple, n = 6) and overall satisfaction (2). Current evidence shows no BRR-specific PROM, with the further validation of the BREAST-Q, currently the only PROM. The aim of this study was Phase III pre-testing of a BRR questionnaire assessing patients’ health related quality of life (HRQL) before and after BRR, in collaboration with the European Organisation for Research and Treatment of Cancer (EORTC). Pre-testing assessed the relevance, acceptability and redundancy of questions in all types of BRRs. This PROM is intended for use alongside the EORTC QLQ-C30, and QLQ-BR23 in women treated for breast cancer before and after mastectomy and all BRR types. Methods: The EORTC BRR HRQL subgroup applied decision-making rules to each question according to eight EORTC criteria comprising 1. priority, 2. relevance and 3. difficulty /consistency across five European languages and cultures. Descriptive statistics used HRQL score criteria: 4. mean &amp;gt;1.5, 5. range &amp;gt;2, 6. floor and ceiling effects &amp;gt;10%, 7. prevalence ratios &amp;gt;30% and 8. compliance &amp;gt;95%. 197 patients (UK, Austria, Belgium, Italy, Sweden) were recruited: 47 prospectively completing pre- and post-BRR questionnaires, and 150 retrospectively reporting only post-BRR questionnaires. 189 patients underwent qualitative debriefing interviews. Preliminary psychometric analyses performed multi-trait scaling using EORTC QLQ-C30 and QLQ- BR23 that were used in final decisions on items and scales. Results: 31 questions /items fulfilled ‘relevance’, with none producing ‘difficulties’. Ten items were not a ‘priority’ in 10% of respondents. Of these, two questions comprising ‘muscle twitching in affected breast’ and ‘problem with donor site swelling’ were deleted, fulfilling less than 5 out of 8 criteria. Deletions of three redundant items comprised ‘weak arm’, which correlated significantly to QLQ-BR23; and ‘shape’ and ‘colour’ of affected nipple with similarities to ‘overall nipple appearance’. Descriptive statistics and clinical judgment reduced the module to 26 items conceptualized into three scales (and items): Disease Treatment /Surgery related symptoms (2), Sexuality (5), and Cosmetic outcomes (breast, n = 10, donor site, n = 4, nipple, n = 4) within the EORTC QLQ-BRR26. The body image and overall satisfaction scales were dropped, with their respective items incorporated into other scales. Discussion: The QLQ-BRR26 has completed phase III development and is available for psychometric validation in a large field international sample that aims to recruit 450 patients across 17 European centres. Psychometric testing will be finalised in Phase IV including the evaluation of the questionnaires’ responsiveness to the effects of BRR subgroups with comparisons to the BREAST-Q. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-19-08.

e24117 Background: The EORTC Item Library is an online, interactive platform comprised of 950 distinct questions (items) from 67 different EORTC patient-reported outcome (PRO) questionnaires, covering a range of symptomatic toxicities, types of functioning, and impact on quality of life. These PROs provide a patient-centred perspective, complementing clinician adverse event (AE) reporting using classifications like the CTCAE. In order to summarize the coverage of symptomatic toxicities and facilitate the identification of items through use of a standardized framework, a mapping study was carried out, aimed at creating a coding system to classify EORTC items according to the CTCAE and link them to corresponding AEs. Methods: All items were searched for within the CTCAE (v5.0) using a deductive approach. Items were coded as linked if they were described within an AE’s title, description, or grading. Items not suitable for CTCAE coding were inductively assigned a descriptive classification. Descriptive classifications were also applied along with CTCAE codes when they provided additional information. Symptoms described in EORTC items but not located in the CTCAE were coded as missing and additional codes were assigned to highlight EORTC items capturing multiple underlying issues and diagnosis only CTCAE codes. Two raters independently coded 249 items and agreement was calculated. The remaining 701 items were coded by one rater and verified by the second, with a third introduced to discuss any discrepancies until a consensus was reached. Results: Agreement for raters following independent coding was 77.9% for at least one AE per item. In total, 625 (65.8%) items were linked to 208 different AEs. Fatigue was the most commonly linked AE, representing 4.9% of linked AEs. The majority of linked items were associated with one (65.6%) or two (23.5%) AEs, with some linked to three or more (10.9%). Multiple linkage resulted from different symptoms relating to the same issue/diagnosis or one symptom relating to multiple diagnoses. Two symptoms captured by six EORTC items but not found in the CTCAE were identified: bowel urgency and tenesmus. Seven descriptive non-CTCAE classifications emerged, with most of these covering the emotional impact of symptom, diagnosis, or treatment (33.6%) and information/satisfaction with care (31.7%). Nineteen items (2%) were linked to multiple underlying issues, and 43 (4.5%) to diagnosis only CTCAE codes. Conclusions: The EORTC Item Library provides extensive coverage of CTCAE symptomatic toxicities, along with other issues that are important to cancer patients, including emotional well-being and satisfaction with care services. Classifying symptomatic PRO items following the CTCAE clinical framework may facilitate future PRO selection and use in clinical trials and routine care.

The interpretation of studies on quality of life (QoL) after lung surgery is often difficult owing to the use of multiple instruments with inconsistent scales and metrics. Although a more standardized approach would be desirable, the most appropriate instrument to be used in this setting is still largely undefined. The aim of the study was to assess the respective ability of two validated QoL instruments (European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30/L13 and Short Form (36) Health Survey (SF-36)) to detect perioperative changes in QoL of patients submitted to pulmonary resection for non-small-cell lung cancer (NSCLC). A prospective study on 33 consecutive patients (May 2009-December 2009) was submitted to pulmonary resection. All patients completed both EORTC QLQ-C30 with lung module 13 and SF-36 pre- and postoperatively (3 months). Preoperative changes of all SF-36 and EORTC scales were assessed by using the Cohen's effect-size method. External convergence between different instruments (SF-36 vs EORTC) was assessed by measuring the correlation of scales evaluating the same concepts (physical, psychosocial, and emotional). The correlation coefficients between standardized perioperative changes (effect sizes) of objective functional parameters (forced expiratory volume in 1s (FEV1) and diffusion lung capacity for carbon monoxide (DLCO)) and SF-36 or EORTC scales were also investigated. A poor correlation (r < 0.5) was detected between most of the scales of the two instruments measuring the same QoL concepts, indicating that they may be complementary in investigating different aspects of QoL. Only the SF-36 and EORTC social functioning scales and the SF-36 mental health and EORTC emotional functioning scales had a correlation coefficient >0.5. In general, EORTC was more sensitive in detecting physical or emotional declines but was more conservative in detecting improvements. Both SF-36 and EORTC showed poor correlations (r < 0.5) between perioperative changes in QoL and FEV1 or DLCO, confirming that objective parameters cannot be surrogates to the subjective perception of QoL. In particular, there was a poor correlation between perceived changes in dyspnea and objective changes in FEV1 or DLCO. EORTC behaved similarly to SF-36 in assessing perioperative changes in generic QoL scales, but, with the use of its lung module, provided a more detailed evaluation of specific symptoms. For this reason, EORTC should be regarded as the instrument of choice for measuring QoL in the thoracic surgery setting.

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