Essential cancer medicines: adding feasibility to the magnitude of clinical benefit value chain.

BACKGROUND: Cancer is a global public health problem, requiring efficient health system investments to deliver sustainable impact on population health. Access to medicines is a critical component of health systems, having a crucial role in delivering therapeutic benefits. Since 1977, the World Health Organization (WHO) has published a Model List of Essential Medicines (EML) that includes key health interventions for the prevention and control of conditions of public health relevance. Essential medicines are selected for inclusion in the EML based on the evidence of efficacy, safety, therapeutic value, and the potential to impact population health. With the rapid changes in the therapeutic landscape of cancer treatment with new medicine approvals, there is a critical need to select and prioritise specific cancer interventions based on their intrinsic value. MATERIALS AND METHODS: The European Society for Medical Oncology (ESMO) has developed a decisional methodology based on a threshold with a minimum set of technical specifications and a consensus-based procedure for decisions to select candidate cancer medicines to be submitted to the WHO for consideration for the WHO EML. RESULTS: ESMO recognises the WHO EML as an important reference guide for medicines that all countries should include in their national EMLs. Cancer medicines on the WHO EML are used in the treatment of the majority of cancers, and are recommended in the evidence-based ESMO Clinical Practice Guidelines that medical oncologists use to treat patients. ESMO's submissions to the WHO EML in 2019 and 2021 and their respective outcomes are presented in the manuscript. CONCLUSION: Due to the rising costs associated with newly available therapies, structured, reproducible, and field-tested tools to evaluate the added clinical benefit from these therapies need to be implemented in pre-selecting potential candidate medicines to be included in the WHO EML. ESMO is proud to collaborate closely with WHO on this important global public health initiative.

ESMO study on the availability and accessibility of biomolecular technologies in oncology in Europe.

BACKGROUND: Access to biomolecular technologies has become an essential requirement to ensure optimal and timely treatment of patients with cancer. This study sought to provide a comprehensive overview of the availability and accessibility of biomolecular technologies to patients, the status of their use and prescription, barriers to access, and potential economic issues related to cost and reimbursement. MATERIALS AND METHODS: A total of 201 field reporters from 48 European countries submitted data through an electronic survey tool between July and December 2021. The survey methodology mirrored that from previous ESMO studies addressing the availability and accessibility of antineoplastic medicines, in Europe and worldwide. The preliminary data were posted on the ESMO website for open peer-review, and amendments were incorporated into the final report. RESULTS: Overall, basic single-gene techniques are widely available, whereas access to advanced biomolecular technologies, including large next-generation sequencing panels and complete genomic profiles, is highly heterogeneous. In most countries, advanced biomolecular technologies remain largely inaccessible in clinical practice, are limited to clinical trials or basic research, and associated with progressively increasing cost as the technique becomes more advanced. Differences also exist regarding national sequencing initiatives or molecular tumour boards. The most important barriers to multiple versus single-gene sequencing techniques are the reimbursement of the test (59% versus 24%), and the availability of a suitable medicine, either through reimbursement of treatment (48% versus 30%), off-label treatment (52% versus 35%), or clinical trial enrolment (53% versus 39%). CONCLUSIONS: Cost and availability of both treatment and test are the two main factors limiting patients' access to advanced biomolecular technologies and as a consequence to innovative anticancer strategies. In the era of precision medicine, tackling the accessibility to biomolecular technologies is a key step to reduce inequalities to transformative cancer care.

ESMO-Magnitude of Clinical Benefit Scale for haematological malignancies (ESMO-MCBS:H) version 1.0.

BACKGROUND: The European Society for Medical Oncology (ESMO)-Magnitude of Clinical Benefit Scale (MCBS) has been accepted as a robust tool to evaluate the magnitude of clinical benefit reported in trials for oncological therapies. However, the ESMO-MCBS hitherto has only been validated for solid tumours. With the rapid development of novel therapies for haematological malignancies, we aimed to develop an ESMO-MCBS version that is specifically designed and validated for haematological malignancies. METHODS: ESMO and the European Hematology Association (EHA) initiated a collaboration to develop a version for haematological malignancies (ESMO-MCBS:H). The process incorporated five landmarks: field testing of the ESMO-MCBS version 1.1 (v1.1) to identify shortcomings specific to haematological diseases, drafting of the ESMO-MCBS:H forms, peer review and revision of the draft based on re-scoring (resulting in a second draft), assessment of reasonableness of the scores generated, final review and approval by ESMO and EHA including executive boards. RESULTS: Based on the field testing results of 80 haematological trials and extensive review for feasibility and reasonableness, five amendments to ESMO-MCBS were incorporated in the ESMO-MCBS:H addressing the identified shortcomings. These concerned mainly clinical trial endpoints that differ in haematology versus solid oncology and the very indolent nature of nevertheless incurable diseases such as follicular lymphoma, which hampers presentation of mature data. In addition, general changes incorporated in the draft version of the ESMO-MCBS v2 were included, and specific forms for haematological malignancies generated. Here we present the final approved forms of the ESMO-MCBS:H, including instructions. CONCLUSION: The haematology-specific version ESMO-MCBS:H allows now full applicability of the scale for evaluating the magnitude of clinical benefit derived from clinical studies in haematological malignancies.

Off-label despite high-level evidence: a clinical practice review of commonly used off-patent cancer medicines.

INTRODUCTION: Off-label use of medicines is generally discouraged. However, several off-patent, low-cost cancer medicines remain off-label for indications in which they are commonly used in daily practice, supported by high-level evidence based on results of phase III clinical trials. This discrepancy may generate prescription and reimbursement obstacles as well as impaired access to established therapies. METHODS: A list of cancer medicines that remain off-label in specific indications despite the presence of high-level evidence was generated and subjected to European Society for Medical Oncology (ESMO) expert peer review to assess for accountability of reasonableness. These medicines were then surveyed on approval procedures and workflow impact. The most illustrative examples of these medicines were reviewed by experts from the European Medicines Agency to ascertain the apparent robustness of the supporting phase III trial evidence from a regulatory perspective. RESULTS: A total of 47 ESMO experts reviewed 17 cancer medicines commonly used off-label in six disease groups. Overall, high levels of agreement were recorded on the off-label status and the high quality of data supporting the efficacy in the off-label indications, often achieving high ESMO-Magnitude of Clinical Benefit Scale (ESMO-MCBS) scores. When prescribing these medicines, 51% of the reviewers had to implement a time-consuming process associated with additional workload, in the presence of litigation risks and patient anxiety. Finally, the informal regulatory expert review identified only 2 out of 18 (11%) studies with significant limitations that would be difficult to overcome in the context of a potential marketing authorisation application without additional studies. CONCLUSIONS: We highlight the common use of off-patent essential cancer medicines in indications that remain off-label despite solid supporting data as well as generate evidence on the adverse impact on patient access and clinic workflows. In the current regulatory framework, incentives to promote the extension of indications of off-patent cancer medicines are needed for all stakeholders.

Methodological and reporting standards for quality-of-life data eligible for European Society for Medical Oncology-Magnitude of Clinical Benefit Scale (ESMO-MCBS) credit.

BACKGROUND: The European Society for Medical Oncology-Magnitude of Clinical Benefit Scale (ESMO-MCBS) has been developed to grade clinical benefit of cancer therapies. Improvement in quality of life (QoL) is considered relevant, especially in the non-curative setting. This is reflected by an upgrade of the preliminary ESMO-MCBS score if QoL is improved compared to the control arm or a downgrade if an improvement in progression-free survival is not paralleled by an improvement in QoL or overall survival. Given the importance of QoL for the final score, a need to ensure the robustness of QoL data was recognised. DESIGN: A checklist was created based on existing guidelines for QoL research. Field testing was carried out using clinical trials that either received an adjustment of the preliminary ESMO-MCBS score based on QoL or had QoL as the primary endpoint. Several rounds of revision and re-testing of the checklist were undertaken until a final consensus was reached. RESULTS: The final checklist consists of four items and can be applied if three prerequisites are met: (i) QoL is at least a secondary endpoint, (ii) evidence of reliability and validity of the instrument is provided, and (iii) a statistically and clinically significant improvement in QoL is observed. The four items on the checklist pertain to the (i) hypothesis, (ii) compliance and missing data, (iii) presentation of the results, and (iv) statistical and clinical relevance. Field testing revealed that a clear QoL hypothesis and correction for multiple testing were mostly lacking, while the main statistical method was always described. CONCLUSIONS: Implementation of the ESMO-MCBS QoL checklist will facilitate objective and transparent decision making on QoL data within the ESMO-MCBS scoring process. Trials published until 1 January 2025 will have to meet the prerequisites and at least two items for crediting QoL benefit in the final ESMO-MCBS score. Trials published thereafter will have to meet all four items.

ESMO Designated Centres of Integrated Oncology and Palliative Care (ESMO DCs): education, research and programme development survey.

BACKGROUND: The European Society for Medical Oncology (ESMO) Designated Centres (DCs) of Integrated Oncology and Palliative Care is an incentive programme established in 2003 aiming to improve the integration of oncology and palliative care services provided by oncologists and oncology centres worldwide. Currently, the ESMO DCs programme has over 250 centres accredited from 54 countries worldwide, in all six world regions. MATERIALS AND METHODS: To evaluate how ESMO can support centres to improve programme development, education and research and vice versa what each single centre can do to improve in these areas, we developed a survey which was shared with all active centres. Two hundred and seven ESMO DCs representing 44 countries were invited to participate. We used content analysis to identify response categories using a stepwise approach. After reviewing and coding all responses to each question separately, they were placed into categories, counted and labelled. RESULTS: Of the 207 centres that were invited to participate, 146 centres started the survey, representing 43 countries. Five overarching topics were identified. They included (i) joint events and educational activities; (ii) sharing of materials and defining common standards; (iii) sharing of experiences, scientific knowledge and expertise; (iv) research collaboration; and (v) ESMO support. Respondents were willing to support the ESMO DC community group in all topics and were also asking ESMO to support their centres in these issues in the future. CONCLUSION: The study showed that the ESMO DCs are willing to provide support to improve education, research and programme development. They are also eager to contribute and collaborate amongst each other, but also request ESMO to offer advice and help to improve these issues in the DCs. In the future, facilitation of joint research projects and development of arenas to share experiences, educational and programme developments, and other resources are to be explored and could be offered to the DCs worldwide.

Prioritising systemic cancer therapies applying ESMO's tools and other resources to assist in improving cancer care globally: the Kazakh experience.

BACKGROUND: In Kazakhstan, cancer is the second leading cause of death with a major public health and economic burden. In the last decade, cancer care and cancer medicine costs have significantly increased. To improve the efficiency and efficacy of cancer care expenditure and planning, the Kazakhstan Ministry of Health requested assistance from the World Health Organization (WHO) and the European Society for Medical Oncology (ESMO) to review its systemic cancer treatment protocols and essential medicines list and identify high-impact, effective regimens. MATERIALS AND METHODS: ESMO developed a four-phase approach to review Kazakhstan cancer treatment protocols: (i) perform a systematic analysis of the country's cancer medicines and treatment protocols; (ii) cross-reference the country's cancer protocols with the WHO Model List of Essential Medicines, the ESMO-Magnitude of Clinical Benefit Scale and the European Medicines Agency's medicine availability and indications database; (iii) extract treatment recommendations from the ESMO Clinical Practice Guidelines; (iv) expert review for all cancer medicines not on the WHO Model List of Essential Medicines and the country treatment protocols. RESULTS: This ESMO four-phase approach led to the update of the Kazakhstan national essential cancer medicines list and the list of cancer treatment protocols. This review has led to the withdrawal of several low-value or non-evidence-based medicines and a budget increase for cancer care to include all essential and highly effective medicines and treatment options. CONCLUSION: When applied effectively, this four-phase approach can improve access to medicines, efficiency of expenditure and sustainability of cancer systems. The WHO-ESMO collaboration illustrated how, by sharing best practices, tools and resources, we can address access to cancer medicines and positively impact patient care.

Access to essential anticancer medicines for children and adolescents in Europe.

BACKGROUND: Essential anticancer medicines are an indispensable component of multidisciplinary treatment of paediatric malignancies. A European Society for Medical Oncology (ESMO) study reported inequalities in the availability of anticancer medicines for adult solid tumours and provided a model for the present survey. The aim of this survey was to assess the accessibility of essential medicines used in paediatric cancer patients aged 0 to 18 years across Europe from 2016 to 2018. METHODS: A list of medicines was drawn with input from the European Society for Paediatric Oncology (SIOP Europe) Clinical Research Council referring to the World Health Organization Model List of Essential Medicines for Children (WHO EMLc) 2017. A survey was sent to nominated national clinician and pharmacist rapporteurs and parent associations in up to 37 countries; answers were obtained from 34 countries. RESULTS: The full survey list contained 68 medicines, including 24 on the WHO EMLc 2017. Health professionals reported that 35% of all medicines were prescribed off-label in at least one country and that 44% were always available in >90% of countries. Only 63% of the EMLc 2017 medicines were reported as always available. The main determinant of unavailability was shortages, reported for 72% of medicines in at least one country. Out-of-pocket costs were reported in eight countries. Twenty-seven percent of orally administered medicines were never available in child-friendly formulations. Parents detailed individual efforts and challenges of facilitating ingestion of oral medicines as prescribed. Inequalities in access to pain control during procedures were reported by parents across Europe. CONCLUSIONS: Children and adolescents with cancer in Europe experience lack of access to essential medicines. Urgent actions are needed to address shortages, financial accessibility, availability of safe age-appropriate oral formulations, and pain management across Europe.

ESMO-Magnitude of Clinical Benefit Scale version 1.1.

BACKGROUND: The ESMO Magnitude of Clinical Benefit Scale (ESMO-MCBS) version 1.0 (v1.0) was published in May 2015 and was the first version of a validated and reproducible tool to assess the magnitude of clinical benefit from new cancer therapies. The ESMO-MCBS was designed to be a dynamic tool with planned revisions and updates based upon recognition of expanding needs and shortcomings identified since the last review. METHODS: The revision process for the ESMO-MCBS incorporates a nine-step process: Careful review of critiques and suggestions, and identification of problems in the application of v1.0; Identification of shortcomings for revision in the upcoming version; Proposal and evaluation of solutions to address identified shortcomings; Field testing of solutions; Preparation of a near-final revised version for peer review for reasonableness by members of the ESMO Faculty and Guidelines Committee; Amendments based on peer review for reasonableness; Near-final review by members of the ESMO-MCBS Working Group and the ESMO Executive Board; Final amendments; Final review and approval by members of the ESMO-MCBS Working Group and the ESMO Executive Board. RESULTS: Twelve issues for revision or amendment were proposed for consideration; proposed amendments were formulated for eight identified shortcomings. The proposed amendments are classified as either structural, technical, immunotherapy triggered or nuanced. All amendments were field tested in a wide range of studies comparing scores generated with ESMO-MCBS v1.0 and version 1.1 (v1.1). CONCLUSIONS: ESMO-MCBS v1.1 incorporates 10 revisions and will allow for scoring of single-arm studies. Scoring remains very stable; revisions in v1.1 alter the scores of only 12 out of 118 comparative studies and facilitate scoring for single-arm studies.

The 'critical mass' survey of palliative care programme at ESMO designated centres of integrated oncology and palliative care.

BACKGROUND: The ESMO Designated Centres (ESMO-DCs) of Integrated Oncology and Palliative Care (PC) Incentive Programme has grown steadily. We aimed to characterise the level of PC clinical services, education and research at ESMO-DCs. METHODS: We sent all 184 ESMO-DCs an electronic survey consisting of 78 questions examining the DC characteristics, palliative care clinical programme (structure, processes, and outcomes), primary PC delivery by oncologists, education, research and attitudes and beliefs towards the ESMO-DC programme. RESULTS: The response rate was 83% (152/184). 115 (76%) ESMO-DCs were from Europe, 87 (57%) were tertiary care centres. 136 (90%) had inpatient consultation teams, 135 (89%) had outpatient PC clinics, 107 (71%) had dedicated acute care beds, and 75 (50%) offered community-based PC. An estimated 70% (interquartile range [IQR] 28-80%) of patients with advanced cancer had a PC consultation before death, occurring 90 days before death (median, IQR 40-150 days) for outpatients and 21 days (IQR 14-45 days) for inpatients. 59 (39%) offered PC fellowship programme; 47 (32%) had mandatory PC rotations for oncology fellows. Ninety-nine (65%) had double-boarded palliative oncologists. 118 (78%) of the ESMO-DCs reported that routine symptom screening was offered in the oncology clinic and 30% of patients had documented end-of-life discussions by their oncologists. Most centres (>80%) perceived the ESMO-DC programme to increase their status. CONCLUSIONS: The ESMO-DCs had a high level of PC infrastructure and provided access to a large proportion of patients with advanced cancer. The survey supports that the 13 criteria required for ESMO designation set a robust framework for integration, stimulated investment of resources into some palliative care programmes prior to accreditation, and raised the interest about palliative care among clinicians, trainees and patients.

ESMO - Magnitude of Clinical Benefit Scale V.1.0 questions and answers.

The ESMO Magnitude of Clinical Benefit Scale (ESMO-MCBS) is a standardised, generic, validated tool to stratify the magnitude of clinical benefit that can be anticipated from anticancer therapies. The ESMO-MCBS is intended to both assist oncologists in explaining the likely benefits of a particular treatment to their patients as well as to aid public health decision makers' prioritise therapies for reimbursement. From its inception the ESMO-MCBS Working Group has invited questions and critiques to promote understanding and to address misunderstandings regarding the nuanced use of the scale, and to identify shortcomings in the scale to be addressed in future planned revisions and updates. The ESMO-MCBS V.1.0 has attracted many questions regarding its development, structure and potential applications. These questions, together with responses from the ESMO-MCBS Working Group, have been edited and collated, and are herein presented as a supplementary resource.