Patient-relevant Clinical Outcomes Research Articles

Initial surgical management of spinal injuries in patients with multiple and/or severe injuries- the 2022 update of the German clinical practice guideline.

Our aim was to update evidence-based and consensus-based recommendations for the initial surgical management of spinal (cord) injuries in patients with multiple and/or severe injuries based on current evidence. This guideline topic is part of the 2022 update of the German Guideline on the Treatment of Patients with Multiple and/or Severe Injuries. MEDLINE and Embase were systematically searched to May 2021. Further literature reports were obtained from clinical experts. Randomised controlled trials, prospective cohort studies, and comparative registry studies were included if they compared interventions and the timing of interventions for the initial surgical management of spinal (cord) injuries in patients with polytrauma and/or severe injuries. We considered patient-relevant clinical outcomes such as mortality, complication rates, and lengths of stay. Risk of bias was assessed using NICE 2012 checklists. The evidence was synthesised narratively, and expert consensus was used to develop recommendations and determine their strength. Seven new studies were identified. All studies compared different moments for the initial surgical management of spinal injuries. Three recommendations were modified, and three additional recommendations were developed. All achieved strong consensus. The following key recommendations are made. (1) Patients with spinal injuries or deformities with confirmed or assumed neurological deficits which can be treated operatively should undergo surgery as soon as possible (ideally on day 1) if their other medical conditions permit. (2) If suggested by fracture morphology with spinal canal compression or translational injury and if spinal neurological damage cannot be ruled out, assume the presence of spinal neurological damage until it can be ruled out. (3) In the absence of neurological signs and/or symptoms, unstable spinal injuries should be treated by early surgical stabilization based on the patient's overall condition. (4) Depending on the injury, an anterior and/or posterior approach or, in exceptional cases, a halo fixation device can be used to stabilize the cervical spine. (5) Posterior internal fixation should be used as the primary surgical technique for stabilizing injuries to the thoracic and lumbar spine.

Initial surgical management of injuries to the lower extremities in patients with multiple and/or severe injuries - A systematic review and clinical practice guideline update.

Our aim was to develop new evidence-based and consensus-based recommendations for the initial inhospital management of lower-extremity injuries in patients with multiple and/or severe trauma. This guideline topic is part of the 2022 update of the German Guideline on the Treatment of Patients with multiple and/or severe Injuries. MEDLINE and Embase were systematically searched to May 2021. Randomised controlled trials, prospective cohort studies, and comparative registry studies were included if they compared interventions for the initial surgical and non-surgical management of fractures, dislocations or vascular injuries of the lower extremities in patients with multiple and/or severe trauma. We considered patient-relevant clinical outcomes such as mortality, complication rates, length of stay, and function. Risk of bias was assessed using NICE 2012 checklists. The evidence was synthesised narratively, and expert consensus was used to develop recommendations and determine their strength. Eleven studies were identified. They addressed time to definitive fixation (n = 10 studies) and amputation (n = 1). Two new recommendations were developed, one was modified. All recommendations achieved strong consensus. This systematic literature review and subsequent expert consensus process resulted in the following new key recommendations. It is recommended that isolated and multiple lower-extremity fractures are managed with primary definitive fixation in patients whose condition is stable. Patients condition is not considered stable should be managed with primary temporary fixation. In addition, it is recommended that dislocations of the lower extremities are reduced and immobilised as early as possible.

PP02 Is Glycated Hemoglobin A Valid Surrogate Endpoint To Evaluate The Effectiveness Of Drugs In Diabetes Mellitus Studies?

IntroductionIn the field of drug development and effectiveness evaluation, the use of surrogate endpoints is acceptable if they reliably predict a positive effect on clinical outcomes such as mortality or morbidity. Hemoglobin A1c (HbA1c) is a widely used surrogate endpoint in phase 3 and 4 clinical trials evaluating drugs in patients with diabetes mellitus (DM). The objective of this study was to investigate whether HbA1c is a valid surrogate endpoint for evaluating the effectiveness of antihyperglycemic drugs in DM trials.MethodsWe conducted a systematic review of randomized placebo-controlled trials evaluating the effect of a treatment on levels of HbA1c and clinical outcomes in patients with DM. The association between the effects of treatment on HbA1c levels and clinical outcomes was then investigated using regression analysis at the trial level. The correlation coefficients (R) were interpreted using the cut-off points suggested by the German Institute for Quality and Efficiency in Health Care (IQWiG). HbA1c was considered a valid surrogate endpoint if it demonstrated a strong association with clinical outcomes (i.e., the lower limit of the 95% confidence interval [CI] of R≥ 0.85).ResultsNineteen phase 3 or 4 randomized controlled trials (RCTs) were identified. All studies included adults with type 2 DM. None of the associations evaluated was strong enough to validate HbA1c as a surrogate endpoint for any clinical outcome: mortality (R 0.34, 95% CI: -0.14, 0.69); myocardial infarction (R 0.20, 95% CI: -0.30, 0.61); heart failure (R 0.08, 95% CI: -0.40, 0.53); kidney injury (R -0.04, 95% CI: -0.52, 0.47); and stroke (R 0.81, 95% CI: 0.54, 0.93).ConclusionsThe evidence from multiple placebo-controlled RCTs of antihyperglycemic drugs in patients with type 2 DM suggests that a reduction in levels of HbA1c does not meet the IQWiG criteria for a valid surrogate endpoint. Consequently, the risk-benefit ratio of antihyperglycemic drugs in terms of patient relevant clinical outcomes, regardless of their hypoglycemic effect, should be the focus of therapeutic, regulatory, and reimbursement decisions.

Association of Repeated Blood Cultures With Mortality in Adult Patients With Gram-Negative Bacilli Bacteremia: A Systematic Review and Meta-analysis.

Performing repeat blood cultures after an initial positive culture (ie, follow-up blood cultures [FUBCs]) in patients with gram-negative bacilli (GNB) bacteremia is controversial. We aimed to comprehensively review the association of FUBCs with improvement in patient-relevant clinical outcomes in GNB bacteremia. We performed a systematic review and random-effects meta-analysis to calculate summary effect estimates. We used hazard ratios as the effect measure. The primary outcome was 30-day or in-hospital mortality, and secondary outcomes were length of treatment and length of hospital stay. We searched PubMed, Embase, and Cochrane Central Register of Controlled Trials (Central) without language restrictions from inception to April 29, 2022. Original clinical studies evaluating the association between FUBCs and mortality in adult patients with GNB bacteremia were included. FUBC details were reviewed. Two independent reviewers used the Risk of Bias in Non-randomised Studies of Interventions tool. We identified 9 eligible retrospective studies. In total, 7778 hospitalized patients with GNB bacteremia were included. The studies were clinically heterogeneous and had a critical risk of bias. The utilization of FUBCs varied across studies (18%-89%). Random-effects meta-analysis of covariate-adjusted estimates found that FUBC use was associated with reduced mortality. Although not a result of the meta-analysis, lengths of treatment and hospital stay were longer for patients with FUBCs than for those without. Adverse events were not reported. FUBC acquisition was associated with lower mortality and longer hospital stay and treatment duration in GNB bacteremia. The risk of bias was critical, and no firm data were available to support mechanisms.

Effectiveness of a complex regional advance care planning intervention to improve care consistency with care preferences: study protocol for a multi-center, cluster-randomized controlled trial focusing on nursing home residents (BEVOR trial)

BackgroundAccording to recent legislation, facilitated advance care planning (ACP) for nursing home (NH) residents is covered by German sickness funds. However, the effects of ACP on patient-relevant outcomes have not been studied in Germany yet. This study investigates whether implementing a complex regional ACP intervention improves care consistency with care preferences in NH residents.MethodsThis is a parallel-group cluster-randomized controlled trial (cRCT) with 48 NHs (≈ 3840 resident beds) between 09/2019 and 02/2023. The intervention group will receive a complex, regional ACP intervention aiming at sustainable systems redesign at all levels (individual, institutional, regional). The intervention comprises comprehensive training of ACP facilitators, implementation of reliable ACP processes, organizational development in the NH and other relevant institutions of the regional healthcare system, and education of health professionals caring for the residents. Control group NHs will deliver care as usual.Primary outcome is the hospitalization rate during the 12-months observation period. Secondary outcomes include the rate of residents whose preferences were known and honored in potentially life-threatening events, hospital days, index treatments like resuscitation and artificial ventilation, advance directives, quality of life, psychological burden on bereaved families, and costs of care.The NHs will provide anonymous, aggregated data of all their residents on the primary outcome and several secondary outcomes (data collection 1). For residents who have given informed consent, we will evaluate care consistency with care preferences and further secondary outcomes, based on chart reviews and short interviews with residents, surrogates, and carers (data collection 2). Process evaluation will aim to explain barriers and facilitators, economic evaluation the cost implications.DiscussionThis study has the potential for high-quality evidence on the effects of a complex regional ACP intervention on NH residents, their families and surrogates, NH staff, and health care utilization in Germany. It is the first cRCT investigating a comprehensive regional ACP intervention that aims at improving patient-relevant clinical outcomes, addressing and educating multiple institutions and health care providers, besides qualification of ACP facilitators. Thereby, it can generate evidence on the potential of ACP to effectively promote patient-centered care in the vulnerable population of frail and often chronically ill elderly.Trial registrationClinicalTrials.gov ID NCT04333303. Registered 30 March 2020.

Caregivers' assessment of meaningful and relevant clinical outcome assessments for Sanfilippo syndrome

ObjectivesSanfilippo syndrome is a rare multisystem disease with no approved treatments. This study explores caregiver perspectives on the most impactful symptoms and patient-relevant clinical outcomes assessments. The pediatric onset and progressive neurodegenerative nature of Sanfilippo limits use of self-report in clinical research. This study obtains Sanfilippo caregiver data to support the selection of fit-for-purpose and patient-relevant clinical outcome assessments (COAs).MethodsWe conducted an asynchronous online focus group (n = 11) followed by individual interviews with caregivers (n = 19) of children with Sanfilippo syndrome. All participants reported on the impact of disease symptoms and level of unmet treatment need across Sanfilippo symptom domains. Focus group participants reviewed existing assessments relating to 8 symptom domains (15 total assessments) and provided feedback on meaningfulness and relevance. Focus group data were used to reduce the number of assessments included in subsequent interviews to 8 COAs across 7 symptom domains: communication, eating, sleep, mobility, pain, behavior and adapting. Interview respondents provided data on meaningfulness and relevance of assessments. Data were coded using an item-tracking matrix. Data summaries were analyzed by caregivers’ responses regarding meaningfulness; relevance to Sanfilippo syndrome; and based on caregiver indication of missing or problematic subdomains and items.ResultsParticipants’ children were 2–24 years in age and varied in disease progression. Caregivers reported communication and mobility as highly impactful domains with unmet treatment needs, followed closely by pain and sleep. Domains such as eating, adaptive skills, and behaviors were identified as impactful but with relatively less priority, by comparison. Participants endorsed the relevance of clinical outcome assessments associated with communication, eating, sleep, and pain, and identified them as highly favorable for use in a clinical trial. Participants specified some refinements in existing assessments to best reflect Sanfilippo symptoms and disease course.DiscussionThe identification of impactful symptoms to treat and relevant and meaningful clinical outcome assessments supports patient-focused drug development. Our results inform targets for drug development and the selection of primary and secondary outcome assessments with high meaningfulness and face validity to Sanfilippo syndrome caregivers. Assessments identified as less optimal might be refined, replaced, or remain if the clinical trial necessitates.

Clinical outcomes of patients treated on the Heidelberg interprofessional training ward vs. care on a conventional surgical ward: A retrospective cohort study

ABSTRACT Interprofessional training wards (IPTW) are a form of interprofessional education enabling trainees of different healthcare professions to work together in teams. Concerns about patient safety are a major barrier to the implementation of IPTWs. The objective of this retrospective study was to analyze patient relevant clinical outcomes on Germany’s first IPTW (Heidelberger Interprofessionelle Ausbildungsstation; HIPSTA) in the Department of Surgery at University Hospital Heidelberg in comparison to a conventional surgical ward (CSW). The setting is a large tertiary care center with a focus on major oncological surgery. The endpoints were postoperative complications according to the Dindo-Clavien Classification and a set of patient-safety outcomes. In total, 232 patients treated on HIPSTA were retrospectively compared with 465 patients on a CSW. Baseline characteristics were comparable between groups. No significant difference between rate or severity of overall postoperative complications was observed. In-hospital mortality did not significantly differ between groups. However, the mean length of hospital stay was significantly shorter on HIPSTA. Furthermore, HIPSTA patients had less frequent reoperations. Patient safety in surgical IPTW was not compromised in comparison to a CSW, and there were some areas where significantly better outcomes were identified.

Association between tocilizumab treatment and clinical outcomes of COVID-19 patients: a systematic review and meta-analysis.

To explore and summarize the association between treatment with tocilizumab and clinical outcomes in COVID-19 patients. We performed a systematic review and meta-analysis (10 RCTs including 3378 patients in the tocilizumab group and 3142 patients in the control group). We systematically searched PubMed and MedRxiv for all RCTs as of June 1, 2021, to assess the benefits and harms of tocilizumab to treat patients with COVID-19. All analyses were carried out using RevMan version 5.4.1. There were nine RCTs published in peer-reviewed journals and one RCTs published as a preprint. The summary RR for all-cause mortality with tocilizumab was 0.89 (95% CI= 0.82-0.96, P= 0.003). There was no significant between-trial heterogeneity (I2= 28%, P= 0.19). However, all peer-reviewed RCTs showed no significant associations between treatment with tocilizumab and reductions in all-cause mortality. We notably found that tocilizumab significantly reduced the rate of intubation or death in patients with COVID-19 with 3 RCTs. Across the 8 RCTs, the summary RR for discharge with tocilizumab was 1.10 (95% CI= 1.03-1.16, P< 0.00001). There was no significant association of tocilizumab with harm on other patient-relevant clinical outcomes, including increasing secondary infection risk, patients of adverse events, or patients of serious adverse events. Tocilizumab significantly increased the rate of hospital discharges in COVID-19 patients. Still, it did not decrease all-cause mortality or increase the risk of secondary infections, patients of adverse events, or patients for serious adverse events. Evidence that tocilizumab affects clinical outcomes in patients with COVID-19 requires further proof.

Celiac Disease Prevalence Among Children with Dermatologic Pathology: Cross Sectional Study with Clinical Case Series

Background. Celiac disease (gluten enteropathy) is relatively rare disease. However, such patients have higher risk of skin pathology than general the population, and their therapy efficacy is limited by the use of gluten-free diet. Therefore, screening of dermatologic patients on celiac disease may be relevant. Objective. Our aim was to study the prevalence of celiac disease among children with skin pathology. Methods. The study included children hospitalized in dermatology department. Screening for celiac disease included detection in blood serum of antibodies (IgA, IgG, IgM) to tissue transglutaminase via rapid tests. In case of positive result of rapid test, we have repeated the estimation of antibodies (IgA, IgG) to tissue transglutaminase via immunochemiluminescent method with ImmunoCAP technology or via enzyme immunoassay. In case of positive serological test, we have performed HLA typing to determine haplotypes of DQ2 and DQ8, as well as esophagogastroduodenojejunoscopy (EGDJS) with biopsy of the duodenal and jejunal mucosa for further histological verification of the diagnosis. Results. We examined 1,000 children with various dermatologic pathologies. Rapid tests showed positive result in 21 patients (2.1%; 95% C11.3-3.2%). The presence of antibodies to tissue transglutaminase was confirmed via additional serological examination in all cases. HLA-haplotypes DQ2/8 were revealed in all patients with positive rapid test results. Typical form of gluten enteropathy was confirmed in 18/21 patients (86%) according to a histological study, thus, estimated prevalence of celiac disease is 1.8% (95% C11.1-2.8%). Conclusion. The prevalence of celiac disease remains underestimated among children with skin diseases. More studies are needed on the diagnostic features of rapid tests on tissue transglutaminase, as well as the benefits of screening for celiac disease to achieve patient-relevant clinical outcomes of skin pathology with wider gluten-free diet.

Beta-blockers versus placebo or no intervention for primary prophylaxis of oesophageal variceal bleeding in children with chronic liver disease or portal vein thrombosis.

Portal hypertension commonly accompanies advanced liver disease and often gives rise to life-threatening complications, including haemorrhage from oesophageal and gastrointestinal varices. Variceal haemorrhage commonly occurs in children with chronic liver disease or portal vein thrombosis. Therefore, prevention is important. Band ligation, beta-blockers, and sclerotherapy have been proposed as alternatives for primary prophylaxis of oesophageal variceal bleeding in children. However, primary prophylaxis is not the current standard of care in paediatric patients because it is unknown whether those treatments are of benefit or harm when used for primary prophylaxis in children and adolescents. To determine the benefits and harms of beta-blockers compared with placebo or no intervention for primary prophylaxis of oesophageal variceal bleeding in children with chronic liver disease or portal vein thrombosis. We searched the Cochrane Hepato-Biliary Group Controlled Trials Register, CENTRAL, PubMed, Embase, LILACS, and Science Citation Index Expanded (April 2020). We screened the reference lists of the retrieved publications and manually searched the main paediatric gastroenterology and hepatology conference (NASPGHAN and ESPGHAN) abstract books from 2008 to December 2019. We searched clinicaltrials.gov, the United States Food and Drug Administration (FDA), the European Medicines Agency (EMA), and the World Health Organization (WHO) for ongoing clinical trials. We imposed no language or document type restrictions on our search. We planned to include randomised clinical trials, irrespective of blinding, language, or publication status to assess benefits and harms. We included observational studies, retrieved with the searches for randomised clinical trials, for a narrative report of harm. We planned to summarise data from randomised clinical trials by standard Cochrane methodologies. We planned to asses risk of bias and use GRADE to assess the certainty of evidence. Our primary outcomes were all-cause mortality, serious adverse events and liver-related morbidity, and health-related quality of life. Our secondary outcomes were oesophageal variceal bleeding and adverse events not considered serious. We planned to use intention-to-treat principle. We planned to analyse data with RevMan Analysis. We found no randomised clinical trials that assessed beta-blockers compared with sham or no intervention for primary prophylaxis of oesophageal variceal bleeding in children with chronic liver disease or portal vein thrombosis. We found four observational studies that reported on harms. As a systematic search for observational studies was not planned, we only listed the reported harms in a table. Randomised clinical trials assessing the benefits or harms of beta-blockers versus placebo or no intervention for primary prophylaxis of oesophageal variceal bleeding in children with chronic liver disease or portal vein thrombosis are lacking. Therefore, trials with adequate power and proper design, assessing the benefits and harms of beta-blockers versus placebo on patient-relevant clinical outcomes, such as mortality, quality of life, failure to control variceal bleeding, and adverse events are needed. Unless such trials are conducted and the results become published, we cannot make any conclusions regarding the benefits or harms of the two interventions.

Band ligation versus sclerotherapy for primary prophylaxis of oesophageal variceal bleeding in children with chronic liver disease or portal vein thrombosis.

Portal hypertension commonly accompanies advanced liver disease and often gives rise to life-threatening complications, including haemorrhage from oesophageal and gastrointestinal varices. Variceal haemorrhage commonly occurs in children with chronic liver disease or portal vein obstruction. Prevention is therefore important. In adults, numerous randomised clinical trials have demonstrated benefits of non-selective beta-blockers and endoscopic variceal ligation as primary prevention in decreasing the risk of variceal haemorrhage. In children, band ligation, beta-blockers, and sclerotherapy have been proposed as alternatives for primary prophylaxis of oesophageal variceal bleeding. However, primary prophylaxis is not the current standard of care in children because it is unknown whether those treatments are of benefit or cause harm when used for primary prophylaxis of oesophageal variceal bleeding in children and adolescents. To determine the benefits and harms of band ligation versus sclerotherapy for primary prophylaxis of oesophageal variceal bleeding in children and adolescents with chronic liver disease or portal vein thrombosis. We searched the Cochrane Hepato-Biliary Group Controlled Trials Register, CENTRAL, PubMed, Embase, LILACS, and Science Citation Index Expanded (27 April 2020). We scrutinised the reference lists of retrieved publications, and performed a manual search from the main paediatric gastroenterology and hepatology conferences (NASPGHAN and ESPGHAN) abstract books from 2008 to 2019. We searched ClinicalTrials.gov, FDA, EMA, and WHO for ongoing clinical trials. There were no language or document type restrictions. We planned to include randomised clinical trials irrespective of blinding, language, or publication status for assessment of benefits and harms. If the search for randomised clinical trials retrieved quasi-randomised and observational studies, then we read them through to extract information on harms. We planned to summarise data from randomised clinical trials by standard Cochrane methodologies. We planned to assess risk of bias and use GRADE to assess the certainty of evidence per outcome. Our primary outcomes were all-cause mortality, serious adverse events and liver-related morbidity, and quality of life. Our secondary outcomes were oesophageal variceal bleeding and adverse events not considered serious. We planned to analyse data with intention-to-treat. We planned to use Review Manager 5 to analyse the data. We found no randomised clinical trials assessing band ligation versus sclerotherapy for primary prophylaxis of oesophageal variceal bleeding in children with chronic liver disease or portal vein thrombosis. Randomised clinical trials assessing the benefits or harms of band ligation versus sclerotherapy for primary prophylaxis of oesophageal variceal bleeding in children with chronic liver disease or portal vein thrombosis are lacking. Therefore, trials with adequate power and proper design, assessing the benefits and harms of band ligation versus sclerotherapy on patient-relevant clinical outcomes such as mortality, quality of life, failure to control variceal bleeding, and adverse events are needed. Unless such trials are conducted and the results become published, we cannot make any conclusions regarding the benefits or harms of these two interventions.

Improving clinical outcomes and patient satisfaction among patients with coronary artery disease: an example of enhancing regional integration between a cardiac centre and a referring hospital

BackgroundValue-based healthcare (VBHC) is a promising strategy to increase patient value. For a successful implementation of VBHC, intensive collaborations between organizations and integrated care delivery systems are key conditions. Our aim was to evaluate the effects of a pilot study regarding enhancing regional integration between a cardiac centre and a referring hospital on patient-relevant clinical outcomes and patient satisfaction.MethodsThe study population consisted of a sample of patients treated for coronary artery disease by use of a coronary artery bypass graft (CABG) or a percutaneous coronary intervention between 2011 and 2016. Since 2013, the two hospitals have implemented different interventions to improve clinical outcomes and the degree of patient satisfaction, e.g. improvement of communication, increased consultant capacity, introduction of outpatient clinic for complex patients, and improved guideline adherence. To identify intervention effects, logistic regression analyses were conducted. Patients’ initial conditions, like demographics and health status, were included in the model as predictors. Clinical data extracted from the electronic health records and the hospitals’ cardiac databases as well as survey-based data were used.ResultsOur findings indicate a non-significant increase of event-free survival of patients treated for coronary artery disease between 2014 and 2016 compared to patients treated between 2011 and 2013 (97.4% vs. 96.7% respectively). This non-significant improvement over time has led to significant better outcomes for patients referred from the study referring hospital compared to patients referred from other hospitals. The level of patient satisfaction (response rate 32.2%; 216 out of 669) was improved and reached statistically significant higher scores regarding patient information and education (p = .013), quality of care (p = .007), hospital admission and stay (p = .032), personal contact with the physician (p = .024), and total impression (p = .007).ConclusionsThis study shows a promising effect of regional integration. An intensified collaboration in the care chain, organized in a structured manner between a cardiac centre and a referring hospital and aiming at high quality, resulted in successful improvement of clinical outcomes and degree of patient satisfaction. The applied method may be used as a starting point of regional integration with other referring hospitals. We encourage others to organize the whole care chain to continuously improve patient-relevant outcomes and patient satisfaction.Trial registrationISRCTN11311830. Registered 01 October 2018 (retrospectively registered).

PDG74 AVAILABILITY OF FDA-APPROVED SURROGATE MARKERS IN REAL-WORLD DATA

Validated surrogate markers that predict patient-relevant clinical outcomes can support more efficient clinical trials and regulatory decisions. While real-world evidence is increasingly used in decision-making, the availability of validated surrogates in real-world data (RWD) sources is unclear. We reviewed FDA-approved surrogates and determined the extent to which surrogate marker results are measurable within a representative claims and electronic health records (EHR) source. We extracted surrogates that were the basis of FDA drug approvals for common therapeutic areas from the FDA’s surrogate endpoints table. Using Optum’s de-identified Integrated Claims-Clinical dataset, we evaluated the percent of patients with surrogate marker results (365 days follow-up) within indication-specific cohorts. Cohorts included prevalent and incident users of drugs for indications corresponding to each surrogate approval, as specified by the FDA. Among the 23 FDA-approved surrogate markers identified for 16 indications, 16 (70%) were laboratory tested molecular biomarkers (e.g. HbA1c, HIV-RNA), 5 (22%) required radiographic assessments (e.g. tumor progression, bone density), and 2 (9%) were physiological assessments (FEV1, blood pressure). Overall, 16 (70%) of 23 surrogate markers could be operationalized in the representative database. The percent of patients with surrogate results across indication-specific cohorts ranged from 4% (FEV1) to 86% (blood pressure). Molecular biomarkers were the most common surrogate type, due to cardiometabolic markers collected in regular clinical practice (LDL, triglycerides, HbA1c). Surrogates from unstructured sources (e.g. clinician notes) and endpoints requiring a sequence of assessments to measure changes over time were available in a subset of indication-specific cohorts with necessary data. This study demonstrates opportunities to use FDA-approved surrogates in RWD studies and monitoring of disease status in real-world settings. Further research is needed to develop and validate algorithms for extracting surrogate outcomes from structured and unstructured health data sources.

Sclerotherapy versus beta-blockers for primary prophylaxis of oesophageal variceal bleeding in children and adolescents with chronic liver disease or portal vein thrombosis.

Portal hypertension commonly accompanies advanced liver disease and often gives rise to life-threatening complications, including bleeding (haemorrhage) from oesophageal and gastrointestinal varices. Variceal bleeding commonly occurs in children with chronic liver disease or portal vein obstruction. Prevention is therefore important. Primary prophylaxis of variceal bleeding in adults is the established standard of care because of the results of numerous randomised clinical trials demonstrating the efficacy of non-selective beta-blockers or endoscopic variceal ligation in decreasing the incidence of variceal bleeding. However, sclerotherapy is the only endoscopic prophylactic option currently available in infants weighing less than 10 kg of bodyweight due to the size of the endoscopic ligator. To assess the benefits and harms of sclerotherapy versus any type of beta-blocker for primary prophylaxis of oesophageal variceal bleeding in children and adolescents with chronic liver disease or portal vein thrombosis. We searched The Cochrane Hepato-Biliary Group Controlled Trials Register, CENTRAL, PubMed, Embase Elsevier, LILACS (Bireme), and Science Citation Index Expanded (Web of Science) in February 2019. We scrutinised the reference lists of the retrieved publications and performed a manual search from the main paediatric gastroenterology and hepatology conferences (NASPGHAN and ESPGHAN) abstract books from January 2008 to December 2018. We searched ClinicalTrials.gov, FDA, EMA, and WHO, for ongoing clinical trials. There were no language or document type restrictions. We planned to include randomised clinical trials irrespective of blinding, language, or publication status, assessing sclerotherapy versus any type of beta-blocker for primary prophylaxis of oesophageal variceal bleeding in children and adolescents with chronic liver disease or portal vein thrombosis. We planned to include quasi-randomised and other observational studies retrieved with the searches for randomised clinical trials for report of harm. We planned to collect and summarise data from randomised clinical trials as described in our protocol, using standard Cochrane methodologies. We found no randomised clinical trials assessing sclerotherapy versus beta-blockers for primary prophylaxis of oesophageal variceal bleeding in children and adolescents with chronic liver disease or portal vein thrombosis. Randomised clinical trials assessing the benefits or harms of sclerotherapy versus beta-blockers for primary prophylaxis of oesophageal variceal bleeding in children and adolescents with chronic liver disease or portal vein thrombosis are lacking. Therefore, trials with adequate power and proper design, assessing the benefits and harms of sclerotherapy versus beta-blockers on patient-relevant clinical outcomes such as mortality, failure to control bleeding, and adverse events are needed. Unless such trials are conducted and the results become published, we cannot make any conclusions regarding the benefits or harms of the two interventions.

Band ligation versus beta-blockers for primary prophylaxis of oesophageal variceal bleeding in children with chronic liver disease or portal vein thrombosis.

Portal hypertension commonly accompanies advanced liver disease and often gives rise to life-threatening complications, including haemorrhage from oesophageal and gastrointestinal varices. Variceal haemorrhage commonly occurs in children with chronic liver disease or portal vein obstruction. Prevention is therefore important. Following numerous randomised clinical trials demonstrating efficacy of non-selective beta-blockers and endoscopic variceal ligation in decreasing the incidence of variceal haemorrhage, primary prophylaxis of variceal haemorrhage in adults has become the established standard of care. Hence, band ligation and beta-blockers have been proposed to be used as primary prophylaxis of oesophageal variceal bleeding in children. To determine the benefits and harms of band ligation compared with any type of beta-blocker for primary prophylaxis of oesophageal variceal bleeding in children with chronic liver disease or portal vein thrombosis. We searched The Cochrane Hepato-Biliary Group Controlled Trials Register (February 2019), CENTRAL (December 2018), PubMed (December 2018), Embase Ovid (December 2018), LILACS (Bireme; January 2019), and Science Citation Index Expanded (Web of Science; December 2018). We scrutinised the reference lists of the retrieved publications and performed a manual search from the main paediatric gastroenterology and hepatology conferences (NASPGHAN and ESPGHAN) abstract books from 2009 to 2018. We searched ClinicalTrials.gov for ongoing clinical trials. There were no language or document type restrictions. We planned to include randomised clinical trials irrespective of blinding, language, or publication status for assessment of benefits and harms. We planned to also include quasi-randomised and other observational studies retrieved with the searches for randomised clinical trials for report of harm. We planned to summarise data from randomised clinical trials using standard Cochrane methodologies. We found no randomised clinical trials assessing band ligation versus beta-blockers for primary prophylaxis of oesophageal variceal bleeding in children with chronic liver disease or portal vein thrombosis. Randomised clinical trials assessing the benefits or harms of band ligation versus beta-blockers for primary prophylaxis of oesophageal variceal bleeding in children with chronic liver disease or portal vein thrombosis are lacking. There is a need for well-designed, adequately powered randomised clinical trials to assess the benefits and harms of band ligation versus beta-blockers for primary prophylaxis of oesophageal variceal bleeding in children with chronic liver disease or portal vein thrombosis. Those randomised clinical trials should include patient-relevant clinical outcomes such as mortality, failure to control bleeding, and adverse events.

Current use and costs of electronic health records for clinical trial research: a descriptive study.

Electronic health records (EHRs) may support randomized controlled trials (RCTs). We aimed to describe the current use and costs of EHRs in RCTs, with a focus on recruitment and outcome assessment. This descriptive study was based on a PubMed search of RCTs published since 2000 that evaluated any medical intervention with the use of EHRs. Cost information was obtained from RCT investigators who used EHR infrastructures for recruitment or outcome measurement but did not explore EHR technology itself. We identified 189 RCTs, most of which (153 [81.0%]) were carried out in North America and were published recently (median year 2012 [interquartile range 2009-2014]). Seventeen RCTs (9.0%) involving a median of 732 (interquartile range 73-2513) patients explored interventions not related to EHRs, including quality improvement, screening programs, and collaborative care and disease management interventions. In these trials, EHRs were used for recruitment (14 [82%]) and outcome measurement (15 [88%]). Overall, in most of the trials (158 [83.6%]), the outcome (including many of the most patient-relevant clinical outcomes, from unscheduled hospital admission to death) was measured with the use of EHRs. The per-patient cost in the 17 EHR-supported trials varied from US$44 to US$2000, and total RCT costs from US$67 750 to US$5 026 000. In the remaining 172 RCTs (91.0%), EHRs were used as a modality of intervention. Randomized controlled trials are frequently and increasingly conducted with the use of EHRs, but mainly as part of the intervention. In some trials, EHRs were used successfully to support recruitment and outcome assessment. Costs may be reduced once the data infrastructure is established.

The US Food and Drug Administration's expedited approval programs: Evidentiary standards, regulatory trade-offs, and potential improvements.

The US Food and Drug Administration has several regulatory programs and pathways to expedite the development and approval of therapeutic agents aimed at treating serious or life-debilitating conditions. A common feature of these programs is the regulatory flexibility, which allows for a customized approval approach that enables market authorization on the basis of less rigorous evidence, in exchange for requiring postmarket evidence generation. An increasing share of therapeutic agents approved by the Food and Drug Administration in recent years are associated with expedited programs. In this article, we provide an overview of the evidentiary standards required by the Food and Drug Administration's expedited development and review programs, summarize the findings of the recent academic literature demonstrating some of the limitations of these programs, and outline potential opportunities to address these limitations. Recent evidence suggests that therapeutic agents in the Food and Drug Administration's expedited programs are approved on the basis of fewer and smaller studies that may lack comparator groups and random allocation, and rather than focusing on clinical outcomes for study endpoints, rely instead on surrogate markers of disease. Once on the market, agents receiving expedited approvals are often quickly incorporated into clinical practice, and evidence generated in the postmarket period may not necessarily address the evidentiary limitations at the time of market entry. Furthermore, not all pathways require additional postmarket studies. Evidence suggests that drugs in expedited approval programs are associated with a greater likelihood that the Food and Drug Administration will take a safety action following market entry. There are several opportunities to improve the timeliness, information value, and validity of the pre- and postmarket studies of therapeutic agents receiving expedited approvals. When use of nonrandomized and uncontrolled studies cannot be avoided prior to market entry, randomized trials should be mandatory in the postmarket period, unless there are strong justifications for not carrying out such studies. In the premarket period, validity of the surrogate markers can be improved by more rigorously evaluating their correlation with patient-relevant clinical outcomes. Opportunities to reduce the duration, complexity, and cost of postmarket randomized trials should not compromise their validity and instead incorporate pragmatic "real-world" design elements. Despite recent enthusiasm for widely using real-world evidence, adaptive designs, and pragmatic trials in the regulatory setting, caution is warranted until large-scale empirical evaluations demonstrate their validity compared to more traditional trial designs.

Innovations in Outcomes and Designs of Clinical Trials for Respiratory Drug Development

Clinical trials for the development of respiratory drugs have for years been reliant upon measurements of physiologic tests, combined with the use of questionnaires. New drugs were mostly administered by inhalation and increasingly in fixed combinations. However, these lung function tests have a lack of sensitivity for patient-relevant clinical outcomes. Moreover, new insights in phenotypes and endotypes of these diseases in the basic mechanisms and the discovery of new targets for therapy, have led to the need for a more personalized patient-centered approach and precision medicine. In recent years, a great number of techniques have been proposed but some need further validation. These include fractional exhaled nitric oxide, health-related quality of life and the use of biomarkers like blood and sputum eosinophils and neutrophils, IgE, sIgE, periostin, copeptin and specific cytokines. Additionally, exhaled breath condensate and lung deposition studies by functional residual imaging and by local bronchial pharmacokinetics can be used. In rare diseases like cystic fibrosis, Lung Clearance Index and CT and PET scan fusion images seem to be valuable outcome measurements. Lastly leverage of lung function tests can be done by using body plethysmography, measuring respiratory impedance, variability and the use of modeling and simulation. The need for a patient-centric approach through all stages of clinical development is becoming mandatory. So, an evolution from classical randomized clinical trials (RCTs) to more efficient and patient-relevant designs will be seen more in the future. RCTs will remain necessary for regulatory submission but more efficient and adaptive designs with lower heterogeneity and the use of pragmatic trials are needed. This evolution from undefined targets to a more targeted approach will lead us closer to precision medicine. In this overview, the unmet medical need for better outcomes and study designs in the development of treatments for respiratory diseases, are discussed.

PET in the Clinical Management of Glioma: Evidence Map

Several studies have assessed PET to complement the anatomic information obtained from other imaging modalities in various clinical contexts for the management of glioma. We constructed an evidence map of clinical evidence on the use of PET in glioma and identified research gaps. We searched PubMed and Scopus (from inception through June 30, 2011) to identify studies assessing the use of PET for glioma regardless of setting of care or indication. We extracted test objectives, study characteristics, and phases of diagnostic evidence and then assessed research diversity and temporal trends in the literature. We excluded studies assessing only technical feasibility and optimization of PET. A total of 129 studies were considered eligible; the number of articles published annually has greatly increased over time (p for trend < 0.001). Most studies (n = 118, 91%) assessed diagnostic or prognostic performance; fewer studies reported on the impact of PET on diagnostic thinking (n = 4, 3%), therapeutic decisions (n = 4, 3%), or patient-relevant clinical outcomes (n = 3; 2%). Fluorine-18 FDG (n = 73, 57%) or (11)C-methionine (n = 44, 34%) were the two most commonly evaluated PET tracers. Pretherapy assessment (n = 72, 56%) and monitoring of treatment response (n = 48, 37%) were the most common settings of test use assessed in the research studies. More primary studies, particularly studies of newer tracers focusing on biopsy or treatment planning, are needed to better characterize the role of PET in specific contexts.

Treatment effect bias in randomised controlled trials using surrogate outcomes: a preliminary cohort study analysis

Background Ideally, decisions on the value of health technologies should be based on evidence from well-conducted clinical trials that assess clinically important final patientrelevant outcomes, such as mortality or impaired quality of life. Pressure to reduce the delay in the availability of technologies to patients has led to an increased reliance on the use of surrogate outcomes [1]. A key tenant of surrogate outcomes is unbiased quantification of the predictive treatment effect on the final patient-relevant clinical outcomes. This study compares the treatment outcome of trials that use a surrogate versus a final patient-relevant primary outcome.