Use of Real-World Data and Evidence in Drug Development of Medicinal Products Centrally Authorized in Europe in 2018-2019.

Real-world data/real-world evidence (RWD/RWE) are considered to have a great potential to complement, in some cases, replace the evidence generated through randomized controlled trials. By tradition, use of RWD/RWE in the postauthorization phase is well-known, whereas published evidence of use in the pre-authorization phase of medicines development is lacking. The primary aim of this study was to identify and quantify the role of potential use of RWD/RWE (RWE signatures) during the pre-authorization phase, as presented in the initial marketing authorization applications of new medicines centrally evaluated with a positive opinion in 2018-2019 (n = 111) by the European Medicines Agency (EMA). Data for the study was retrieved from the evaluation overviews of the European Public Assessment Reports (EPARs), which reflect the scientific conclusions of the assessment process and are accessible through the EMA website. RWE signatures were extracted into an RWE Data Matrix, including 11 categories divided over 5 stages of the drug development lifecycle. Nearly all EPARs included RWE signatures for the discovery (98.2%) and life-cycle management (100.0%). Half of them included RWE signatures for the full development phase (48.6%) and for supporting regulatory decisions at the registration (46.8%), whereas over a third (35.1%) included RWE signatures for the early development. RWE signatures were more often seen for orphan and conditionally approved medicines. Oncology, hematology, and anti-infectives stood out as therapeutic areas with most RWE signatures in their full development phase. The findings bring unprecedented insights about the vast use of RWD/RWE in drug development supporting the regulatory decision making.

Precision oncology in metastatic colorectal cancer - from biology to medicine.

Remarkable progress has been made in the development of biomarker-driven targeted therapies for patients with multiple cancer types, including melanoma, breast and lung tumours, although precision oncology for patients with colorectal cancer (CRC) continues to lag behind. Nonetheless, the availability of patient-derived CRC models coupled with in vitro and in vivo pharmacological and functional analyses over the past decade has finally led to advances in the field. Gene-specific alterations are not the only determinants that can successfully direct the use of targeted therapy. Indeed, successful inhibition of BRAF or KRAS in metastatic CRCs driven by activating mutations in these genes requires combinations of drugs that inhibit the mutant protein while at the same time restraining adaptive resistance via CRC-specific EGFR-mediated feedback loops. The emerging paradigm is, therefore, that the intrinsic biology of CRC cells must be considered alongside the molecular profiles of individual tumours in order to successfully personalize treatment. In this Review, we outline how preclinical studies based on patient-derived models have informed the design of practice-changing clinical trials. The integration of these experiences into a common framework will reshape the future design of biology-informed clinical trials in this field.

Blueprint for cancer research: Critical gaps and opportunities.

We are experiencing a revolution in cancer. Advances in screening, targeted and immune therapies, big data, computational methodologies, and significant new knowledge of cancer biology are transforming the ways in which we prevent, detect, diagnose, treat, and survive cancer. These advances are enabling durable progress in the goal to achieve personalized cancer care. Despite these gains, more work is needed to develop better tools and strategies to limit cancer as a major health concern. One persistent gap is the inconsistent coordination among researchers and caregivers to implement evidence-based programs that rely on a fuller understanding of the molecular, cellular, and systems biology mechanisms underpinning different types of cancer. Here, the authors integrate conversations with over 90 leading cancer experts to highlight current challenges, encourage a robust and diverse national research portfolio, and capture timely opportunities to advance evidence-based approaches for all patients with cancer and for all communities.

Cannabidiol in the treatment of epilepsy: Current evidence and perspectives for further research.

The therapeutic potential of cannabidiol (CBD) in seizure disorders has been known for many years, but it is only in the last decade that major progress has been made in characterizing its preclinical and clinical properties as an antiseizure medication. The mechanisms responsible for protection against seizures are not fully understood, but they are likely to be multifactorial and to include, among others, antagonism of G protein-coupled receptor, desensitization of transient receptor potential vanilloid type 1 channels, potentiation of adenosine-mediated signaling, and enhancement of GABAergic transmission. CBD has a low and highly variable oral bioavailability, and can be a victim and perpetrator of many drug-drug interactions. A pharmaceutical-grade formulation of purified CBD derived from Cannabis sativa has been evaluated in several randomized placebo-controlled adjunctive-therapy trials, which resulted in its regulatory approval for the treatment of seizures associated with Dravet syndrome, Lennox-Gastaut syndrome and tuberous sclerosis complex. Interpretation of results of these trials, however, has been complicated by the occurrence of an interaction with clobazam, which leads to a prominent increase in the plasma concentration of the active metabolite N-desmethylclobazam in CBD-treated patients. Despite impressive advances, significant gaps in knowledge still remain. Areas that require further investigation include the mechanisms underlying the antiseizure activity of CBD in different syndromes, its pharmacokinetic profile in infants and children, potential relationships between plasma drug concentration and clinical response, interactions with other co-administered medications, potential efficacy in other epilepsy syndromes, and magnitude of antiseizure effects independent from interactions with clobazam. This article is part of the special issue on 'Cannabinoids'.

ENSAT registry-based randomized clinical trials for adrenocortical carcinoma.

Adrenocortical carcinoma (ACC) is an orphan disease lacking effective systemic treatment options. The low incidence of the disease and high cost of clinical trials are major obstacles in the search for improved treatment strategies. As a novel approach, registry-based clinical trials have been introduced in clinical research, so allowing for significant cost reduction, but without compromising scientific benefit. Herein, we describe how the European Network for the Study of Adrenal Tumours (ENSAT) could transform its current registry into one fit for a clinical trial infrastructure. The rationale to perform randomized registry-based trials in ACC is outlined including an analysis of relevant limitations and challenges. We summarize a survey on this concept among ENSAT members who expressed a strong interest in the concept and rated its scientific potential as high. Legal aspects, including ethical approval of registry-based randomization were identified as potential obstacles. Finally, we describe three potential randomized registry-based clinical trials in an adjuvant setting and for advanced disease with a high potential to be executed within the framework of an advanced ENSAT registry. Thus we, therefore, provide the basis for future registry-based trials for ACC patients. This could ultimately provide proof-of-principle of how to perform more effective randomized trials for an orphan disease.

Continuidad del cuidado / Continuity of care

El concepto de continuidad del cuidado (CoC) suele utilizarse para describir en qué medida los pacientes ven al mismo profesional a lo largo del tiempo, aunque más específicamente es un atributo o característica del proceso de atención de salud de un individuo en el que la calidad de la conexión y retroalimentación de los eventos que se suceden influyen en la experiencia final de sentirse cuidado. La CoC abarca diferentes dominios conceptuales: la continuidad de la información, de la relación y del manejo. Se han utilizado diferentes instrumentos de medición que pueden agruparse en herramientas elaboradas a partir de reportes de pacientes (como por ej., encuestas) o a partir de datos administrativos (como los indicadores de prestador usual de cuidados o el indicador de Bice y Boxerman). Existen también investigaciones que evaluaron el impacto sanitario de la CoC. Si bien muchas de ellas muestran gran heterogeneidad en cuanto a los indicadores y los desenlaces utilizados, se observa una tendencia clara que parece indicar que a mayor nivel de continuidad del cuidado, mejores resultados en salud. (AU)

The concept of continuity of care (CoC) is often used to describe the extent to which patients see the same professional over time, but more specifically it is an attribute or characteristic of an individual's health care process in which the quality of the connection and feedback of the events that follow influences the final experience of feeling cared for. CoC encompasses different conceptual domains: continuity of information, relationship, and management. Different measurement instruments have been used, which can be grouped into tools developed from patient reports (e.g. surveys) or from administrative data (e.g. usual caregiver indicators or the Bice & Boxerman indicator). There is also research that has assessed the health impact of CoC. While many of them show great heterogeneity in terms of the indicators and outcomes used, there is a clear trend that seems to indicate that the higher the level of continuity ofcare, the better the health outcomes. (AU)

Teleoncology: The Youngest Pillar of Oncology.

The core pillars of multimodal care of patients with cancer are surgical, radiation, and medical oncology. The global pandemic of coronavirus disease 2019 (COVID-19) has suddenly resurrected a new pillar in oncology care: teleoncology. With oncologists reaching out to patients through telemedicine, it is possible to evaluate and fulfill patients' needs; triage patients for elective procedures; screen them for influenza-like illness; provide them with guidance for hospital visits, if needed; and bridge oral medications and treatments when a hospital visit is not desirable because of any high risk-benefit ratio. Teleoncology can bring great reassurance to patients at times when reaching an oncology center is challenging, and more so in resource-constrained countries. Evidence-based treatment protocols, dispensable by teleoncology, already exist for many sites of cancer and they can provide a bridge to treatment when patients are unable to reach cancer centers for their standard treatment. The young pillar of teleoncology is going to remain much longer than COVID-19.

Integration of partners of young women with cancer in oncofertility evidence-based informational resources.

Oncofertility has evolved over the years, with a prodigious amount of research documenting the importance of fertility for young patients with cancer, and the potential impact that fertility impairments due to cancer treatments has on their Quality of Life (QoL). Multiple professional bodies and scientific societies have included fertility as an integral part of clinical management. Clinical guidelines advocate that health professionals have the duty to discuss the risk of infertility and fertility preservation options as early as possible and refer to fertility specialists when appropriate. Collectively, fertility decisions are regarded as difficult for both patients and providers. Since providing fertility-related information is vital for better decision making, researchers and policy makers have concentrated their efforts in developing educational tools to aid decisions and guidelines to optimize the delivery of this information, focusing mainly on patients-providers and largely neglecting the role and influence that partners play in this process. Here, we reflect on the importance of partners in fertility decisions, with a focus on the provision of fertility-related information that is also geared towards partner. We highlight the need to involve partners in fertility discussions, and that their needs should be taken into account in both clinical guidelines and in the development of educational tools, for an optimal decision-making process.

Medicinal plants utilized in Thai Traditional Medicine for diabetes treatment: Ethnobotanical surveys, scientific evidence and phytochemicals.

ETHNOPHARMACOLOGICAL RELEVANCE: Diabetes mellitus remains the most lethal metabolic disease of contemporaneous times and despite the therapeutic arsenal currently available, research on new antidiabetic agents remains a priority. In recent years, the revitalization of Thai Traditional Medicine (TTM) became a clear priority for the Thai government, and many efforts have been undertaken to accelerate research on herbal medicines and their use in medical services in various hospitals. Additionally, and particularly in rural areas, treatment of diabetes and associated symptomatology frequently relies on herbal preparations recommended by practitioners of TTM. In the current work, medicinal plants used in Thailand for treating diabetes, as well as their hypoglycaemic pharmacological evidences and potential therapeutic use for diabetes-related complications were reviewed. MATERIALS AND METHODS: Ethnopharmacological information on the plant materials used in TTM for diabetes treatment was collected through literature search in a range of scientific databases using the search terms: diabetes, folk medicine, Thailand medicinal plants, traditional medicine. Information regarding scientific evidence on the antidiabetic effects of surveyed species was obtained considering not only the most common taxonomic designation, but also taxonomic synonyms, and including the keywords 'diabetes' and 'hypoglycaemic effect'. RESULTS: A total of 183 species known to be used for diabetes management in TTM were reviewed, with 30% of them still lacking experimental evidences to support claims regarding the mechanisms and phytochemicals underlying their antidiabetic properties. Moreover, a total of 46 bioactives displaying effective antidiabetic effects have been isolated from 24 species, their underlying mechanism(s) of action being fully or partially disclosed. CONCLUSIONS: We deliver the most extensive survey dealing with the ethnomedicinal knowledge of Thai medicinal plants utilized on diabetes management. We are certain that the current review will spark further research on Thai plants for the development of new standardized phytomedicines through drug discovery programmes.

Ten Years of Sports Health: Authorship Characteristics and Levels of Evidence.

CONTEXT: Sports Health: A Multidisciplinary Approach, now 10 years into production, has been ranked a top-25 journal in sport sciences and has tripled its impact throughout its existence. OBJECTIVE: To evaluate authorship trends and levels of evidence (LOE) of articles published in Sports Health from 2009 to 2018. The secondary aim was to analyze funding sources and internationalization throughout the journal's tenure. DATA SOURCES: All clinical studies published in Sports Health between the years 2009 and 2018 were examined. STUDY SELECTION: All publications from the provided years were electronically reviewed by 2 reviewers and evaluated for inclusion criteria. Editorials, society news, memorials, letters to the editor, and corrigenda were excluded. STUDY DESIGN: Systematic review. LEVEL OF EVIDENCE: Level 5. DATA EXTRACTION: Articles were examined for number of authors, presence of female authorship, funding, country of origin, international collaboration, academic degree or certification of first and senior authors, and LOE. Clinical articles were assigned LOE based on guidelines from the University of Oxford's Centre for Evidence-Based Medicine. RESULTS: A total of 654 articles were examined. The percentage of high-LOE studies increased throughout the study period. The percentage of publications with female authors also increased throughout the study period. The mean number of authors per article increased from 3.2 to 4.6 over the 10-year period (P < 0.05). The percentage of publications with international collaboration stayed consistent, while the number of countries per year increased during the study period. Overall, institutions from 23 countries have published in Sports Health since its inception to the time of this study. CONCLUSION: Female authorship in Sports Health surpasses industry standards, and the percentage of high-LOE studies remains remarkably high. Sports Health has stayed true to its multidisciplinary scope, as evidenced by the authors' varying degrees and numerous countries that publish in the journal.

Epidemiological guideline influence on the therapeutic trend and patient outcome of uterine cervical cancer in Japan: Japan society of gynecologic oncology guideline evaluation committee project.

OBJECTIVE: The Japan Society of Gynecologic Oncology published its first clinical guidelines for uterine cervical cancer in 2007 which has been revised twice in 2011 and 2017. The aim of this study was to investigate the influence of the first guideline publication on the therapeutic trend and patient outcome by analyzing uterine cervical cancer cases registered to the cancer registry organized by the Japan Society of Obstetrics and Gynecology. METHODS: Data of uterine cervical cancer cases registered to the cancer registry from 2000 to 2012 were provided. Epidemiological and clinical trend were analyzed by the Chi-squared test with subsequent standardized residual analysis. Overall survival among the patients registered between 2004 and 2009 was analyzed using the Fine and Gray competing risk model. RESULTS: 68,707 cases were registered during the study period. A trend analysis revealed that the guideline publication may have led to a decrease in neoadjuvant chemotherapy in parallel with an increase in radiation therapy mainly in stage II and III patients undergoing primary treatment. A survival analysis indicated that the introduction of the guideline may have improved overall survival among stage III uterine cervical cancer patients, even though a significant difference was not observed in all of the cases. CONCLUSIONS: This study demonstrated the potential influence of the guideline publication on the clinical trend and patient outcome. As this is the first assessment of the guideline for uterine cervical cancer in Japan, continuous evaluation is necessary to further comprehend the significance of this guideline.

Local Ablative Therapies for Oligometastatic and Oligoprogressive Non-Small Cell Lung Cancer.

More than half of all patients with non-small cell lung cancer (NSCLC) have metastatic disease at the time of diagnosis. A subset of these patients has oligometastatic disease, which exists in an intermediary state between locoregional and disseminated metastatic disease. In addition, some metastatic patients on systemic therapy may have limited disease progression, or oligoprogression. Historically, treatment of metastatic NSCLC was palliative in nature, with little expectation of long-term survival. However, an accumulation of evidence over the past 3 decades now demonstrates that local ablative therapy to sites of limited metastases or progression can improve patient outcomes for this complex disease. This review examines the evidence behind local ablative therapy in oligometastatic and oligoprogressive NSCLC, with a focus on surgery, stereotactic radiotherapy, and radiofrequency ablation.

Oligometastatic and Oligoprogression Disease and Local Therapies in Prostate Cancer.

Our understanding of metastatic disease is rapidly advancing, with recent evidence supporting an oligometastatic state currently defined by patients having a limited (typically ≤5) number of metastatic deposits. The optimal management of these patients is also shifting toward increased integration of local therapies, with emerging evidence suggesting metastasis-directed therapy can improve overall survival. Additionally, the use of stereotactic ablative radiation therapy within castration-sensitive oligometastatic prostate cancer cohorts appears to forestall the need to initiate systemic therapy, which has unfavorable side effect profiles, such as androgen deprivation therapy, while itself being associated with little toxicity. We review the literature surrounding the use of metastasis-directed therapy in the treatment of oligometastatic prostate cancer by reviewing the evidence for its use within 3 subgroups: de novo synchronous, oligorecurrent, and oligoprogressive disease.

Oligometastatic Disease and Interventional Oncology: Rationale and Research Directions.

Oligometastatic disease (OMD) is generally defined as a stage of clinically or radiographically demonstrated metastatic disease limited in total disease burden and without rapid spread. Interventional oncology performs local therapies for primary and metastatic cancers, including OMD. Interventional oncology treatments can be pursued both as definitive therapy and for palliative purposes. Applied to OMD, these interventions can offer patients a decreasing overall tumor burden, minimizing cancer morbidity, and early evidence suggests a survival benefit. Here, we discuss the range of interventional oncology treatments, including ablation, chemoembolization, radioembolization, and irreversible electroporation. We describe the rationale for their application to OMD and discuss future directions for research.

An Update on Level of Evidence Trends in Facial Plastic Surgery Research.

Background: Knowledge of the quality of evidence in facial plastic surgery research is essential for the implementation of evidence-based practices. The purpose of this study is to provide an update over the past decade as to whether the level of evidence in leading journals featuring topics in facial plastic surgery has changed in comparison with prior reports. Materials and Methods: This study is a systematic review, designed to evaluate the level of evidence observed in the facial plastic surgery literature over time. Five journals were queried using facial plastic surgery keywords for four selected years for a 10-year period. After screening, articles were assessed for the presence of various methodological traits and were evaluated for overall level of evidence. These variables were compared across the years studied to evaluate trends in level of evidence. Results: A total of 826 articles were included for final review. For all selected years, level IV or level V evidence was the most prevalent level of evidence. Over time, significantly less level IV (p = 0.009) and significantly more level II (p = 0.007) evidence was published. The proportion of studies reporting confidence intervals (p < 0.001) and p-values (p = 0.02) were significantly greater in later years. Conclusions: The level of evidence of facial plastic surgery literature has increased over time, as demonstrated by an increased proportion of level II evidence, decreased proportion of level IV evidence, and increased use of p-values and confidence intervals. The absolute number of randomized controlled trials continues to remain low.