Search

Patients with rare diseases often have limited or no options for approved treatments or participation in clinical trials. In such cases, expanded access (or “compassionate use”) provides a potential means of accessing unapproved investigational medicines. It is also possible to capture and analyze clinical data from such use, but doing so is controversial. In this perspective, we offer examples of evidence derived from expanded access programs for rare diseases to illustrate its potential value to the decision-making of regulators and payers in the European Union and the United States. We discuss ethical and regulatory aspects to the use of expanded access data, with a focus on rare disease medicines. The heterogeneous approach to expanded access among countries within the European Union leaves uncertainties to what extent data can be collected and analyzed. We recommend the issuance of new guidance on data collection during expanded access, harmonization of European pathways, and an update of existing European compassionate use guidance. We hereby aim to clarify the supportive role of expanded access in evidence generation. Harmonization across Europe of expanded access regulations could reduce manufacturer burdens, improve patient access, and yield better data. These changes would better balance the need to generate quality evidence with the desire for pre-approval access to investigational medicine.

Objectives: Although vacuum-assisted excision (VAE) is a safe and effective alternative to surgical excision (SE), the latter is most commonly used for the management of benign and high-risk breast lesions. To evaluate the healthcare benefit of VAE, hospital costs and cosmetic outcome after VAE were compared to SE. Additionally, the impact of VAE implementation on hospital costs was investigated. Methods: This was a single-centre retrospective cohort study with two cohorts: “VAE” and “SE”. All patients with a benign or high-risk lesion excised by VAE or SE from January 2016 up to December 2019 were included. Cosmetic outcome was measured with the BCTOS-cosmetic subscale, and hospital costs were presented as mean (SD) and median (IQR). Results: During the study period, 258 patients with 295 excised lesions were included. The initial procedure was VAE in 102 patients and SE in 156 patients. Hospital costs after (median € 2324) were significantly lower than before (median € 3,144) implementation of VAE (mean difference € 1,004, p < 0.001), most likely attributable to the lower costs for patients treated with VAE (mean difference € 1,979, p < 0.001). Mean cosmetic outcome was comparable between VAE (median 1.35) and SE (median 1.44, p = 0.802). Conclusions: Implementing VAE as an alternative treatment option for benign and high-risk breast lesions resulted in a large decrease in hospital costs but a cosmetic benefit of VAE could not be demonstrated in this retrospective study. Advances in knowledge: Costs associated with the complete patient pathway were included and not only VAE was compared to SE but also the before cohort was compared to the after cohort to demonstrate the benefit of VAE implementation in clinical practice. Additionally, cosmetic outcome was compared between VAE and SE using patient reported outcome measures.

Regulatory authorization of oncology drugs, including immune-checkpoint inhibitors, is often based on enhanced efficacy and acceptable toxicity profiles, investigated in randomized, open-label clinical trials. Regulatory approval decisions of the United States (US) Food and Drug Administration (FDA) and the European Medicines Agency (EMA) are frequently compared and contrasted, specifically based on review requirements, and time to approval or refusal decisions. We reviewed databases of the US FDA, the EMA and Clinicaltrials.gov, from January 1, 2015 until December 31, 2021, and analyzed regulatory approvals for immune-checkpoint inhibitors in the treatment of non-small cell lung cancer (NSCLC). We specifically focused on time to approval duration of each immune-checkpoint inhibitor, and considerations of patient-reported outcomes (PROs) by each regulatory agency. Despite similarities in the regulatory pathways and methods used for immune-checkpoint inhibitor approvals, NSCLC indications that stood out in terms of outcome divergence were mainly first-line drugs for treatment naïve patients. The US FDA was quicker to reach approval decisions, when compared with the EMA. The US FDA and the EMA both recognize the value of PROs as important patient-centered endpoints. Policy statement: There are several regulatory structures in the US and Europe that aim to leverage the latest clinical trial evidence and speed up the regulatory approval processes. In our study, the preponderance of outcome differences in approvals were not influenced by the expedited drug development and access programs. Increased harmonization and collaboration on the PRO measurement and validation are encouraged among these agencies to improve the efficiency of regulatory decisions in the future.

We conducted a systematic literature review to identify and review the concepts and questionnaires used to assess the impact of caregiving on caregivers for adults with a mental disorder. With our study, we aimed to provide an overview and categorize the conceptualization and operationalization of the impact of caregiving, with special attention for the complexity and multi-conceptualization of concepts. Embase, Medline, PsycInfo, Web of Science Core Collection, Cochrane Central Register of Trials, Cinahl Plus, Econlit and Google Scholar were systematically searched for articles from 1 January 2004 to 31 December 2019. Eligible articles were peer-reviewed studies that assessed the impact of caregiving for informal caregivers of adults with a reported mental disorder by means of a questionnaire. The complete study protocol can be found on PROSPERO (CRD42020157300). A total of 144 questionnaires were identified that assessed the impact of caregiving. Based on similarities in meaning, concepts were classified into 15 concept clusters. The most frequently assessed concept clusters were mental health, caregiving burden, other caregiving consequences, family impact, and overall health-related outcomes. The use of concept clusters differed per diagnosis group, with diagnoses, such as schizophrenia, using a wide range of caregiving impact concepts and other diagnoses, such as personality disorders, only using a limited range of concepts. This is the first study that identified and reviewed the concepts and questionnaires that are used to assess the impact of caregiving. Caregiving is researched from a broad array of perspectives, with the identification of a variety of concepts and dimensions and use of non-specific questionnaires. Despite increasing interest in this field of research, a high degree of variability remains abundant with limited consensus. This can partially be accredited to differences in the naming of concepts. Ultimately, this review can serve as a referen

(1) Background: This study investigated how potential shifts in patients’ formal and informal care utilization during the COVID-19 pandemic impacted their informal caregivers in terms of their subjective burden, psychological wellbeing, and happiness. (2) Methods: A retrospective cohort study design was employed for a panel of Dutch informal caregivers of persons with mental health problems (n = 219) in June 2020. Descriptive statistics and differences between means were determined for the patients’ informal and care utilization and informal caregivers’ subjective burden, happiness, and psychological wellbeing. Three mediation analyses were conducted using the PROCESS macro. (3) Results: Informal caregivers reported significantly worse happiness and subjective burden scores during the COVID-19 pandemic compared with before the lockdown. There were minimal shifts in patient’s care utilization reported, with the exception of a decrease in significant emotional and practical support provided by the informal caregiver. In the mediation analyses, there was not a significant indirect effect of shifts in patients’ formal care utilization on informal caregivers’ subjective burden, psychological wellbeing, and happiness through shifts in patients’ informal care utilization. (4) Discussion and conclusion: Whilst we found that shifts in patients’ care utilization during the first wave of the pandemic did not affect the informal caregiver in the short term, it is unclear what the long-term impact of the pandemic might be on informal caregivers. More research should be conducted to understand the implications of short- and long-term impact of substitution on informal caregivers of persons with mental health problems, with special consideration of the COVID-19 context and uptake of e-health technology.

Background: Despite the need for a proper economic evaluation of new radiotherapies, the economic burden of radiotherapy-induced adverse effects remains unclear. A systematic review has been conducted to identify the existing evidence of healthcare resource use and costs related to radiotherapy-induced adverse effects and also to provide recommendations for including this evidence in economic evaluations. Methods: This systematic review of healthcare resource use and/or medical costs related to radiotherapy-induced adverse effects was performed up until 2020, focusing on patients with head and neck cancer, brain cancer, prostate cancer, eye cancer and breast cancer. Results: Resource use for treating the same adverse effects varied considerably across studies; for instance, the cost for mucositis ranged from USD 2949 to USD 17,244. This broad range could be related to differences in (1) severity of adverse effects in the study population, (2) study design, (3) cost estimation approach and (4) country and clinical practice. Conclusions: Our findings revealed unignorable differences for the same adverse effects, which implied that the potential for the economic burden of adverse effects was being overestimated or underestimated in economic evaluation for radiotherapy.

OBJECTIVES: Phase III cancer clinical trials are expensive and time-consuming phases in drug development. Effective patient enrolment can reduce delays and save costs, offering patients an opportunity to benefit from innovative treatments. However, the current evidence base does not fully explain the persistence of barriers to patient enrolment in phase III cancer clinical trials. The aim was to explore clinicians' and pharmaceutical representatives' views on these barriers. DESIGN: A qualitative study was performed. In-depth information was collected from 15 experts in the field of oncology clinical trials, in particular clinical oncologists acting as principal investigators (PIs) and clinical research associates. By means of semistructured interviews, based on a questionnaire derived from our newly developed conceptual framework, they were asked to identify barriers to patient enrolment they had experienced and comment on barriers identified in literature. FINDINGS: Existing knowledge on barriers to patient enrolment was confirmed by all interviewees. Two new key barriers to patient enrolment were identified, that is, insufficient attention to the importance of clinical trial-based research in medical training and a trust gap between PIs and pharmaceutical representatives. A third important barrier was increasingly narrow patient inclusion criteria. CONCLUSIONS: The success rate of patient enrolment in phase III cancer clinical trials highly depends on the clinicians' willingness to take part in clinical trials. Raising awareness of the importance of clinical trials in medical training and among practising oncologists is recommended. Furthermore, to reduce barriers to patient enrolment, it is essential that both clinicians and pharmaceutical representatives acknowledge each other's expertise, become acquainted with each other's procedures and regulations, and work on building trust relationships. Finally, in accordance with our key findings, we propose to add t

Background and Objectives: Endoxifen is the active metabolite of tamoxifen, and a minimal plasma concentration of 16 nM has been suggested as a threshold above which it is effective in reducing the risk of breast cancer recurrence. The aim of the current analysis was to investigate the cost-effectiveness of therapeutic drug monitoring (TDM)-guided tamoxifen dosing. Methods: A cost-effectiveness analysis was performed from a Dutch healthcare perspective, using a partitioned survival model and a lifetime horizon. The reduction in subtherapeutic treatment following TDM is modelled as improved rates of recurrence-free survival (RFS) and overall survival (OS) in comparison to standard tamoxifen treatment. A probabilistic sensitivity analysis (PSA) and a series of scenario analyses were performed to assess the robustness of the results. Results: Base-case results estimated a total increase in life years and quality-adjusted life years (QALYs) for TDM of 0.40 and 0.53, respectively. Total costs for TDM and standard tamoxifen treatment are €32,893 and €39,524, respectively. The TDM intervention results in both more QALYs and less healthcare costs, indicating a dominating effect for TDM. The PSA results indicate that the probability of TDM being cost-effective is 92% when using a willingness-to-pay threshold of €20,000. Conclusions: TDM-guided dose optimization of tamoxifen is estimated to save costs and increase QALYs for early breast cancer patients.