Toward a Useful and Cost-Effective Workup in Chronic Polyneuropathy: The EXPRESS Study Protocol.

BACKGROUND: Knowledge gaps exist about the usefulness and extent of blood tests and nerve conduction studies in the workup of polyneuropathy. We hypothesize that a limited workup improves costs spent on diagnostics without loss of diagnostic reliability or disadvantageous effect on treatment choice in many patients with a clinical diagnosis of chronic polyneuropathy. We aim to determine which investigations are necessary in the workup of patients with suspected chronic polyneuropathy clinically diagnosed by neurologists in an outpatient clinic and will perform an early health technology assessment. METHODS: This is a prospective multicenter quality in healthcare evaluation. We compare two diagnostic strategies, both performed on all participants: the standard care by each patient's neurologist and the proposed (limited) workup by the study panel members consisting of neurologists with experience in neuromuscular diseases. RESULTS: The primary outcome is the effectiveness of a limited workup expressed as concordance between the patient's neurologist diagnosis and the panel diagnosis. This will be related to differences in costs and impact on treatment or patient management otherwise. Other outcomes are burden/gain for the patient in terms of number of investigations, time to diagnosis, hospital visits, sick leave, loss of productivity, expenses, experienced quality of care. CONCLUSION: This multicenter prospective observational study on quality in health care will provide improved evidence about the components of a cost-effective workup for patients with chronic polyneuropathy.

A Health Technology Assessment Based on Chinese Guideline: Active Vitamin D and Its Analogs in the Treatment of Osteoporosis.

Objective: To quantitatively assess all dosage forms of three active vitamin D and its analogs, namely, calcitriol, alfacalcidol, and eldecalcitol, to provide a basis for the selection of active vitamin D and its analogs in hospitals. Methods: In this study, three active vitamin D and its analogs were evaluated by quantitative scoring in five dimensions, including pharmaceutical properties (28 points), efficacy (27 points), safety (25 points), economy (10 points), and other attributes (10 points). Results: The final scores of quantitative assessment for the selection of alfacalcidol soft capsules, calcitriol soft capsules I, calcitriol soft capsules II, alfacalcidol tablets, alfacalcidol capsules, alfacalcidol oral drops, calcitriol injection, and eldecalcitol soft capsules were 73.17, 72.06, 71.52, 71.29, 69.62, 68.86, 65.60, 64.05 points. Conclusion: Based on the scoring results, alfacalcidol soft capsules, calcitriol soft capsules I, calcitriol soft capsules II, alfacalcidol tablets can be entered into the medication list of medical institutions as strongly recommended drugs. This study offers guidance on selecting and using active vitamin D and its analogs in hospitals, with consideration for the patient's needs.

Experiences of patient organizations' involvement in medicine appraisal and reimbursement processes in Finland - a qualitative study.

BACKGROUND: This study investigated how patient representatives have experienced their involvement in medicines appraisal and reimbursement processes with the Council for Choices in Health Care in Finland (COHERE) and the Pharmaceuticals Pricing Board (PPB) and how authorities perceive the role of patient organizations' input. METHODS: Semi-structured thematic individual and pair interviews were conducted in 2021 with representatives (n = 14) of patient organizations and government officials (n = 7) of the Ministry of Social Affairs and Health. The interview data were analyzed using qualitative content analysis. RESULTS: Patient representatives expressed their appreciation for the PPB and the COHERE in creating consultation processes and systematic models that support involvement. However, there were many challenges: patient representatives were uncertain about how their submissions were utilized in official processes and whether their opinions had any significance in decision-making. Patients or patient organizations lack representation in appraisal and decision-making bodies, and patient representatives felt that decision-making lacked transparency. The importance of patient involvement was highlighted by the authorities, but they also emphasized that the patient organizations' contributions were complementary to the other materials. Submissions regarding the medications used to treat rare diseases and those with limited research evidence were considered particularly valuable. However, the submissions may not necessarily have a direct impact on decisions. CONCLUSIONS: The interviews provided relevant input for the development of involvement processes at the PPB and COHERE. The interviews confirmed the need for increased transparency in the medicines assessment, appraisal, and decision-making procedures in Finland.

Navigating the path towards successful implementation of the EU HTA Regulation: key takeaways from the 2023 Spring Convention of the European Access Academy.

BACKGROUND: The European Regulation on Health Technology Assessment (EU HTA R), effective since January 2022, aims to harmonize and improve the efficiency of common HTA across Member States (MS), with a phased implementation from January 2025. At "midterms" of the preparation phase for the implementation of the Regulation our aim was to identify and prioritize tangible action points to move forward. METHODS: During the 2023 Spring Convention of the European Access Academy (EAA), participants from different nationalities and stakeholder backgrounds discussed readiness and remaining challenges for the Regulation's implementation and identified and prioritized action points. For this purpose, participants were assigned to four working groups: (i) Health Policy Challenges, (ii) Stakeholder Readiness, (iii) Approach to Uncertainty and (iv) Challenges regarding Methodology. Top four action points for each working group were identified and subsequently ranked by all participants during the final plenary session. RESULTS: Overall "readiness" for the Regulation was perceived as neutral. Prioritized action points included the following: Health Policy, i.e. assess adjustability of MS laws and health policy processes; Stakeholders, i.e. capacity building; Uncertainty, i.e. implement HTA guidelines as living documents; Methodology, i.e. clarify the Population, Intervention, Comparator(s), Outcomes (PICO) identification process. CONCLUSIONS: At "midterms" of the preparation phase, the focus for the months to come is on executing the tangible action points identified at EAA's Spring Convention. All action points centre around three overarching themes: harmonization and standardization, capacity building and collaboration, uncertainty management and robust data. These themes will ultimately determine the success of the EU HTA R in the long run.

Development and Evaluation of a Software Designed by a Nursing and Technology Team to Assess the Health Status of Adults over 65 Years of Age / Desarrollo y evaluación de un software diseñado por un equipo de enfermería y tecnología para la valoración del estado de salud de los adultos mayores de 65 año / Desenvolvimento e avaliação de um software desenvolvido por uma equipe de enfermagem e tecnologia para avaliação do estado de saúde de adultos com mais de 65 anos

Objective. This work sought to develop the Actuasalud platformas a useful tool for nursing that permits assessing health, in term of frailty, in population over 65 years of age. Methods. For the design and development of Actuasalud, two working groups were formed: one from nursing with different profiles, to identify the scientific content and a computer science group responsible for the software programming and development. Both teams adapted the scientific content to the technology so that the tool would allow for population screening with detection of health problems and frailty states. Results. The software was developed in three large blocks that include all the dimensions of frailty: a) sociodemographic variables, b) comorbidities, and c) assessment tools of autonomy-related needs that evaluate the dimensions of frailty. At the end of the evaluation, a detailed report is displayed through bar diagram with the diagnosis of each of the dimensions assessed. The assessment in the participating elderly showed that 44.7% (n = 38) of the population was considered not frail, and 55.3%; (n = 47) as frail. Regarding associated pathologies, high blood pressure (67.1%; n = 57), osteoarthritis and/or arthritis (55.3%; n = 47), diabetes (48.2%; n = 41) and falls during the last year (35.3%; n = 30) were highlighted. Conclusion.Actuasalud is an application that allows nursing professionals to evaluate frailty and issue a quick diagnosis with ordered sequence,which helps to provide individualized care to elderly individuals according to the problems detected during the evaluation.

Objetivo. Desarrollar la plataforma Actuasalud como una herramienta útil para enfermería que permita evaluar la salud, en términos de fragilidad, en población mayor de 65 años. Métodos. Para el diseño y desarrollo de Actuasalud,se constituyeron dos grupos de trabajo: uno de enfermería con diferentes perfiles para identificar el contenido científico y uno informático que se responsabilizó de la programación y desarrollo del software. Ambos equipos adaptaron el contenido científico a la tecnología de manera que la herramienta permitiese hacer un cribado poblacional con detección de problemas de salud y estados de fragilidad. Resultados. Se desarrolló el software en tres grandes bloques que incluyen todas las dimensiones de fragilidad: a) variables sociodemográficas, b) comorbilidades y c) herramientas de evaluación de necesidades relacionadas con la autonomía que evalúan las dimensiones de fragilidad. Al finalizar la evaluación, se visualiza un informe detallado mediante diagrama de barras con el diagnóstico de cada una de las dimensiones evaluadas. La evaluación en los mayores participantes mostró que el 44.7% (n = 38) de la población se consideró como no frágil, y un 55.3%; (n = 47) como frágiles. En cuanto a las patologías asociadas, destacaron hipertensión arterial (67,1 %; n = 57), artrosis y/o artritis (55.3%; n = 47), diabetes (48.2 %; n = 41) y caídas en el último año (35,3 %; n = 30). Conclusión.Actuasalud es una aplicación que permite a los profesionales de enfermería evaluar fragilidad y emitir un diagnóstico de forma ágil con secuencia ordenada que ayuda a brindar cuidados individualizados a personas mayores de acuerdo los problemas detectados en la evaluación.

Objetivo. Desenvolver a plataforma Actuasalud como uma ferramenta útil para a enfermagem que permite avaliar a saúde, em termos de fragilidade, numa população com mais de 65 anos. Métodos. Para a concepção e desenvolvimento do Actuasalud foram formados dois grupos de trabalho: um grupo de enfermagem com perfis diferentes, para identificar o conteúdo científico, e um grupo de informática que foi responsável pela programação e desenvolvimento do software. Ambas as equipas adaptaram o conteúdo científico à tecnologia para que a ferramenta permitisse o rastreio da população para detectar problemas de saúde e estados de fragilidade. Resultados. O software foi desenvolvido em três grandes blocos que incluem todas as dimensões da fragilidade: a) variáveis sociodemográficas, b) comorbidades ec) instrumentos de avaliação de necessidades relacionadas à autonomia que avaliam as dimensões da fragilidade. Ao final da avaliação é apresentado um relatório detalhado através de um diagrama de barras com o diagnóstico de cada uma das dimensões avaliadas. A avaliação nos idosos mostrou que 44.7% (n=38) da população foi considerada não frágil e 55.3%; (n=47) como frágil. Quanto às patologias associadas, destacaram-se a hipertensão arterial (67.1%; n=57), a osteoartrite e/ou artrite (55.3%; n=47), a diabetes (48.2%; n=41) e as quedas no último ano (35.3%; n=30). Conclusão. Actuasalud é um aplicativo que permite ao profissional de enfermagem avaliar a fragilidade e emitir um diagnóstico de forma ágil e com sequência ordenada que auxilia no atendimento individualizado ao idoso de acordo com os problemas detectados na avaliação.

Trióxido de arsénico en pacientes con leucemia promielocítica aguda en recaída / Trióxido de arsénico em pacientes com leucemia promielocítica aguda recuperável

INTRODUCCIÓN: Cuadro clínico: La leucemia promielocítica aguda (LPA) representa el 5% a 20% de los casos de leucemia mieloide aguda (LMA) (1,2); sin embargo, entre pacientes de origen latino se ha reportado una frecuencia de 38%. En Perú, a pesar de que no se tienen reportes de la frecuencia de la leucemia promielocítica aguda (LPA), en un estudio realizado entre el año 1996 y 2008 en el Hospital Nacional Edgardo Rebagliati Martins se observó que el 52% y 38% de los pacientes con LPA se encontraban entre los grupos etarios de 16 - 40 años y 41 - 60 años, respectivamente (3). En pacientes con LPA sin tratamiento la mediana de sobrevida es menor a un mes, debido al sangrado descontrolado (4). Sin embargo, con los avances recientes en las terapias, la sobrevida ha mejorado y la mayoría de los pacientes alcanza la remisión completa y se mantiene. El tratamiento de la LPA comprende tres etapas: remisión o inducción, consolidación y mantenimiento. Del total de pacientes con LPA tratados con ácido trans-retinoico (ATRA) más quimioterapia con antraciclinas, el 10 % al 20% sufre una recaída. El objetivo de tratamiento de este grupo de pacientes es alcanzar la remisión molecular, con planes de proseguir con quimioterap

Abiraterona, apalutamida, darolutamida e enzalutamida para o tratamento de indivíduos com câncer de próstata sensível à castração e metastático (CPSCm) / Abiraterone, apalutamide, darolutamide, and enzalutamide for the treatment of individuals with metastatic castration-sensitive prostate cancer (mSCLC)

INTRODUÇÃO: O câncer de próstata é uma neoplasia maligna com grande impacto em saúde pública, sendo a segunda neoplasia mais comum entre os homens. Estima-se que, entre os anos de 2020 e 2022, ocorreram 65.840 novos casos de câncer de próstata no Brasil a cada ano. A TPA é a base do tratamento do câncer de próstata, e o câncer avançado que responde ao tratamento hormonal é classificado como CPSCm. Estudos recentes demonstraram que a adição de novos agentes direcionados ao eixo do receptor de andrógeno (androgen receptor-axis targeted, ARAT) (apalutamida, darolutamida e enzalutamida), assim como o inibidor da síntese de androgênios (abiraterona), à TPA em homens com CPSCm pode melhorar a sobrevida geral e a sobrevida livre de progressão em comparação com TPA isoladamente, ao passo que diretrizes clínicas atualmente desaconselham o uso da TPA isolada nesta população. Abiraterona é recomendada no SUS para pacientes com CP resistente à castração com uso prévio de quimioterapia, mas não para CPSCm. PERGUNTA DE PESQUISA: Abiraterona, apalutamida, darolutamida e enzalutamida, combinados à TPA são mais eficazes e seguros no tratamento de indivíduos com CPSCm comparados às opções usuais na prática clínica do SUS? Consideram-se opções usuais a quimioterapia com docetaxel ou antiandrogênicos não esteroides (NSAA, b

Riociguate para pacientes adultos com hipertensão arterial pulmonar (HAP ­ Grupo I) que não alcançaram resposta satisfatória com terapia dupla com PDE5i e ERA, como alternativa à terapia tripla com selexipague / Riociguate for adult patients with pulmonary arterial hypertension (PAH ­ Group I) who do not reach satisfactory response with dual therapy with PDE5i and ERA, as an alternative to triple therapy with selexipague

INTRODUÇÃO: Hipertensão pulmonar (HP) é definida pela presença de uma pressão arterial pulmonar média (PAPm) em repouso ≥25 mmHg. O Grupo 1 da HP é o mais bem caracterizado dos cinco grupos, engloba uma variedade de distúrbios, incluindo pacientes com HP idiopática, HP hereditária, HP induzida por medicamentos ou associada a distúrbios sistêmicos de colágeno, doenças cardíacas congênitas, doença hepática, esquistossomose ou vírus da imunodeficiência humana (HIV). Doença rara, estima-se mundialmente uma prevalência de aproximadamente 15 casos/1.000.000 indivíduos, com uma incidência anual de 2 a 5 casos/1.000.000 adultos (1,2). Doença grave, com sobrevida mediana de 2,8 anos, possui tratamento no SUS estabelecido em PCDT, que inclui além de bloqueadores do canal de cálcio, inibidores da fosfodiesterase 5 (PDE5i) ­ sildenafila; antagonistas de receptor da endotelina 1 (ERA) ­ ambrisentana e bosentana; prostanoides ­ iloprosta e selexipague. Pacientes que mantém um risco intermediário ou alto apesar de terapia dupla com ERA e PDE5i devem associar ao tratamento preferencialmente selexipague, tendo o iloprosta como alternativa. Riociguate é um estimulador de guanilato ciclase solúvel (sGC) administrado por via oral que não está incorporado no PCDT para o tratamento da HP grupo 1, apesar de aprovado em bula para esta indicação. PERGUNTA: A terapia dupla (riociguate + ERA) é eficaz e segura no tratamento de pacientes com HAP do grupo 1 que não alcançaram resposta satisfatória com terapia dupla com PDE5i + ERA em comparação à terapia tripla (PDE5i + ERA + selexipague)? EVIDÊNCIAS CLÍNICAS: O demandante localizou apenas evidências que suportam a eficácia e segurança da substituição do PDE5i pelo riociguate, em monoterapia ou em combinação com ERA. Não há evidência para a proposta terapia dupla (riociguate + ERA) versus tripla (ERA + PDE5i + selexipague). AVALIAÇÃO ECONÔMICA: O demandante conduziu uma avaliação de custo-minimização com base na ausência de comprovação de superioridade entre as opções de tratamento. A economia de recursos seria entre R$ 113,15 (cenário considerando menor preço BPS) a R$ 11.092,35 (cenário preços SIGTAP) a favor da terapia dupla (riociguate + ERA) por paciente-ano. Porém, ao considerar o uso de iloprosta ao invés de selexipague na composição da terapia tripla, haveria um incremento de R$ 26.685,15 por paciente-ano. ANÁLISE DE IMPACTO ORÇAMENTÁRIO: Para a estimativa do impacto orçamentário foram combinados dados epidemiológicos com demanda aferida (pacientes tratados com bosentena, ambrisentana, sildenafila e iloprosta no SUS), valores projetados (tendência linear) para 2025, onde haveria 5.958 pacientes, sendo então considerados um percentual (75%) (3) de falha à terapia dupla e um percentual (24,8%) de elegíveis à terapia combinada tripla (4). Para o cenário alternativo, com a incorporação do riociguate, o market share da terapia dupla foi estimado entre 15% até 42% ao longo de cinco anos. Estimou-se, com base no cenário de preços SIGTAP e com 100% dos pacientes em terapia tripla fazendo uso do selexipague, uma economia de cerca de 18 milhões de reais em cinco anos. EXPERIÊNCIAS INTERNACIONAIS: Foram pesquisadas diversas agências de avaliação de tecnologias em saúde e outros institutos, mas não foi encontrado nenhum posicionamento em relação à incorporação do riociguate versus selexipague. MONITORAMENTO DO HORIZONTE TECNOLÓGICO: Foram identificadas 07 tecnologias para compor o esquema terapêutico de pessoas adultas com hipertensão arterial pulmonar HAP I, que atenda às características desta demanda. Uma em fase 3 e em pré-registro na EMA e FDA: sotatercepte. Duas em fase 3 de desenvolvimento seralutinibe e ralinepag. Todas estas 3 envolveram centros de pesquisa no Brasil. E quatro em fase 2 de desenvolvimento: imatinibe, KER-012, LTP001 e MK-5475. CONSIDERAÇÕES FINAIS: Os estudos RESPITE e REPLACE apresentam evidências de que pacientes com HAP em uso de PDE5i com resposta insuficiente podem se beneficiar da substituição do tratamento pelo riociguate. Não há evidências sobre a comparação entre a terapia dupla (riociguate + ERA) versus tripla (selexipague + PDE5i + ERA). O demandante apresentou comparações indiretas que consideraram populações diferentes e análises de subgrupos sem poder estatístico, concluindo que, por não haver diferença estatística, as opções dupla e tripla teriam igual eficácia. Tal conclusão é inadequada, pois não há dados que corroborem para superioridade ou equivalência de eficácia entre as opções. Não foram localizadas evidências de comparação de riociguate versus selexipague com qualquer combinação de medicamentos. O parecerista considera relevante o risco de que se incorporado o riociguate, que este seja utilizado em monoterapia, em substituição ao PDE5i, e que o demandante não apresentou análises econômicas para esta comparação. Pela falta de evidência atual, um modelo que compare a terapia dupla versus a tripla terá limitações importantes, pois faltam dados de eficácia. Em uma análise de custo-minimização, observa-se economia de recursos a favor da terapia dupla, exceto se a terapia tripla for composta de iloprosta, ao invés de selexipague. PERSPECTIVA DO PACIENTE: A Chamada Pública nº 50/2023 esteve aberta entre 29/12/2023 e 21/01/2024, recebendo 16 inscrições. A participante relatou que, em 2021, apresentou sintomas como cansaço, falta de ar, desmaios e edemas, os quais foram se agravando. Consultou diferentes especialistas e teve repetidos episódios de internamento até que recebeu o diagnóstico de HAP primária idiopática veno-oclusiva. Iniciou o tratamento com sildenafila e ambrisentana. Posteriormente, foi acrescentado iloprosta ao esquema, retirado após poucos meses de uso em virtude dos eventos adversos. Em janeiro de 2023, iniciou o uso do riociguate, em substituição à sildenafila, pois a terapia estava dando pouco resultado. Considerou que, com a utilização do riociguate, houve melhora do seu estado de saúde e da qualidade de vida, conseguindo respirar sem suporte de oxigênio, assim como realizar atividades cotidianas. Atualmente, utiliza um esquema composto por ambrisentana, riociguate e selexipague. RECOMENDAÇÃO PRELIMINAR DA CONITEC: Diante do exposto, os membros do Comitê de Medicamentos da Conitec, em sua 128ª Reunião ordinária, realizada em 10 de abril de 2024, deliberaram que a matéria fosse disponibilizada em consulta pública com recomendação preliminar desfavorável à incorporação do riociguate associado a ERA para tratamento de pacientes adultos com hipertensão arterial pulmonar (HAP ­ Grupo I) que não alcançaram resposta satisfatória com terapia dupla com PDE5i e ERA, como alternativa à terapia tripla com selexipague. Para essa recomendação, a Conitec considerou principalmente a escassez de dados sobre a eficácia e segurança comparativa dos tratamentos, cujas evidências restringem-se ao uso dos tratamentos em monoterapia ou em terapia dupla para cerca de 70% da amostra. Ainda, a Comissão ponderou que as análises apresentadas estavam baseadas em desfechos secundários e análises de subgrupos, o que gerou um intervalo de credibilidade amplo, inadequadamente utilizado para afirmar igualdade de eficácia. Considerou ainda questionável o modelo de custo-minimização e a economia de recursos apresentada, pois apesar de o selexipague ser a opção de preferência quando necessária a terapia tripla, o uso de iloprosta em terapia tripla associado ao ERA e PDE5i também é indicado no PCDT e seria uma opção de menor custo que a terapia dupla de riociguate com ERA. CONSULTA PÚBLICA: A Consulta Pública nº 26 foi realizada entre os dias 24/05/2024 e 12/06/2024, recebendo o total de 334 contribuições. Dentre estas, 331 discordaram da recomendação preliminar da Conitec, uma concordou e duas expressaram não ter opinião formada. Entretanto, examinando essas contribuições, notase que esses participantes, na verdade, também discordam da recomendação inicial, uma vez que enviaram comentários defendendo e justificando a importância da incorporação do riociguate. Os principais argumentos em prol da incorporação abordaram a importância do acesso público ao medicamento e da ampliação das opções de tratamento, a possibilidade de manter a terapia dupla e o incremento à qualidade de vida trazido pela utilização do medicamento em avaliação. Sobre os resultados positivos e facilidades referentes ao uso tecnologia em avaliação, os participantes com experiência com o riociguate indicaram os benefícios para a saúde e o aumento da qualidade de vida. RECOMENDAÇÃO FINAL DA CONITEC: Os membros do Comitê de Medicamentos da Conitec, em sua 131ª Reunião Ordinária, no dia 04 de julho de 2024, deliberaram, por maioria simples, recomendar a não incorporação do riociguate associado a ERA para tratamento de pacientes adultos com hipertensão arterial pulmonar (HAP ­ Grupo I) que não alcançaram resposta satisfatória com terapia dupla com PDE5i e ERA, como alternativa à terapia tripla com selexipague. Para essa recomendação, os membros do Comitê de Medicamentos consideraram que as incertezas na síntese de evidências e na avaliação econômica da recomendação inicial foram mantidas. Assim, foi assinado o Registro de Deliberação nº 910/2024. DECISÃO: não incorporar, no âmbito do Sistema Único de Saúde - SUS, o riociguate associado a ERA para o tratamento de pacientes adultos com hipertensão arterial pulmonar (HAP - Grupo I) que não alcançaram resposta satisfatória com terapia dupla com PDE5i e ERA, como alternativa à terapia tripla com selexipague, publicada no Diário Oficial da União número 163, seção 1, página 140, em 23 de agosto de 2024.

Abiraterona, apalutamida, darolutamida e enzalutamida para o tratamento de indivíduos com câncer de próstata resistente à castração (CPRC) não metastático e metastático em pacientes virgens de tratamento e metastático em pacientes com uso prévio de quimioterapia / Abiraterone, apalutamide, darolutamide, and enzalutamide for the treatment of individuals with nonmetastatic and metastatic castration-resistant prostate cancer (CRPC) in treatment-naïve patients and metastatic in chemotherapy-experienced patients

INTRODUÇÃO: O câncer de próstata é, atualmente, a segunda neoplasia mais comum entre os homens em todo o mundo e compreende 13,5% de todos os diagnósticos de câncer nesta população. A apalutamida, enzalutamida e darolutamida são medicamentos da classe dos inibidores de receptor de androgênio e a abiraterona é um inibidor da síntese de androgênios. Entretanto, todas estas tecnologias são consideradas como agentes direcionados ao eixo do receptor de andrógeno (ARAT) de segunda geração, atuando como antagonistas não esteroidais do receptor de andrógeno, que podem ser associados à terapia de privação androgênica (TPA), e atuam inibindo a ação da testosterona ou da diidrotestosterona ao se ligarem aos receptores androgênicos periféricos sem ativar a expressão gênica. No SUS, abiraterona está disponível apenas para CPRCm com uso prévio de docetaxel. Apesar disso abiraterona e enzalutamida são recomendadas em diretrizes internacionais para CPRCm (virgens e com uso prévio de quimioterapia) e apalutamida, darolutamida e enzalutamida são recomendadas para CPRCnm. PERGUNTAS DE PESQUISA: 1) Apalutamida, darolutamida ou enzalutamida combinadas à TPA são eficazes e seguras no tratamento de indivíduos com câncer de próstata não metastático resistente à castração comparadas à TPA isolada ou TPA + bicalutamida?; 2) Abiraterona ou enzalutamida combinadas à TPA são eficazes e seguras no tratamento de indivíduos com câncer d

Ixequizumabe para o tratamento de adultos com espondiloartrite axial com resposta prévia inadequada ou intolerância aos inibidores do fator de necrose tumoral / Ixequizumab for the treatment of adults with axial spondyloarthritis with inadequate prior response or intolerance to tumor necrosis factor inhibitors

INTRODUÇÃO: A espondiloartrite axial é uma doença inflamatória crônica, de origem autoimune, que acomete preferencialmente a coluna vertebral. O tratamento da doença tem por objetivo aliviar os sintomas, melhorar a capacidade funcional, manter a capacidade laboral e/ou escolar, diminuir as complicações e prevenir ao máximo o dano esquelético do indivíduo, e inclui drogas de diferentes classes (anti-inflamatórios não esteroidais ­ AINE, glicocorticoides e medicamentos modificadores do curso da doença) que são utilizadas de acordo com a gravidade da doença. PERGUNTA: Em relação aos medicamentos biológicos disponíveis no SUS, ixequizumabe é eficaz e seguro em pacientes com espondiloartrite axial com resposta prévia inadequada ou intolerância aos inibidores do fator de necrose tumoral? SÍNTESE DAS EVIDÊNCIAS: A evidência encontrada, sendo identificado um ensaio clínico e duas revisões sistemáticas, mostrou que não há diferença estatisticamente significativa entre todos os biológicos na maioria dos desfechos. Para o desfecho ASAS40, na análise entre ixequizumabe e os comparadores de interesse deste documento não foi observado diferenças estatísticas: ixequizumabe versus certolizumabe (risco relativo 1,49 [IC95% 0,88-2,52]), infliximabe (1,51 [IC95% 0,84-2,72]), golimumabe (1,06 [0,67-1,64]), adalimumabe (0,98 [0,67-1,45]), etanercepte (1,07 [IC95% 0,70-1,63]), e secuquinumabe (1,29 [0,78-2,14]). Para esse desfecho, ixequizumabe apresentou maior eficácia na comparação com placebo. Resultados semelhantes aos anteriormente mencionados foram observados para outros desfechos de eficácia avaliados (ASAS20, BASDAI, ASDAS e outros Patient Reported Outcomes). Em relação à segurança, não houve diferença estatisticamente significativa entre as intervenções ativas. A certeza da evidência foi baixa na comparação entre ixequizumabe e os demais comparadores ativos, e moderada na comparação com placebo. AVALIAÇÃO ECONÔMICA (AE): Ixequizumabe apresentou desempenho semelhante em termos de eficácia e segurança em relação aos demais medicamentos biológicos (adalimumabe, etanercepte, infliximabe, golimumabe, secuquinumabe e certolizumabe), e, portanto, foi desenvolvida uma análise de custo-minimização. O horizonte temporal foi de 2 anos, sendo calculado os custos dos medicamentos para o primeiro e ano subsequente, pelo fato de que alguns dos comparadores possuem dose inicial e de manutenção diferentes. Foi considerado apenas os custos de aquisição dos medicamentos. O resultado da análise principal demonstrou que o custo de ixequizumabe, tanto no primeiro ano, como no ano subsequente, foi superior a todos os demais medicamentos biológicos em comparação, com a diferença de custo anual variando entre 44 mil reais e 54 mil reais (a depender do comparador). ANÁLISE DE IMPACTO ORÇAMENTÁRIO (AIO): O número de pacientes elegíveis para a indicação proposta do tratamento de espondilite ancilosante foi obtido por meio de dados do DATASUS, sendo estimados em torno de 5 e 7 mil novos pacientes a cada ano. O market share utilizado para o ixequizumabe foi de 3% no primeiro ano, chegando a 10% no quinto ano de análise. O impacto orçamentário incremental foi de R$ 7 milhões no primeiro ano, chegando a R$ 100 milhões no quinto ano de análise, totalizando R$ 251 milhões em cinco anos. PERSPECTIVA DO PACIENTE: Foi aberta a chamada pública nº 42/2023 para inscrição de participantes para a perspectiva do paciente, durante o período de 10/11/2023 a 20/11/2023, e 18 pessoas se inscreveram. A seleção dos representantes titular e suplente ocorreu por meio de sorteio realizado em plataforma digital, com transmissão em tempo real e com gravação enviada posteriormente para todos os inscritos. Durante o seu relato, a representante, diagnosticada com espondilite anquilosante há cinco anos, relatou que o uso do ixequizumabe controlou os sintomas e teve impactos positivos na sua qualidade de vida, permitindo-lhe, atualmente, retomar suas atividades diárias, como caminhar e trabalhar. MONITORAMENTO DO HORIZONTE TECNOLÓGICO (MHT): Foram detectadas 4 (quatro) tecnologias para compor o esquema terapêutico de pacientes adultos diagnosticados com EpA radiográfica e não radiográfica, previamente tratados com medicamentos biológicos (anti-TNF) e falhos. Um inibidor de IL-17 (bimequizumabe) e três inibidores da janus quinase (tofacitinibe, upadacitinibe e filgotinibe). O tofacitinibe e o upadacitinibe possuem registro na FDA para a população deste relatório. RECOMENDAÇÕES INTERNACIONAIS: Foram encontradas recomendações do NICE (National Institute for Health and Care Excellence - Reino Unido) e CADTH (Canadian Agency for Drugs and Technologies in Health - Canadá) recomendando o ixequizumabe para tratamento da espondiloartrite. Não foram encontradas avaliações da ixequizumabe na SMC (Scottish Medicines Consortium ­ SMC - Escócia) e PBAC (Pharmaceutical Benefits Advisory Committee - Austrália) para a indicação em questão. CONSIDERAÇÕES FINAIS: De forma geral, não foi identificada diferenças em termos de eficácia e segurança na comparação entre ixequizumabe e outros biológicos disponíveis no SUS. O resultado da análise de custo-minimização demonstrou que o custo de ixequizumabe, tanto no primeiro ano, como no ano subsequente, foi superior a todos os demais medicamentos biológicos em comparação, com a diferença de custo anual variando entre 44 mil reais e 54 mil reais (a depender do comparador). Além disso, na análise de impacto orçamentário, observou-se que a incorporação de ixequizumabe no SUS para indicação proposta tem como resultado um incremento de custos. Apesar disso, é possível que frente à competição com outros biológicos já disponíveis no SUS, o preço de ixequizumabe reduza, em caso de incorporação, o que poderia reduzir os resultados obtidos e a discrepância em relação aos medicamentos atualmente em uso no SUS. RECOMENDAÇÃO PRELIMINAR DA CONITEC: Os membros do Comitê de Medicamentos presentes na 128ª Reunião Ordinária, realizada no dia 11 de abril de 2024, deliberaram por unanimidade encaminhar o tema para consulta pública com recomendação preliminar desfavorável à incorporação do ixequizumabe para o tratamento de adultos com espondiloartrite axial com resposta prévia inadequada ou intolerância aos inibidores do fator de necrose tumor. Consideraram-se elevados os custos incrementais estimados nas análises de custo-minimização e de impacto orçamentário. CONSULTA PÚBLICA: A consulta pública nº 27/2024 ficou vigente no período entre 24/05/2024 e 12/06/2024, durante o qual foram recebidas 75 contribuições, sendo que 74 (99%) expressaram a opinião de que a tecnologia em questão deve ser incorporada e 1 (1%) que não deve ser incorporada no SUS. Como argumento para discordância, os participantes destacaram que se trata de um medicamento seguro, eficaz e que sua incorporação representaria mais uma opção de tratamento em casos de falha terapêutica. Aqueles com experiência no uso do ixequizumabe pontuaram que ele contribui para o controle da doença após falha terapêutica, possui baixa toxicidade e impacta positivamente na qualidade de vida. Contudo, há dificuldades de acesso e a tecnologia apresenta alguns eventos adversos. Aqueles com experiência com outros medicamentos para o tratamento da condição de saúde em questão apontaram que estes também são eficazes e seguros, porém, podem apresentar falha terapêutica, sendo necessário ter outras opções medicamentosas. Além disso, há risco aumentado para infecções e tuberculose. Foram identificadas 16 (21%) contribuições não vazias para evidências clínicas e 9 (12%) para estudos econômicos. Em relação às contribuições feitas nos campos de "Evidências Científicas" e "Estudos econômicos", diversas destacaram o potencial clínico (por exemplo, alcance de remissão clínica) do uso do ixequizumabe para o tratamento da espondiloartrite, incluindo para pacientes atualmente alegadamente desassistidos (contraindicação ao uso de antiTNF). Após submissão de proposta comercial pela empresa detentora do registro do medicamento, os resultados das avaliações econômicas atualizados foram substancialmente menores comparados àqueles da reunião inicial (ACM: maior custo incremental entre R$ 2 e 12 mil, a depender do comparador; IO acumulados em cinco anos de até 34 milhões de reais). RECOMENDAÇÃO FINAL DA CONITEC: Aos 3 (três) dias do mês de julho de 2024, reuniu-se o Comitê de Medicamentos da Comissão Nacional de Incorporação de Tecnologias no Sistema Único de Saúde ­ Conitec, regulamentado pelo Decreto nº 7.646, de 21 de dezembro de 2011, e os membros deliberaram, por unanimidade, recomendar a não incorporação do ixequizumabe para o tratamento de adultos com espondiloartrite axial com resposta prévia inadequada ou intolerância aos inibidores do fator de tumoral. Os membros do Comitê de Medicamentos entenderam que o tratamento com ixequizumabe não é superior ou mais vantajoso economicamente que os já incorporados ao Sistema Único de Saúde. Foi assinado o registro de deliberação nº 907/2024. DECISÃO: não incorporar, no âmbito do Sistema Único de Saúde - SUS, o ixequizumabe para o tratamento de adultos com espondiloartrite axial com resposta prévia inadequada ou intolerância aos inibidores do fator de necrose tumoral, publicada no Diário Oficial da União número 163, seção 1, página 140, em 23 de agosto de 2024.

A Systematic Review of Modeling Approaches to Evaluate Treatments for Relapsed Refractory Multiple Myeloma: Critical Review and Considerations for Future Health Economic Models.

BACKGROUND AND OBJECTIVE: Multiple myeloma is a rare incurable hematological cancer in which most patients relapse or become refractory to treatment. This systematic literature review aimed to critically review the existing economic models used in economic evaluations of systemic treatments for relapsed/refractory multiple myeloma and to summarize how the models addressed differences in the line of therapy and exposure to prior treatment. METHODS: Following a pre-approved protocol, literature searches were conducted on 17 February, 2023, in relevant databases for models published since 2014. Additionally, key health technology assessment agency websites were manually searched for models published as part of submission dossiers since 2018. Reported information related to model conceptualization, structure, uncertainty, validation, and transparency were extracted into a pre-defined extraction sheet. RESULTS: In total, 49 models assessing a wide range of interventions across multiple lines of therapy were included. Only five models specific to heavily pre-treated patients and/or those who were refractory to multiple treatment classes were identified. Most models followed a conventional simple methodology, such as partitioned survival (n = 28) or Markov models (n = 9). All included models evaluated specific interventions rather than the whole treatment sequence. Where subsequent therapies were included in the model, these were generally only considered from a cost and resource use perspective. The models generally used overall and progression-free survival as model inputs, although data were often immature. Sensitivity analyses were frequently reported (n = 41) whereas validation was only considered in less than half (n = 19) of the models. CONCLUSIONS: Published economic models in relapsed/refractory multiple myeloma rarely followed an individual patient approach, mainly owing to the higher need for complex data assumptions compared with simpler modeling approaches. As many patients experience disease progression on multiple treatment lines, there is a growing need for modeling complex treatment strategies, leading to more sophisticated approaches in the future. Maintaining transparency, high reporting standards, and thorough analyses of uncertainty are crucial to support these advancements.

Pharmaceutical innovativeness index: methodological approach for assessing the value of medicines - a case study of oncology drugs.

BACKGROUND: We propose a framework to assess the value of pharmaceutical innovations, with explicit clinical and methodological parameters, based on the therapeutic value and health needs. RESEARCH DESIGN AND METHODS: The study was based on the adaptation of health technology assessment methods documented in the literature, which was applied to a sample of oncological drugs. Difficulties and issues during the application of those tools were identified and addressed to develop a new framework with new and revised domains and clear classification criterion for each domain. Scores were assigned to each level and domain according to their relevance to generate the final score of innovativeness. RESULTS: The Pharmaceutical Innovation Index (PII) includes four domains, two related to clinical and social dimensions - Therapeutic Need and Added Therapeutic Value - and other two about methodological features - Study Design and Quality (risk of bias). The scores combined after assigned to each domain results Index of the Innovativeness of the medicines represents the degree of pharmaceutical innovation. CONCLUSION: This work proposes a transparent methodology with well-defined criteria and script; the algorithm developed with authors' weightings and criteria may be switched to best adjust to other applications, perspective or clinical indications, while keeping the transparency and objectiveness.

Benefits and harms of antenatal and newborn screening programmes in health economic assessments: the VALENTIA systematic review and qualitative investigation.

Background: Health economic assessments are used to determine whether the resources needed to generate net benefit from an antenatal or newborn screening programme, driven by multiple benefits and harms, are justifiable. It is not known what benefits and harms have been adopted by economic evaluations assessing these programmes and whether they omit benefits and harms considered important to relevant stakeholders. Objectives: (1) To identify the benefits and harms adopted by health economic assessments in this area, and to assess how they have been measured and valued; (2) to identify attributes or relevance to stakeholders that ought to be considered in future economic assessments; and (3) to make recommendations about the benefits and harms that should be considered by these studies. Design: Mixed methods combining systematic review and qualitative work. Systematic review methods: We searched the published and grey literature from January 2000 to January 2021 using all major electronic databases. Economic evaluations of an antenatal or newborn screening programme in one or more Organisation for Economic Co-operation and Development countries were considered eligible. Reporting quality was assessed using the Consolidated Health Economic Evaluation Reporting Standards checklist. We identified benefits and harms using an integrative descriptive analysis and constructed a thematic framework. Qualitative methods: We conducted a meta-ethnography of the existing literature on newborn screening experiences, a secondary analysis of existing individual interviews related to antenatal or newborn screening or living with screened-for conditions, and a thematic analysis of primary data collected with stakeholders about their experiences with screening. Results: The literature searches identified 52,244 articles and reports, and 336 unique studies were included. Thematic framework resulted in seven themes: (1) diagnosis of screened for condition, (2) life-years and health status adjustments, (3) treatment, (4) long-term costs, (5) overdiagnosis, (6) pregnancy loss and (7) spillover effects on family members. Diagnosis of screened-for condition (115, 47.5%), life-years and health status adjustments (90, 37.2%) and treatment (88, 36.4%) accounted for most of the benefits and harms evaluating antenatal screening. The same themes accounted for most of the benefits and harms included in studies assessing newborn screening. Long-term costs, overdiagnosis and spillover effects tended to be ignored. The wide-reaching family implications of screening were considered important to stakeholders. We observed good overlap between the thematic framework and the qualitative evidence. Limitations: Dual data extraction within the systematic literature review was not feasible due to the large number of studies included. It was difficult to recruit healthcare professionals in the stakeholder's interviews. Conclusions: There is no consistency in the selection of benefits and harms used in health economic assessments in this area, suggesting that additional methods guidance is needed. Our proposed thematic framework can be used to guide the development of future health economic assessments evaluating antenatal and newborn screening programmes. Study registration: This study is registered as PROSPERO CRD42020165236. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: NIHR127489) and is published in full in Health Technology Assessment; Vol. 28, No. 25. See the NIHR Funding and Awards website for further award information.

Every year the NHS offers pregnant women screening tests to assess the chances of them or their unborn baby having or developing a health condition. It also offers screening tests for newborn babies to look for a range of health conditions. The implementation of screening programmes and the care for women and babies require many resources and funding for the NHS, so it is important that screening programmes represent good value for money. This means that the amount of money the NHS spends on a programme is justified by the amount of benefit that the programme gives. We wanted to see whether researchers consider all the important benefits and harms associated with screening of pregnant women and newborn babies when calculating value for money. To do this, we searched all studies available in developed countries to identify what benefits and harms they considered. We also considered the views of parents and healthcare professionals on the benefits and harms screening that creates for families and wider society. We found that the identification of benefits and harms of screening is complex because screening results affect a range of people (mother­baby, parents, extended family and wider society). Researchers calculating the value for money of screening programmes have, to date, concentrated on a narrow range of benefits and harms and ignored many factors that are important to people affected by screening results. From our discussions with parents and healthcare professionals, we found that wider impacts on families are an important consideration. Only one study we looked at considered wider impacts on families. Our work also found that parent's ability to recognise, absorb and apply new information to understand their child's screening results or condition is important. Healthcare professionals involve in screening should consider this when supporting families of children with a condition. We have created a list for researchers to identify the benefits and harms that are important to include in future studies. We have also identified different ways researchers can value these benefits and harms, so they are incorporated into their studies in a meaningful way.

Comparison of surgical or non-surgical management for non-acute anterior cruciate ligament injury: the ACL SNNAP RCT.

Background: Anterior cruciate ligament injury of the knee is common and leads to decreased activity and risk of secondary osteoarthritis of the knee. Management of patients with a non-acute anterior cruciate ligament injury can be non-surgical (rehabilitation) or surgical (reconstruction). However, insufficient evidence exists to guide treatment. Objective(s): To determine in patients with non-acute anterior cruciate ligament injury and symptoms of instability whether a strategy of surgical management (reconstruction) without prior rehabilitation was more clinically and cost-effective than non-surgical management (rehabilitation). Design: A pragmatic, multicentre, superiority, randomised controlled trial with two-arm parallel groups and 1:1 allocation. Due to the nature of the interventions, no blinding could be carried out. Setting: Twenty-nine NHS orthopaedic units in the United Kingdom. Participants: Participants with a symptomatic (instability) non-acute anterior cruciate ligament-injured knee. Interventions: Patients in the surgical management arm underwent surgical anterior cruciate ligament reconstruction as soon as possible and without any further rehabilitation. Patients in the rehabilitation arm attended physiotherapy sessions and only were listed for reconstructive surgery on continued instability following rehabilitation. Surgery following initial rehabilitation was an expected outcome for many patients and within protocol. Main outcome measures: The primary outcome was the Knee Injury and Osteoarthritis Outcome Score 4 at 18 months post randomisation. Secondary outcomes included return to sport/activity, intervention-related complications, patient satisfaction, expectations of activity, generic health quality of life, knee-specific quality of life and resource usage. Results: Three hundred and sixteen participants were recruited between February 2017 and April 2020 with 156 randomised to surgical management and 160 to rehabilitation. Forty-one per cent (n = 65) of those allocated to rehabilitation underwent subsequent reconstruction within 18 months with 38% (n = 61) completing rehabilitation and not undergoing surgery. Seventy-two per cent (n = 113) of those allocated to surgery underwent reconstruction within 18 months. Follow-up at the primary outcome time point was 78% (n = 248; surgical, n = 128; rehabilitation, n = 120). Both groups improved over time. Adjusted mean Knee Injury and Osteoarthritis Outcome Score 4 scores at 18 months had increased to 73.0 in the surgical arm and to 64.6 in the rehabilitation arm. The adjusted mean difference was 7.9 (95% confidence interval 2.5 to 13.2; p = 0.005) in favour of surgical management. The per-protocol analyses supported the intention-to-treat results, with all treatment effects favouring surgical management at a level reaching statistical significance. There was a significant difference in Tegner Activity Score at 18 months. Sixty-eight per cent (n = 65) of surgery patients did not reach their expected activity level compared to 73% (n = 63) in the rehabilitation arm. There were no differences between groups in surgical complications (n = 1 surgery, n = 2 rehab) or clinical events (n = 11 surgery, n = 12 rehab). Of surgery patients, 82.9% were satisfied compared to 68.1% of rehabilitation patients. Health economic analysis found that surgical management led to improved health-related quality of life compared to non-surgical management (0.052 quality-adjusted life-years, p = 0.177), but with higher NHS healthcare costs (£1107, p < 0.001). The incremental cost-effectiveness ratio for the surgical management programme versus rehabilitation was £19,346 per quality-adjusted life-year gained. Using £20,000-30,000 per quality-adjusted life-year thresholds, surgical management is cost-effective in the UK setting with a probability of being the most cost-effective option at 51% and 72%, respectively. Limitations: Not all surgical patients underwent reconstruction, but this did not affect trial interpretation. The adherence to physiotherapy was patchy, but the trial was designed as pragmatic. Conclusions: Surgical management (reconstruction) for non-acute anterior cruciate ligament-injured patients was superior to non-surgical management (rehabilitation). Although physiotherapy can still provide benefit, later-presenting non-acute anterior cruciate ligament-injured patients benefit more from surgical reconstruction without delaying for a prior period of rehabilitation. Future work: Confirmatory studies and those to explore the influence of fidelity and compliance will be useful. Trial registration: This trial is registered as Current Controlled Trials ISRCTN10110685; ClinicalTrials.gov Identifier: NCT02980367. Funding: This award was funded by the National Institute of Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 14/140/63) and is published in full in Health Technology Assessment; Vol. 28, No. 27. See the NIHR Funding and Awards website for further award information.

The study aimed to find out whether it is better to offer surgical reconstruction or rehabilitation first to patients with a more long-standing injury of their anterior cruciate ligament in their knee. This injury causes physical giving way of the knee and/or sensations of it being wobbly (instability). The instability can affect daily activities, work, sport and can lead to arthritis. There are two main treatment options for this problem: non-surgical rehabilitation (prescribed exercises and advice from physiotherapists) or an operation by a surgeon to replace the damaged ligament (anterior cruciate ligament reconstruction). Although studies have highlighted the best option for a recently injured knee, the best management was not known for patients with a long-standing injury, perhaps occurring several months previously. Because the surgery is expensive to the NHS (around £100 million per year), it was also important to look at the costs involved. We carried out a study recruiting 316 non-acute anterior cruciate ligament-injured patients from 29 different hospitals and allocated each patient to either surgery or rehabilitation as their treatment option. We measured how well they did with special function and activity scores, patient satisfaction and costs of treatment. Patients in both groups improved substantially. It was expected that some patients in the rehabilitation group would want surgery if non-surgical management was unsuccessful. Forty-one per cent of patients who initially underwent rehabilitation subsequently elected to have reconstructive surgery. Overall, the patients allocated to the surgical reconstruction group had better results in terms of knee function and stability, activity level and satisfaction with treatment than patients allocated to the non-operative rehabilitation group. There were few problems or complications with either treatment option. Although the surgery was a more expensive treatment option, it was found to be cost-effective in the UK setting. The evidence can be discussed in shared decision-making with anterior cruciate ligament-injured patients. Both strategies of management led to improvement. Although a rehabilitation strategy can be beneficial, especially for recently injured patients, it is advised that later-presenting non-acute and more long-standing anterior cruciate ligament-injured patients undergo surgical reconstruction without necessarily delaying for a period of rehabilitation.

Cefiderocol for treating severe aerobic Gram-negative bacterial infections: technology evaluation to inform a novel subscription-style payment model.

Background: To limit the use of antimicrobials without disincentivising the development of novel antimicrobials, there is interest in establishing innovative models that fund antimicrobials based on an evaluation of their value as opposed to the volumes used. The aim of this project was to evaluate the population-level health benefit of cefiderocol in the NHS in England, for the treatment of severe aerobic Gram-negative bacterial infections when used within its licensed indications. The results were used to inform the National Institute for Health and Care Excellence guidance in support of commercial discussions regarding contract value between the manufacturer and NHS England. Methods: The health benefit of cefiderocol was first derived for a series of high-value clinical scenarios. These represented uses that were expected to have a significant impact on patients' mortality risks and health-related quality of life. The clinical effectiveness of cefiderocol relative to its comparators was estimated by synthesising evidence on susceptibility of the pathogens of interest to the antimicrobials in a network meta-analysis. Patient-level costs and health outcomes of cefiderocol under various usage scenarios compared with alternative management strategies were quantified using decision modelling. Results were reported as incremental net health effects expressed in quality-adjusted life-years, which were scaled to 20-year population values using infection number forecasts based on data from Public Health England. The outcomes estimated for the high-value clinical scenarios were extrapolated to other expected uses for cefiderocol. Results: Among Enterobacterales isolates with the metallo-beta-lactamase resistance mechanism, the base-case network meta-analysis found that cefiderocol was associated with a lower susceptibility relative to colistin (odds ratio 0.32, 95% credible intervals 0.04 to 2.47), but the result was not statistically significant. The other treatments were also associated with lower susceptibility than colistin, but the results were not statistically significant. In the metallo-beta-lactamase Pseudomonas aeruginosa base-case network meta-analysis, cefiderocol was associated with a lower susceptibility relative to colistin (odds ratio 0.44, 95% credible intervals 0.03 to 3.94), but the result was not statistically significant. The other treatments were associated with no susceptibility. In the base case, patient-level benefit of cefiderocol was between 0.02 and 0.15 quality-adjusted life-years, depending on the site of infection, the pathogen and the usage scenario. There was a high degree of uncertainty surrounding the benefits of cefiderocol across all subgroups. There was substantial uncertainty in the number of infections that are suitable for treatment with cefiderocol, so population-level results are presented for a range of scenarios for the current infection numbers, the expected increases in infections over time and rates of emergence of resistance. The population-level benefits varied substantially across the base-case scenarios, from 896 to 3559 quality-adjusted life-years over 20 years. Conclusion: This work has provided quantitative estimates of the value of cefiderocol within its areas of expected usage within the NHS. Limitations: Given existing evidence, the estimates of the value of cefiderocol are highly uncertain. Future work: Future evaluations of antimicrobials would benefit from improvements to NHS data linkages; research to support appropriate synthesis of susceptibility studies; and application of routine data and decision modelling to assess enablement value. Study registration: No registration of this study was undertaken. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment Policy Research Programme (NIHR award ref: NIHR135591), conducted through the Policy Research Unit in Economic Methods of Evaluation in Health and Social Care Interventions, PR-PRU-1217-20401, and is published in full in Health Technology Assessment; Vol. 28, No. 28. See the NIHR Funding and Awards website for further award information.

This project tested new methods for estimating the value to the NHS of an antimicrobial, cefiderocol, so its manufacturer could be paid fairly even if very little drug is used in order to reduce the risk of bacteria becoming resistant to the product. Clinicians said that the greatest benefit of cefiderocol is when used for complicated urinary tract infections and pneumonia acquired within hospitals caused by two types of bacteria (called Enterobacterales and Pseudomonas aeruginosa), with a resistance mechanism called metallo-beta-lactamase. Because there were no relevant clinical trial data, we estimated how effective cefiderocol and alternative treatments were by doing a systematic literature review of studies that grew bacteria from infections in the laboratory and tested the drugs on them. We linked this to data estimating the long-term health and survival of patients. Some evidence was obtained by asking clinicians detailed questions about what they thought the effects would be based on their experience and the available evidence. We included the side effects of the alternative treatments, some of which can cause kidney damage. We estimated how many infections there would be in the UK, whether they would increase over time and how resistance to treatments may change over time. Clinicians told us that they would also use cefiderocol to treat intra-abdominal and bloodstream infections, and some infections caused by another bacteria called Stenotrophomonas. We estimated how many of these infections there would be, and assumed the same health benefits as for other types of infections. The total value to the NHS was calculated using these estimates. We also considered whether we had missed any additional elements of value. We estimated that the value to the NHS was £18­71 million over 20 years. This reflects the maximum the NHS could pay for use of cefiderocol if the health lost as a result of making these payments rather than funding other NHS services is not to exceed the health benefits of using this antimicrobial. However, these estimates are uncertain due to limitations with the evidence used to produce them and assumptions that had to be made.

Laparoscopic cholecystectomy versus conservative management for adults with uncomplicated symptomatic gallstones: the C-GALL RCT.

Background: Gallstone disease is a common gastrointestinal disorder in industrialised societies. The prevalence of gallstones in the adult population is estimated to be approximately 10-15%, and around 80% remain asymptomatic. At present, cholecystectomy is the default option for people with symptomatic gallstone disease. Objectives: To assess the clinical and cost-effectiveness of observation/conservative management compared with laparoscopic cholecystectomy for preventing recurrent symptoms and complications in adults presenting with uncomplicated symptomatic gallstones in secondary care. Design: Parallel group, multicentre patient randomised superiority pragmatic trial with up to 24 months follow-up and embedded qualitative research. Within-trial cost-utility and 10-year Markov model analyses. Development of a core outcome set for uncomplicated symptomatic gallstone disease. Setting: Secondary care elective settings. Participants: Adults with symptomatic uncomplicated gallstone disease referred to a secondary care setting were considered for inclusion. Interventions: Participants were randomised 1: 1 at clinic to receive either laparoscopic cholecystectomy or observation/conservative management. Main outcome measures: The primary outcome was quality of life measured by area under the curve over 18 months using the Short Form-36 bodily pain domain. Secondary outcomes included the Otago gallstones' condition-specific questionnaire, Short Form-36 domains (excluding bodily pain), area under the curve over 24 months for Short Form-36 bodily pain domain, persistent symptoms, complications and need for further treatment. No outcomes were blinded to allocation. Results: Between August 2016 and November 2019, 434 participants were randomised (217 in each group) from 20 United Kingdom centres. By 24 months, 64 (29.5%) in the observation/conservative management group and 153 (70.5%) in the laparoscopic cholecystectomy group had received surgery, median time to surgery of 9.0 months (interquartile range, 5.6-15.0) and 4.7 months (interquartile range 2.6-7.9), respectively. At 18 months, the mean Short Form-36 norm-based bodily pain score was 49.4 (standard deviation 11.7) in the observation/conservative management group and 50.4 (standard deviation 11.6) in the laparoscopic cholecystectomy group. The mean area under the curve over 18 months was 46.8 for both groups with no difference: mean difference -0.0, 95% confidence interval (-1.7 to 1.7); p-value 0.996; n = 203 observation/conservative, n = 205 cholecystectomy. There was no evidence of differences in quality of life, complications or need for further treatment at up to 24 months follow-up. Condition-specific quality of life at 24 months favoured cholecystectomy: mean difference 9.0, 95% confidence interval (4.1 to 14.0), p < 0.001 with a similar pattern for the persistent symptoms score. Within-trial cost-utility analysis found observation/conservative management over 24 months was less costly than cholecystectomy (mean difference -£1033). A non-significant quality-adjusted life-year difference of -0.019 favouring cholecystectomy resulted in an incremental cost-effectiveness ratio of £55,235. The Markov model continued to favour observation/conservative management, but some scenarios reversed the findings due to uncertainties in longer-term quality of life. The core outcome set included 11 critically important outcomes from both patients and healthcare professionals. Conclusions: The results suggested that in the short term (up to 24 months) observation/conservative management may be a cost-effective use of National Health Service resources in selected patients, but subsequent surgeries in the randomised groups and differences in quality of life beyond 24 months could reverse this finding. Future research should focus on longer-term follow-up data and identification of the cohort of patients that should be routinely offered surgery. Trial registration: This trial is registered as ISRCTN55215960. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 14/192/71) and is published in full in Health Technology Assessment; Vol. 28, No. 26. See the NIHR Funding and Awards website for further award information.

The C-GALL study assessed the benefits, in terms of symptoms, quality of life and costs, of cholecystectomy versus observation (conservative management: by the patient and general practitioner that might include dietary advice and pain management and surgery if needed). Four hundred and thirty-four patients with symptomatic gallstones were randomly allocated surgery or conservative management. The main symptom of ongoing bodily pain and some other quality-of-life measures were assessed over the next 2 years using postal questionnaires. After 2 years, 70% of those allocated to surgery had been operated on and 37% of the observation group either had an operation or were waiting for one. There was no difference in bodily pain or overall quality of life between the groups. However, participants in the surgery group reported fewer ongoing problems related to their gallstone disease or after surgery than those in the conservative management group. Surgery was, however, more costly than conservative management. The C-GALL study has shown that for some patients, a conservative management approach may be a sufficient and less costly way of managing their gallstone symptoms rather than going straight on the waiting list for surgery. More research is needed to identify which patients benefit most from surgery.

Peripherally inserted central catheter design and material for reducing catheter failure and complications.

BACKGROUND: Peripherally inserted central catheters (PICCs) facilitate diagnostic and therapeutic interventions in health care. PICCs can fail due to infective and non-infective complications, which PICC materials and design may contribute to, leading to negative sequelae for patients and healthcare systems. OBJECTIVES: To assess the effectiveness of PICC material and design in reducing catheter failure and complications. SEARCH METHODS: The University of Queensland and Cochrane Vascular Information Specialist searched the Cochrane Vascular Specialised Register, CENTRAL, MEDLINE, Embase, and CINAHL databases and the WHO ICTRP and ClinicalTrials.gov trials registers to 16 May 2023. We aimed to identify other potentially eligible trials or ancillary publications by searching the reference lists of retrieved included trials, as well as relevant systematic reviews, meta-analyses, and health technology assessment reports. We contacted experts in the field to ascertain additional relevant information. SELECTION CRITERIA: We included randomised controlled trials (RCTs) evaluating PICC design and materials. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Our primary outcomes were venous thromboembolism (VTE), PICC-associated bloodstream infection (BSI), occlusion, and all-cause mortality. Secondary outcomes were catheter failure, PICC-related BSI, catheter breakage, PICC dwell time, and safety endpoints. We assessed the certainty of evidence using GRADE. MAIN RESULTS: We included 12 RCTs involving approximately 2913 participants (one multi-arm study). All studies except one had a high risk of bias in one or more risk of bias domain. Integrated valve technology compared to no valve technology for peripherally inserted central catheter design Integrated valve technology may make little or no difference to VTE risk when compared with PICCs with no valve (risk ratio (RR) 0.71, 95% confidence interval (CI) 0.19 to 2.63; I² = 0%; 3 studies; 437 participants; low certainty evidence). We are uncertain whether integrated valve technology reduces PICC-associated BSI risk, as the certainty of the evidence is very low (RR 0.20, 95% CI 0.01 to 4.00; I² = not applicable; 2 studies (no events in 1 study); 257 participants). Integrated valve technology may make little or no difference to occlusion risk when compared with PICCs with no valve (RR 0.86, 95% CI 0.53 to 1.38; I² = 0%; 5 studies; 900 participants; low certainty evidence). We are uncertain whether use of integrated valve technology reduces all-cause mortality risk, as the certainty of evidence is very low (RR 0.85, 95% CI 0.44 to 1.64; I² = 0%; 2 studies; 473 participants). Integrated valve technology may make little or no difference to catheter failure risk when compared with PICCs with no valve (RR 0.80, 95% CI 0.62 to 1.03; I² = 0%; 4 studies; 720 participants; low certainty evidence). We are uncertain whether integrated-valve technology reduces PICC-related BSI risk (RR 0.51, 95% CI 0.19 to 1.32; I² = not applicable; 2 studies (no events in 1 study); 542 participants) or catheter breakage, as the certainty of evidence is very low (RR 1.05, 95% CI 0.22 to 5.06; I² = 20%; 4 studies; 799 participants). Anti-thrombogenic surface modification compared to no anti-thrombogenic surface modification for peripherally inserted central catheter design We are uncertain whether use of anti-thrombogenic surface modified catheters reduces risk of VTE (RR 0.67, 95% CI 0.13 to 3.54; I² = 15%; 2 studies; 257 participants) or PICC-associated BSI, as the certainty of evidence is very low (RR 0.20, 95% CI 0.01 to 4.00; I² = not applicable; 2 studies (no events in 1 study); 257 participants). We are uncertain whether use of anti-thrombogenic surface modified catheters reduces occlusion (RR 0.69, 95% CI 0.04 to 11.22; I² = 70%; 2 studies; 257 participants) or all-cause mortality risk, as the certainty of evidence is very low (RR 0.49, 95% CI 0.05 to 5.26; I² = not applicable; 1 study; 111 participants). Use of anti-thrombogenic surface modified catheters may make little or no difference to risk of catheter failure (RR 0.76, 95% CI 0.37 to 1.54; I² = 46%; 2 studies; 257 participants; low certainty evidence). No PICC-related BSIs were reported in one study (111 participants). As such, we are uncertain whether use of anti-thrombogenic surface modified catheters reduces PICC-related BSI risk (RR not estimable; I² = not applicable; very low certainty evidence). We are uncertain whether use of anti-thrombogenic surface modified catheters reduces the risk of catheter breakage, as the certainty of evidence is very low (RR 0.15, 95% CI 0.01 to 2.79; I² = not applicable; 2 studies (no events in 1 study); 257 participants). Antimicrobial impregnation compared to non-antimicrobial impregnation for peripherally inserted central catheter design We are uncertain whether use of antimicrobial-impregnated catheters reduces VTE risk (RR 0.54, 95% CI 0.05 to 5.88; I² = not applicable; 1 study; 167 participants) or PICC-associated BSI risk, as the certainty of evidence is very low (RR 2.17, 95% CI 0.20 to 23.53; I² = not applicable; 1 study; 167 participants). Antimicrobial-impregnated catheters probably make little or no difference to occlusion risk (RR 1.00, 95% CI 0.57 to 1.74; I² = 0%; 2 studies; 1025 participants; moderate certainty evidence) or all-cause mortality (RR 1.12, 95% CI 0.71 to 1.75; I² = 0%; 2 studies; 1082 participants; moderate certainty evidence). Antimicrobial-impregnated catheters may make little or no difference to risk of catheter failure (RR 1.04, 95% CI 0.82 to 1.30; I² = not applicable; 1 study; 221 participants; low certainty evidence). Antimicrobial-impregnated catheters probably make little or no difference to PICC-related BSI risk (RR 1.05, 95% CI 0.71 to 1.55; I² = not applicable; 2 studies (no events in 1 study); 1082 participants; moderate certainty evidence). Antimicrobial-impregnated catheters may make little or no difference to risk of catheter breakage (RR 0.86, 95% CI 0.19 to 3.83; I² = not applicable; 1 study; 804 participants; low certainty evidence). AUTHORS' CONCLUSIONS: There is limited high-quality RCT evidence available to inform clinician decision-making for PICC materials and design. Limitations of the current evidence include small sample sizes, infrequent events, and risk of bias. There may be little to no difference in the risk of VTE, PICC-associated BSI, occlusion, or mortality across PICC materials and designs. Further rigorous RCTs are needed to reduce uncertainty.