Reasons for supply side driven drug shortages - A mixed-methods study on first-level, higher-level, and root causes from the perspective of marketing authorization holders.

BACKGROUND: Drug shortages impact multiple stakeholders and are detrimental to patient safety. Additionally, drug shortages are an extensive financial burden. In Germany, drug shortages, according to data from the federal ministry for drug and medical products (BfArM), have been increasing by 18% between 2018 and 2021. Studies show that shortages are most frequently supply side driven and that often reasons remain unknown. OBJECTIVE: The aim is to develop a holistic understanding of supply side causes for drug shortages in Germany from marketing authorization holders' perspectives and to derive implications for shortage mitigation. METHODS: A mixed-methods research design, with a grounded theory approach based on a structured literature review, BfArM data analysis, and semi-structured interviews, was used. RESULTS: Input factor supply issues, manufacturing issues, logistics issues, product recalls, and product discontinuations were identified as first-level causes. Furthermore, a theory on their connection to higher-level causes related to business decision-making, as well as root causes linked to regulations, company values, internal processes, market dynamics, external shocks, and macroeconomic factors, was developed. CONCLUSION: Actions to mitigate drug shortages in Germany (e.g., improving business processes, diversifying tender criteria) were derived. These may thus increase patient safety and decrease the financial burden on the healthcare system.

"Digital biomarkers" in preclinical heart failure models - a further step towards improved translational research.

Innovations in the development of novel heart failure therapies are essential to further increase the predictive value of early research findings. Animal models are still playing a pivotal role in 'translational research'. In recent years, the transferability from animal studies has been more and more critically discussed due to persistent high attrition rates in clinical trials. However, there is an increasing trend to implement mobile health devices in preclinical studies. These devices can increase the predictive value of animal models by providing more accurate and translatable data and protect from confounding factors. This review outlines the current prevalence and opportunities of these techniques in preclinical heart failure research studies to accelerate the integration of these important tools. A literature screening for preclinical heart failure studies in large animals implementing telemetry devices over the last decade was performed. Twelve out of 43 publications were included. A variety of different hemodynamic and cardiac parameters can be recorded in conscious state by means of telemetry devices in both, the animal model and the patient. The measurement quality is consistently rated as valid and robust. Mobile health technologies functioning as digital biomarkers represent a more predictive approach compared to the traditionally used invasive measurement techniques, due to the possibility of continuous data collection in the conscious animal. Furthermore, they help to implement the 3R concept (reduction, refinement, replacement) in animal research. Despite this, the use of these techniques in preclinical research has been restrained to date.

Healthcare Providers' Knowledge of Value-Based Care in Germany: An Adapted, Mixed-Methods Approach.

BACKGROUND: Value-Based Care (VBC) is being discussed to provide better outcomes to patients, with an aim to reimburse healthcare providers (HCPs) based on the quality of care they deliver. Little is known about German HCPs' knowledge of VBC. This study aims to investigate the knowledge of HCPs of VBC and to identify potential needs for further education toward implementation of VBC in Germany. METHODS: For evidence generation, we performed a literature search and conducted an online survey among HCPs at 89 hospitals across Germany. The questionnaire was based on published evidence and co-developed with an expert panel using a mixed methods approach. RESULTS: We found HCPs to believe that VBC is more applicable in surgery than internal medicine and that well-defined cycles of care are essential for its application. HCPs believe that VBC can reduce health care costs significantly. However, they also assume that implementing VBC will be challenging. CONCLUSIONS: The concept in general is well perceived, however, HCPs do not want to participate in any financial risk sharing. Installing an authority/independent agency that measures achieved value, digital transformation, and that improves the transition between the inpatient and the outpatient sectors are top interests of HCPs.

There's an app for that, but nobody's using it: Insights on improving patient access and adherence to digital therapeutics in Germany.

Background: Mobile health applications and their subset digital therapeutics-defined as evidence-based software interventions to prevent, manage, or treat a medical condition-offer great potential to improve patient care. However, such solutions often struggle to reach widespread adoption. Objective: This study seeks to explore healthcare stakeholders' roles and potential for fostering patient access and adherence to evidence-based digital therapeutics and thereby improve health outcomes from the perspective of digital therapeutics developers and distributors. Methods: Semi-structured qualitative and semiquantitative interviews were conducted with 19 experts from developers and distributors of digital therapeutics in Germany to discuss their perceived relevance of different healthcare stakeholders and strategies in promoting patient access and adherence to digital therapeutics. Results: Healthcare professionals were found to have the greatest potential to promote both access and patient adherence to digital therapeutics, followed by health insurers, pharmaceutical companies, and patients themselves. In terms of patient access, healthcare professionals have potential due to their ability to prescribe digital therapeutics. Other stakeholders' potential stems from their capacity to influence healthcare professionals prescription decision. In terms of patient adherence, only healthcare professionals are of high relevance by onboarding patients and monitoring digital therapeutics use. Most healthcare stakeholders currently do not fully leverage their potential. Further educating healthcare professionals and simplifying processes for them, empowering patients to seek treatment with digital therapeutics, and designing digital therapeutics' product features for better adherence can help improve patient access and adherence. Conclusions: Established healthcare stakeholders and digital therapeutics developers both need to take action to improve patient access and adherence to digital therapeutics. Several macro-level changes can support these efforts, including broader information dissemination, improved financial incentives, simplified prescription and activation processes, and a wider adoption of blended care and pay-for-performance payment models.

[GPs education about organ donation: what factors influence the success?] / Aufklärung über Organspende in der Hausarztpraxis : Welche Faktoren beeinflussen den Erfolg?

BACKGROUND: According to the new legislation on organ donation in Germany, general practitioners (GPs) should regularly inform and educate their patients about organ donation from March 1, 2022. This is because of the persistently low organ donation rate in Germany. So far, there is a lack of information about the factors influencing the medical education of patients regarding organ donation provided by GPs. METHOD: GPs were surveyed via a web-based questionnaire in November and December 2021. 215 data sets have been utilized. RESULTS: GPs see themselves in charge for educating people about organ donation (86%). However, most of them invest little time in educating patients. 75% of GPs think that there is no time available for educational talks in the daily routine and 80% perceive difficulties in raising the issue of organ donation due to social taboos. Only 24% of GPs are aware of the new legislation. Only half of the respondents feel sufficiently informed to provide information about organ donation. On average, GPs consider a reimbursement of about 40 euros to be appropriate. CONCLUSIONS: GPs have not dealt much with the topic of organ donation and need more comprehensive information for the education of patients. GPs require more time to accommodate education in everyday life. Younger citizens can only be reached by GPs to a limited extent. This group must be addressed by other means.

Toward the institutionalization of quantum computing in pharmaceutical research.

Innovative pharmaceutical companies have started to explore quantum computing (QC). In this article, we provide a collective industry perspective from QC domain leaders at leading pharmaceutical companies. There are immediate nonfinancial benefits in engaging with QC, some likely financial returns in the short term in drug development, manufacturing, and supply chain, and potentially large scientific benefits in drug discovery long term. We discuss the required activities for institutionalizing QC: how to create an understanding of QC among researchers and management, which and how to deploy external resources, and how to identify the problems to be addressed with QC. If (and once) deployable, QC will likely have a similar trajectory to that of computer-aided drug design (CADD) and artificial intelligence (AI) during the 1990s and 2010s, respectively.

Perspective of German medical faculties on digitization in the healthcare sector and its influence on the curriculum.

Background: The German healthcare sector is in the process of being disrupted by digitization. Universities are asked to reflect on the consequences and develop strategies to prepare their medical students for a digitalized health care sector. The current state of research does not systematically record the associated activities of individual medical faculties in Germany. Objective: This study was designed to survey the status-quo of how German medical faculties view the digitization progress and to what extend digital capability building is already integrated into the curricula. Methods: A questionnaire with three focus areas was developed: Firstly, the general view of the medical faculties on digitization; secondly, concrete measures to prepare students for digital change and thirdly, the overarching organizational and regulatory conditions. The data was collected through short, questionnaire-based telephone interviews among those responsible for the curriculum at their faculty. The datasets collected were anonymized and statistically evaluated. Results: 30 interviews were conducted. The majority of faculty representatives agreed that digitization will change the role of physicians (87% agreement). Changes caused by individual digitization trends were however viewed to be less likely, e.g., whether medical expertise will become less important due to digital assistance systems (20% agreement), whether physician positions will be replaced by robots and algorithms (7% agreement), or whether hierarchies in hospitals will flatten (13% agreement). Digitization was seen to be of major importance for medical studies (93% agreement). Associated content should be given a higher priority in the curriculum (87% agreement). Two-thirds of faculty representatives believed that overarching institutions such as politics and medical associations ought to have more concrete plans for implementing the digital transformation and that innovations should be implemented in practice faster. Conclusion: While most faculty representatives attach great importance to the digitization of the health care system for university education, various questions about structural teaching measures to prepare students for the digital change show that there is no uniform education of medical students for a digitized health care system. We were also able to show that most faculty representatives are dissatisfied with the regulatory and organizational conditions of digitization in the medical sector.

Physicians' Attitudes Toward Prescribable mHealth Apps and Implications for Adoption in Germany: Mixed Methods Study.

BACKGROUND: In October 2020, Germany became the first country, worldwide, to approve certain mobile health (mHealth) apps, referred to as DiGA (Digitale Gesundheitsanwendungen, in German, meaning digital health applications), for prescription with costs covered by standard statutory health insurance. Yet, this option has only been used to a limited extent so far. OBJECTIVE: The aim of this study was to investigate physicians' and psychotherapists' current attitudes toward mHealth apps, barriers to adoption, and potential remedies. METHODS: We conducted a two-stage sequential mixed methods study. In phase one, semistructured interviews were conducted with physicians and psychotherapists for questionnaire design. In phase two, an online survey was conducted among general practitioners, physicians, and psychotherapists. RESULTS: A total of 1308 survey responses by mostly outpatient-care general practitioners, physicians, and psychotherapists from across Germany who could prescribe DiGA were recorded, making this the largest study on mHealth prescriptions to date. A total of 62.1% (807/1299) of respondents supported the opportunity to prescribe DiGA. Improved adherence (997/1294, 77.0%), health literacy (842/1294, 65.1%), and disease management (783/1294, 60.5%) were most frequently seen as benefits of DiGA. However, only 30.3% (393/1299) of respondents planned to prescribe DiGA, varying greatly by medical specialty. Professionals are still facing substantial barriers, such as insufficient information (1135/1295, 87.6%), reimbursement for DiGA-related medical services (716/1299, 55.1%), medical evidence (712/1298, 54.9%), legal uncertainties (680/1299, 52.3%), and technological uncertainties (658/1299, 50.7%). To support professionals who are unsure of prescribing DiGA, extended information campaigns (1104/1297, 85.1%) as well as recommendations from medical associations (1041/1297, 80.3%) and medical colleagues (1024/1297, 79.0%) were seen as the most impactful remedies. CONCLUSIONS: To realize the benefits from DiGA through increased adoption, additional information sharing about DiGA from trusted bodies, reimbursement for DiGA-related medical services, and further medical evidence are recommended.

[New German laws on organ donation-clinicians' perspectives on effects, potential and limitations]. / Die neue Gesetzgebung zur Organspende ­ Wirkung, Potenzial und Grenzen aus der Sicht klinisch tätiger Ärzt:innen.

BACKGROUND: The new German laws on organ donation of 2019 and 2020 intend to increase the organ donation rate. They include the optimization of organizational structures, the introduction of an online registry to document the patient's will and measures to improve information of the public. To date, little is known about clinicians' perspectives on these new laws. METHODS: We conducted a two-stage sequential-mixed-method study. As part of an online survey, 1235 physicians from more than 90 hospitals throughout Germany participated. RESULTS: Many clinicians name structural deficits as causes for the low donation rate in Germany. Less than half of the physicians who are exposed to organ donors regularly consider themselves to be adequately educated about organ donation. Physicians' educational discussions with patients have a significant influence on patients' decision-making but are rarely provided by doctors. In the decision-making situation, relatives are often overwhelmed because they have dealt with the topics of death and organ donation too little during their lifetime. General practitioners play a key role in educating and informing the population. Only a few respondents expect a positive impact on the organ donation rate by the introduction of an online donation registry. CONCLUSION: With the latest legislation, the most relevant structural deficits named by physicians have been addressed. An additional increase in organ donation rate could be achieved through professionalized care for relatives. A more frequent public discussion about death and organ donation could facilitate decision-making by relatives in individual cases.

sGC stimulation lowers elevated blood pressure in a new canine model of resistant hypertension.

Therapy-resistant hypertension is a serious medical problem, causing end-organ damage, stroke, and heart failure if untreated. Since the standard of care fails in resistant hypertension patients, there is still a substantial unmet medical need for effective therapies. Active stimulation of soluble guanylyl cyclase via novel soluble guanylyl cyclase stimulators might provide an effective treatment option. To test this hypothesis, we established a new experimental dog model and investigated the effects of the soluble guanylyl cyclase-stimulator BAY 41-2272. In beagle dogs, a resistant hypertension phenotype was established by combining unilateral renal wrapping with the occlusion of the renal artery in the contralateral kidney. The most frequently used antihypertensive drugs were administered orally, either alone or in combination, and their acute effect on telemetric measured blood pressure was assessed and compared with that of BAY 41-2272. The chosen disease stimulus led to a moderate and stable increase in blood pressure. Even high doses of standard-of-care antihypertensives only slightly decreased blood pressure. In contrast, the administration of the soluble guanylyl cyclase stimulator BAY 41-2272 as standalone therapy led to a dose-dependent reduction in blood pressure (-14.1 ± 1.8 mmHg). Moreover, BAY 41-2272 could also further decrease blood pressure in addition to a triple combination of standard-of-care antihypertensives (-28.6 ± 13.2 mmHg). BAY 41-2272 was highly efficient as a standalone treatment in resistant hypertension but was also effective in addition to standard-of-care treatment. These data strongly suggest that soluble guanylyl cyclase stimulators might provide an effective pharmacologic therapy for patients with resistant hypertension.

Quantum computing's potential for drug discovery: Early stage industry dynamics.

Quantum computing (QC) is expected to revolutionize drug research by performing tasks classical supercomputers are not capable of. However, practically useful quantum computation is not yet a reality, and thus it is still unclear when and whether QC will be capable of solving real-world issues in drug discovery. By identifying the QC-related activities of pharmaceutical companies, startups, and academia in the field of drug discovery and development, we show that QC has gained traction across all of these stakeholder groups, that there is focus on developing utilities related to lead optimization and compound screening, and that there is a need for collaboration in the highly dynamic QC ecosystem.

Multicenter Analysis of Acquired Undescended Testis and Its Impact on the Timing of Orchidopexy.

OBJECTIVE: To assess whether late orchidopexy for undescended testis represents delayed treatment of primary undescended testis or later-occurring acquired undescended testis. STUDY DESIGN: We examined boys undergoing orchidopexy for cryptorchidism regarding age at surgery and entity of undescended testis. We characterized differences between primary undescended testis and acquired undescended testis and evaluated the knowledge regarding the diagnosis and management of acquired undescended testis among practicing physicians. We conducted an observational study using a mixed-method multicenter cross-sectional design. A total of 310 consecutive boys undergoing orchidopexy for undescended testis at 6 pediatric medical centers in Germany between April 2016 and June 2018 were investigated regarding testicular position at birth and age at surgery. In addition, a survey on acquired undescended testis management was carried out in 1017 multidisciplinary physicians and final-year medical students. RESULTS: Only 13% of all patients were operated on in their first year of life. Among patients with known previous testicular position (67%), primary undescended testis (n = 103) and acquired undescended testis (n = 104) were equally frequent. More than one-half (56%) of orchidopexies performed after the first year of life were due to acquired undescended testis. Remarkably, only 15% of physicians considered acquired undescended testis as an indication for late surgery. CONCLUSIONS: Acquired undescended testis is more common than previously perceived and accounts for a significant proportion of "late" orchidopexies in patients with undescended testis. Acquired undescended testis needs to be better recognized in clinical practice and screening should continue in older children with previously descended testes. TRIAL REGISTRATION: German Clinical Trials Registry: DRKS00015903.

Digital Competencies and Attitudes Toward Digital Adherence Solutions Among Elderly Patients Treated With Novel Anticoagulants: Qualitative Study.

BACKGROUND: Nonadherence to medication is a driver of morbidity and mortality, and complex medication regimens in patients with chronic diseases foster the problem. Digital technology might help, but despite numerous solutions being developed, none are currently widely used, and acceptance rates remain low, especially among the elderly. OBJECTIVE: This study aimed to better understand and operationalize how new digital solutions can be evaluated. Particularly, the goal was to identify factors that help digital approaches targeting adherence to become more widely accepted. METHODS: A qualitative study using a conceptual grounded theory approach was conducted. We included patients aged 65 years and older who routinely took new oral anticoagulants. To generate theses about the digital competencies of the target group with daily medication intake, face-to-face interviews were conducted, recorded, and anonymized. After coding the interviews, categories were generated, discussed, and combined with several theses until saturation of the statements was reached. RESULTS: The methodological approach led to the finding that after interviews in 20 of 77 potentially available patients, a saturation of statements was reached. The average patient's age was 75 years, and 50% (10/20) of the subjects were female. The data identified five main coding categories-Diseases and medicine, Technology, Autonomy, Patient narrative, and Attitude toward technologies-each including positive and negative subcategories. Main categories and subcategories were summarized as Adherence Radar, which can be considered as a framework to assess the potential of adherence solutions in the process of prototyping and can be applied to all adherence tools in a holistic manner. CONCLUSIONS: The Adherence Radar can be used to increase the acceptance rate of digital solutions targeting adherence. For a patient-centric design, an app should be adapted to the individual patient's needs. According to our results, this application should be based on gender and educational background as well as the individual physician-patient relationship. If used in a proper, individualized manner, digital adherence solutions could become a new cornerstone for the treatment of chronically ill individuals.

Perception of the Progressing Digitization and Transformation of the German Health Care System Among Experts and the Public: Mixed Methods Study.

BACKGROUND: Health care systems worldwide are struggling to keep rising costs at bay with only modest outcome improvement among many diseases. Digitization with technologies like Artificial Intelligence or Machine Learning algorithms might address this. Although digital technologies have been successfully applied in clinical studies the effect on the overall health care system so far was limited. The regulatory ecosystem or data privacy might be responsible, but other reasons may also predominate. OBJECTIVE: We analyzed how the digitization of the German health care market is currently perceived among different stakeholders and investigated reasons for its slow adaption. METHODS: This was a mixed methods study split into a qualitative Part A using the conceptual approach of the Grounded Theory and a quantitative Part B using the Delphi method. For Part A we interviewed experts in the health care system and converted the results into 17 hypotheses. The Delphi method consisted of an online survey which was sent to the participants via email and was available for three months. For the assessment of the 17 hypotheses, the participants were given a six-point Likert scale. The participants were grouped into patients, physicians, and providers of services within the German health care market. RESULTS: There was a strong alignment of opinions on the hypotheses between experts (N=21) and survey participants (N=733), with 70.5% overall agreement on 12/17 hypotheses. Physicians demonstrated the lowest level of agreement with the expert panel at 88% (15/17) disagreement, with the hypotheses "H8: Digitization in the health care system will free up jobs," and "H6: Digitization in the health care system will empower the patients," perceived to be in profound disagreement (P=.036 and P<.001, respectively). CONCLUSIONS: Despite the firm agreement among participants and experts regarding the impact of digitization on the health care system, physicians demonstrated a more negative attitude. We assume that this might be a factor contributing to the slow adoption of digitization in practice. Physicians might be struggling with changing power structures, so future measures to transform the market should involve them to a larger degree.

Test-Retest Reliability of Non-Invasive Cardiac Output Measurement during Exercise in Healthy Volunteers in Daily Clinical Routine / Confiabilidade Teste-Reteste de Medição Não-Invasiva de Débito Cardíaco durante Exercício em Voluntários Saudáveis sob Condições Clínicas de Rotina

Abstract Background: Thoracic bioreactance (TB), a noninvasive method for the measurement of cardiac output (CO), shows good test-retest reliability in healthy adults examined under research and resting conditions. Objective: In this study, we evaluate the test-retest reliability of CO and cardiac power (CPO) output assessment during exercise assessed by TB in healthy adults under routine clinical conditions. Methods: 25 test persons performed a symptom-limited graded cycling test in an outpatient office on two different days separated by one week. Cardiorespiratory (power output, VO2peak) and hemodynamic parameters (heart rate, stroke volume, CO, mean arterial pressure, CPO) were measured at rest and continuously under exercise using a spiroergometric system and bioreactance cardiograph (NICOM, Cheetah Medical). Results: After 8 participants were excluded due to measurement errors (outliers), there was no systematic bias in all parameters under all conditions (effect size: 0.2-0.6). We found that all noninvasively measured CO showed acceptable test-retest-reliability (intraclass correlation coefficient: 0.59-0.98; typical error: 0.3-1.8). Moreover, peak CPO showed better reliability (intraclass correlation coefficient: 0.80-0.85; effect size: 0.9-1.1) then the TB CO, thanks only to the superior reliability of MAP (intraclass correlation coefficient: 0.59-0.98; effect size: 0.3-1.8). Conclusion: Our findings preclude the clinical use of TB in healthy subject population when outliers are not identified.

Resumo Fundamento: A biorreatância torácica (BT), um método não invasivo destinado à medição do débito cardíaco (DC), mostra boa confiabilidade teste-reteste em adultos saudáveis examinados em condições de pesquisa e repouso. Objetivo: No presente estudo, avaliamos a confiabilidade teste-reteste da avaliação do DC e trabalho cardíaco (TC) durante exercício, avaliado por BT em adultos saudáveis sob condições clínicas de rotina. Métodos: 25 indivíduos realizaram teste ergométrico gradual sintoma-limitante em ambiente ambulatorial em dois dias diferentes, com intervalo de uma semana. Parâmetros cardiorrespiratórios (trabalho cardíaco, VO2máx) e hemodinâmicos (frequência cardíaca, volume sistólico, DC, pressão arterial média, TC) foram medidos em repouso e continuamente sob exercício utilizando sistema espiroergométrico e cardiógrafo de biorreatância (NICOM, Cheetah Medical). Resultados: Após 8 participantes terem sido excluídos devido a erros de medição (outliers), não houve viés sistemático em nenhum dos parâmetros em todas as condições (tamanho do efeito: 0,2-0,6). Observamos que todos os débitos cardíacos medidos de forma não invasiva apresentaram níveis aceitáveis de confiabilidade teste-reteste (coeficiente de correlação intraclasse: 0,59-0,98; erro típico: 0,3-1,8). Além disso, TC máximo apresentou melhor confiabilidade (coeficiente de correlação intraclasse: 0,80-0,85; tamanho do efeito: 0,9-1,1), seguido do DC pela BT, graças apenas à confiabilidade superior da PAM (coeficiente de correlação intraclasse: 0,59-0,98; tamanho do efeito: 0,3-1,8). Conclusão: Nossos achados impedem o uso clínico da BT em indivíduos saudáveis quando outliers não forem identificados.

Test-Retest Reliability of Non-Invasive Cardiac Output Measurement during Exercise in Healthy Volunteers in Daily Clinical Routine.

BACKGROUND: Thoracic bioreactance (TB), a noninvasive method for the measurement of cardiac output (CO), shows good test-retest reliability in healthy adults examined under research and resting conditions. OBJECTIVE: In this study, we evaluate the test-retest reliability of CO and cardiac power (CPO) output assessment during exercise assessed by TB in healthy adults under routine clinical conditions. METHODS: 25 test persons performed a symptom-limited graded cycling test in an outpatient office on two different days separated by one week. Cardiorespiratory (power output, VO2peak) and hemodynamic parameters (heart rate, stroke volume, CO, mean arterial pressure, CPO) were measured at rest and continuously under exercise using a spiroergometric system and bioreactance cardiograph (NICOM, Cheetah Medical). RESULTS: After 8 participants were excluded due to measurement errors (outliers), there was no systematic bias in all parameters under all conditions (effect size: 0.2-0.6). We found that all noninvasively measured CO showed acceptable test-retest-reliability (intraclass correlation coefficient: 0.59-0.98; typical error: 0.3-1.8). Moreover, peak CPO showed better reliability (intraclass correlation coefficient: 0.80-0.85; effect size: 0.9-1.1) then the TB CO, thanks only to the superior reliability of MAP (intraclass correlation coefficient: 0.59-0.98; effect size: 0.3-1.8). CONCLUSION: Our findings preclude the clinical use of TB in healthy subject population when outliers are not identified.

[The Polypill - A Practicable Approach?] / Die Polypill ­ Ein praktikables Konzept?

Polypills used in cardiovascular prevention contain combinations of aspirin, lipid-lowering drugs and blood pressure-lowering drugs. The use of polypills can improve adherence while physicians express concerns about therapy safety and flexibility.

A proof-of-concept trial of HELIOX with different fractions of helium in a human study modeling upper airway obstruction.

BACKGROUND: Helium in oxygen (HELIOX) can relieve airway obstruction and lower the work of breathing because it increases the threshold at which turbulent gas flow is induced. Less turbulent and more laminar flow lowers the work of breathing. According to guidelines, the fraction of Helium in HELIOX should be maximized (e.g. to 79%). Here, we investigate whether HELIOX with less than 60% of Helium is able to relieve the sensation of dyspnea in healthy volunteers. METHODS: 44 volunteers underwent resistive loading breathing different gases (medical air and HELIOX with a fraction of 25%, 50% or 75% helium in oxygen) in a double-blinded crossover design. Subjects rated their degree of dyspnea (primary outcome parameter) and the variability of noninvasively measured systolic blood pressure was assessed. RESULTS: Dyspnea was significantly reduced by HELIOX-containing mixtures with a fraction of helium of 25% or more. Similarly, blood pressure variability was reduced significantly even with helium 25% during respiratory loading with the higher load, whereas with the smaller load an effect could only be obtained with the highest helium fraction of 75%. CONCLUSION: In this clinical trial, HELIOX with less than 60% of helium in oxygen decreased the sensation of dyspnea and blood pressure variability, a surrogate parameter for airway obstruction. Therefore, higher oxygen fractions might be applied without losing the helium-related benefits for the treatment of upper airway obstruction. TRIAL REGISTRATION: Registration with clinical trials (NCT00788788) and EMA (EudraCT number: 2006-005289-37).

How soon will digital endpoints become a cornerstone for future drug development?

Digital technologies are transforming healthcare and will provide the basis for more patient-centric innovation in the pharmaceutical industry. Digital endpoints in clinical studies have the potential to drive innovation and reduce costly late-stage failures. This is also currently under consideration by regulatory agencies, such as the US Food and Drug Administration (FDA). The academic-industrial collaboration MOBILISED-D aims to implement and validate real-world walking speed (RWS) as a digital endpoint accepted by regulatory authorities as a first of its class. Previous work has shown that loss of mobility driven by chronic illness and frailty in older patients can be a relevant readout or effect of different diseases and various organ systems.