Introduction: Clinical oncology trial design constantly adapts and evolves to meet the needs of all stakeholders, from patients to regulators. This evolution has however also led to an increase in the complexity of clinical development, and investigators are expected to invest more time and money in planning and running their studies and overall clinical and regulatory pathway. Methods: Here we review recent innovations in trial designs, study endpoints, and relevant regulatory guidelines, before making recommendations to enhance the clinical trial ecosystem in the EU. Results: Innovative clinical study designs that go beyond traditional randomised, double-blinded, placebocontrolled trials often promise greater flexibility and efficiency in the conduct of oncology studies, but adoption has been slow. Furthermore, the increased complexity associated with innovative trials means that coordination between all relevant stakeholders is essential to every phase of clinical development. Despite recent advances, there is a risk that Europe is becoming seen as a less attractive location for clinical trials, and this article outlines initiatives and possible steps to improve patient access to medicines and processes across Europe. Policy summary: Innovative trial designs promise more efficient, flexible, and inclusive clinical trials, but more needs to be done to encourage their adoption if the advantages outweigh the limitations. Partnership and coordination between all stakeholders, from patients to regulators, and at all phases, is more important than ever. Finally, effective action is needed to make Europe a more attractive destination for clinical research and to improve access to innovative medicines for patients.

Conducting randomized clinical trials (RCTs) is challenging. For this reason, in earlier phases of drug development and rare diseases with limited sample sizes, there is a tendency to omit control groups and to replace them with historical information for perceived feasibility arguments. This has significant implications for interpretation of trial results. We present headline results from a trial in stem cell transplantation, where fludarabine and clofarabine were investigated for induction chemotherapy in high-risk acute myeloid leukaemia or advanced myelodysplastic syndrome. The trial was initially designed as single-arm trial (SAT) and is discussed here from the planning and assessment perspective. Changes in the treatment setting or patient selection may lead to 'promising results' in SATs, which are difficult to identify and may raise unwarranted hopes which cannot be confirmed in a subsequent randomized trial. RCTs should be used to achieve a straightforward interpretation of the results, even if the sample size is small. Interpreting SATs is only straightforward in very rare instances where the underlying treatment effect is large and the outcome in each individual patient surpasses all previous clinical experience.

The COVID-19 pandemic triggered an unprecedented research effort to develop vaccines and therapeutics. Urgency dictated that development and regulatory assessment were accelerated, while maintaining all standards for quality, safety and efficacy. To speed up evaluation the European Medicines Agency (EMA) implemented "rolling reviews" allowing developers to submit data for assessment as they became available. We discuss the clinical trial designs and the applied statistical approaches in vaccine efficacy trials, focusing on aspects such as multiple testing, interim and updated analyses, and reporting of results for the first four vaccines recommended for approval by the EMA. The fast accrual of COVID-19 cases in the clinical vaccine efficacy trials led to multiple data updates within a short time frame, which had consequences for the evaluation and interpretation of results. Key trial results are discussed in the light of these aspects. Notably, the aspects discussed did not affect the benefit/risk relationship in a meaningful way, which was clearly positive for all four vaccines. Assessment of the development and evaluation of the four vaccine trials during the pandemic has led to a proposal for standardized terminology for trials with multiple analyses and a recommendation to appropriately preplan the timing of primary and updated analyses. For the reporting of updated estimates of vaccine efficacy, we discuss how to best describe the uncertainty around estimates of vaccine efficacy (e.g., via confidence intervals). Finally, we briefly highlight the benefit of a comprehensive discussion on estimands for vaccine efficacy trials. for this article are available online.

This article provides a summary of discussions from the American Statistical Association (ASA) Biopharmaceutical (BIOP) Section Open Forum organized by the ASA BIOP Statistical Methods in Oncology Scientific Working Group in coordination with the US FDA Oncology Center of Excellence and LUNGevity Foundation on January 14, 2021, and February 8, 2021. Diverse stakeholders including oncologists, patient advocates, experts from international regulatory agencies, academicians, and representatives of the pharmaceutical industry engaged in a discussion on how best to incorporate lessons learned during the COVID-19 pandemic into the design of future oncology trials. While recognizing that decentralized or hybrid cancer trials may increase variability associated with measurement error and potentially increase bias in treatment effect estimation, panel discussions highlighted the importance of flexibility for decreasing patient burden, which has the potential to increase access to and retention in cancer clinical trials and may broaden the representation of real-world patients in the trial setting.

The Cancer Drug Development Forum (CDDF)'s 'Histology independent drug development - is this the future for cancer drugs?' workshop was set up to explore the current landscape of histology independent drug development, review the current regulatory landscape and propose recommendations for improving the conduct of future trials. The first session considered lessons learnt from previous trials, including innovative solutions for reimbursement. The session explored why overall survival represents the most valuable endpoint, and the importance of duration of response, which can be captured with swimmer and spider plots. The second session on biomarker development and treatment optimisation considered current regulations for companion diagnostics, FDA guidance on histology independent drug development in oncology, and the need to establish cut-offs for the biomarker of tumour mutational burden to identify the patients most likely to benefit from PDL1 treatment. The third session reviewed novel trial designs, including basket, umbrella and platform trials, and statistical approaches of hierarchical modelling where homogeneity between study cohorts enables information to be borrowed between cohorts. The discussion highlighted the need to agree 'common assessment standards' to facilitate pooling of data across studies. In the fourth session, the sharing of data sets was recognised as a key step for improving equity of access to precision medicines across Europe. The session considered how the European Health Data Space (EHDS) could streamline access to medical records, emphasizing the importance of introducing greater accountability into the digital space. In conclusion the workshop proposed 11 recommendations to facilitate histology agnostic drug development.

BACKGROUND Our kidney transplant waitlist includes 20% re-transplantations (TX2). Knowing what to expect is a clinical obligation. MATERIAL AND METHODS We compared graft and patient survival of all 162 TX2 patients, transplanted 2000 to 2009, with 162 patients after first transplantation (TX1) matched for age, sex, living/non-living donation, and transplantation date. Patient follow-up was 10 years. RESULTS TX2 graft and patient survivals were inferior to TX1 (p<0.001 and p=0.047). TX2 patients had a longer cumulative dialysis vintage, more human leucocyte antigen (HLA) mismatches, more panel-reactive HLA antibodies, more often received induction therapy with rabbit-antithymocyte globulin (rATG), and had a lower body mass index (all p<0.05). Death from infection and graft failure by rejection was more frequent after TX2 (both p<0.05) but not after TX1. Multivariable Cox regression analysis revealed that both cohorts had graft failure and death risk associated with infection and cardiovascular disease, and graft failure by humoral rejection. However, only TX2 patients had an additional risk of graft failure with early inferior graft function and of patient death with ≥2 comorbidities. Moreover, Kaplan-Meier analysis showed that TX2 and not TX1 patients had a lower graft and patient survival associated with infection and with ≥2 comorbidities (all p<0.05). CONCLUSIONS Re-transplantation is associated with worse graft outcomes mainly because of immunologic and graft-quality reasons, although the high number of comorbidities and infection severities aside from cardiovascular disease drive mortality. The more frequent rATG induction of TX2 patients could promote infection by enhancing immunosuppression. By addressing comorbidities, outcomes could possibly be improved.

Background Adoptive transfer of virus-specific T cells (VSTs) represents a prophylactic and curative approach for opportunistic viral infections and reactivations after transplantation. However, inadequate frequencies of circulating memory VSTs in the T-cell donor’s peripheral blood often result in insufficient enrichment efficiency and purity of the final T-cell product, limiting the effectiveness of this approach. Methods This pilot study was designed as a cross-over trial and compared the effect of a single bout (30 min) of high-intensity interval training (HIT) with that of 30 min of continuous exercise (CONT) on the frequency and function of circulating donor VSTs. To this end, we used established immunoassays to examine the donors’ cellular immune status, in particular, with respect to the frequency and specific characteristics of VSTs restricted against Cytomegalovirus (CMV)-, Epstein–Barr-Virus (EBV)- and Adenovirus (AdV)-derived antigens. T-cell function, phenotype, activation and proliferation were examined at different time points before and after exercise to identify the most suitable time for T-cell donation. The clinical applicability was determined by small-scale T-cell enrichment using interferon- (IFN-) γ cytokine secretion assay and virus-derived overlapping peptide pools. Results HIT proved to be the most effective exercise program with up to fivefold higher VST response. In general, donors with a moderate fitness level had higher starting and post-exercise frequencies of VSTs than highly fit donors, who showed significantly lower post-exercise increases in VST frequencies. Both exercise programs boosted the number of VSTs against less immunodominant antigens, specifically CMV (IE-1), EBV (EBNA-1) and AdV (Hexon, Penton), compared to VSTs against immunodominant antigens with higher memory T-cell frequencies. Conclusion This study demonstrates that exercise before T-cell donation has a beneficial effect on the donor’s cellular immunity with respect to the proportion of circulating functionally active VSTs. We conclude that a single bout of HIT exercise 24 h before T-cell donation can significantly improve manufacturing of clinically applicable VSTs. This simple and economical adjuvant treatment proved to be especially efficient in enhancing virus-specific memory T cells with low precursor frequencies.

Cardiovascular risk rapidly increased following exposure to air pollution. Changes in human autonomic regulation have been implicated based on epidemiological associations between exposure estimates and indirect autonomic nervous system measurements. We conducted a mechanistic study to test the hypothesis that, in healthy older individuals, well-defined experimental exposure to ultrafine carbon particles (UFP) increases sympathetic nervous system activity and more so with added ozone (O3). Eighteen participants (age >50 years, 6 women) were exposed to filtered air (Air), UFP, and UFP + O3 combination for 3 hours during intermittent bicycle ergometer training in a randomized, crossover, double-blind fashion. Two hours following exposure, respiration, electrocardiogram, blood pressure, and muscle sympathetic nerve activity (MSNA) were recorded at supine rest, during deep breathing, and during a Valsalva manoeuvre. Catechols and inflammatory marker levels were measured in venous blood samples. Induced sputum was obtained 3.5 h after exposure. Combined exposure to UFP + O3 but not UFP alone, caused a significant increase in sputum neutrophils and circulating leucocytes. Norepinephrine was modestly increased while the ratio between plasma dihydroxyphenylglycol (DHPG) and norepinephrine levels, a marker for norepinephrine clearance, was reduced with UFP + O3. Resting MSNA was not different (47 ± 12 with Air, 47 ± 14 with UFP, and 45 ± 14 bursts/min with UFP + O3). Indices of parasympathetic heart rate control were unaffected by experimental air pollution. Our study suggests that combined exposure to modest UFP and O3 levels increases peripheral norepinephrine availability through decreased clearance rather than changes in central autonomic activity. Pulmonary inflammatory response may have perturbed pulmonary endothelial norepinephrine clearance.

Patients suffering from type 2 diabetes are at an increased risk of developing classical microvascular complications such as retinopathy, neuropathy, and nephropathy, which represent a significant health burden. Tight control of blood glucose, blood pressure, and serum cholesterol reduce the risk of microvascular complications but effective pharmacologically targeted treatment options for the treatment and prevention of diabetic microangiopathy are still lacking. Pharmacological inhibition of sodium glucose cotransporter 2 (SGLT2) might have the potential to directly protect against microvascular complications and could represent a potential treatment option. Randomized controlled clinical proof of concept trials are needed to investigate a potential central role of SGLT2 inhibitors in the prevention of diabetic microangiopathy and its classical clinical complications of retinopathy, neuropathy, and nephropathy.

Background Meta-information provided about health apps on app stores is often the only readily available source of quality-related information before installation. Objective The purpose of this study was to assess whether physicians deem a predefined set of quality principles as relevant for health apps; whether they are able to identify corresponding information in a given sample of app descriptions; and whether, and how, this facilitates their informed usage decisions. Methods All members of the German Society for Internal Medicine were invited by email to participate in an anonymous online survey over a 6-week period. Participants were randomly assigned one app description focusing on cardiology or pulmonology. In the survey, participants were asked three times about whether the assigned description sufficed for a usage decision: they were asked (1) after giving an appraisal of the relevance of nine predefined app quality principles, (2) after determining whether the descriptions covered the quality principles, and (3) after they assessed the availability of detailed quality information by means of 25 additional key questions. Tests for significance of changes in their decisions between assessments 1 and 2, and between assessments 2 and 3, were conducted with the McNemar-Bowker test of symmetry. The effect size represents the discordant proportion ratio sum as a quotient of the test statistics of the Bowker test and the number of observation units. The significance level was set to alpha=.05 with a power of 1-beta=.95. Results A total of 441 of 724 participants (60.9%) who started the survey fully completed the questionnaires and were included in the evaluation. The participants predominantly rated the specified nine quality principles as important for their decision (approximately 80%-99% of ratings). However, apart from the practicality criterion, information provided in the app descriptions was lacking for both groups (approximately 51%-92%). Reassessment of the apps led to more critical assessments among both groups. After having familiarized themselves with the nine quality principles, approximately one-third of the participants (group A: 63/220, 28.6%; group B: 62/221, 28.1%) came to more critical usage decisions in a statistically significant manner (McNemar-Bowker test, groups A and B: P<.001). After a subsequent reassessment with 25 key questions, critical appraisals further increased, although not in a statistically significant manner (McNemar-Bowker, group A: P=.13; group B: P=.05). Conclusions Sensitizing physicians to the topic of quality principles via questions about attitudes toward established quality principles, and letting them apply these principles to app descriptions, lead to more critical appraisals of the sufficiency of the information they provided. Even working with only nine generic criteria was sufficient to bring about the majority of decision changes. This may lay the foundation for aiding physicians in their app-related decision processes, without unduly taking up their valuable time.

Background and study aims Patients with primary sclerosing cholangitis (PSC) require repeated endoscopic retrograde cholangiography (ERC). Our aim was to evaluate whether patients with PSC require higher doses of sedation during ERC. Patients and methods We retrospectively analyzed all patients undergoing ERC from 2006 to 2013 who received conscious sedation with propofol and midazolam. The duration of the intervention and a potential progression of propofol consumption or intervention time by visit number were analyzed. Univariable and multivariable analyses were performed to identify independent factors which influence propofol consumption. Results A total of 2962 ERC procedures were performed in 1211 patients. Patients with PSC (n = 157) underwent 461 ERC procedures whereas patients without PSC (n = 1054) had 2501 ERC examinations. The total median propofol dose was 450 mg (290 – 630 mg) for patients with PSC and 300 mg (200 – 450 mg) for the non-PSC group (P < 0.05). The propofol consumption in patients with PSC was increased by a factor of 1.24 (P = 0.0071) independent of intervention time. Younger age (< 60.8 years) and duration of the intervention were associated with a higher need for sedation by factors of 1.21 and 1.71, respectively (P < 0.0001). The robustness of the results was tested in a sensitivity analysis which confirmed the results (P < 0.0001). Conclusions Patients with PSC may require higher doses of sedation for ERC compared to other patient groups independent of age and duration of ERC. The higher dosage of sedation has to be taken into account when using ERC to treat a patient with PSC.

BackgroundMuch of the evidence linking air pollutant exposure with changes in human cardiovascular autonomic regulation relied on epidemiological studies, exposure estimates, and indirect autonomic nervous system measurements. We tested the hypothesis that in healthy older individuals, experimental exposure to fine particles increases sympathetic nervous system activity and more so with addition of ozone.Material and MethodsEighteen healthy participants (age >50 years) completed all study visits and were included in the final analysis. Participants were exposed to clean air (‘placebo’), ultrafine particles (UFP, 50μg/m3), and combination of UFP+ozone (250 ppb) for 3 hours combined with intermittent bicycle ergometer training in a randomized, three‐period, cross‐over, double‐blind fashion. Three hours following exposure, respiration, ECG, blood pressure, and muscle sympathetic nerve activity (MSNA) were continuously recorded at supine rest, during deep breathing, and during a Valsalva maneuver. Venous blood samples for plasma catecholamine measurements were taken at baseline. Induced sputum was obtained at the end of each study day.ResultsCombined exposure to ozone and UFP but not UFP alone caused a significant increase in sputum neutrophils and circulating leucocytes. We did not detect significant effects on blood pressure or heart rate. Resting MSNA was 47±12 with clean air, 47±14 with UFP, and 45±14 bursts/min with UFP+ozone. Maximum MSNA during Valsalva phase IIb was similar. Yet, with UFP+ozone plasma norepinephrine concentrations were significantly increased with concomitant reduction in the dihydroxyphenylglycol (DHPG)/norepinephrine ratio. Respiratory sinus arrhythmia and Valsalva ratio were unaffected by experimental air pollution.ConclusionExposure to ultrafine particles with or without ozone does not elicit clinically relevant changes in central sympathetic or parasympathetic activity in healthy older subjects. The paradoxical norepinephrine increase with UFP+ozone may be explained by reduced peripheral norepinephrine uptake and metabolism.Support or Funding InformationMM was funded by a grant from the German Research Foundation (Deutsche Forschungsgemeinschaft, DFG, awarded to JJ: JO 284/8‐1). The German Aerospace Center (DLR) supported JT, KH, and MM (50 WB1117, 50WB1517).

Background End-to-end and end-to-side anastomoses remain the most common techniques in microsurgical free flap reconstruction. Still, there is an ongoing effort to optimize established techniques and develop novel techniques. Numerous comparative studies have investigated flow dynamics and patency rates of microvascular anastomoses and their impact on flap survival. In contrast, few studies have investigated whether the type of anastomosis influences the outcome of microvascular free flap reconstruction of a lower extremity. Patients and Methods Retrospectively, we investigated the outcome of 131 consecutive free flaps for lower extremity reconstruction related to the anastomotic technique. Results No statistical significance between arterial or venous anastomoses were found regarding the anastomotic techniques (p = 0.5470). However, evaluated separately by vessel type, a trend toward statistical significance for anastomotic technique was observed in the arterial (p = 0.0690) and venous (p = 0.1700) vessels. No thromboses were found in arterial end-to-end anastomoses and venous end-to-side anastomoses. More venous (n = 18) than arterial thromboses (n = 9) occurred in primary anastomoses undergoing microsurgical free flap reconstruction (p = 0.0098). Flap survival rate was 97.37% in the end-to-end arterial group versus 86.36% in the end-to-side group. No thromboses were found in five arterial anastomoses using T-patch technique. Conclusion For lower extremities, there is a connate higher risk for venous thrombosis in anastomotic regions compared with arterial thrombosis. We observed divergent rates for thromboses between end-to-end and end-to-side anastomoses.However, if thrombotic events are explained by anastomotic technique and vessel type, the latter carries more importance.

Metaplastic breast carcinoma (MBC) comprises a heterogeneous group of tumors with difficult to predict biological behavior. A subset of MBC, characterized by spindle-shaped tumor cells with a myoepithelial-like immunophenotype, was entered into a retrospective study (n = 42, median follow-up time 43 months). Molecular parameters (DNA sequences of mutation hot spots in AKT1, ALK, APC, BRAF, CDH1, CTNNB1, EGFR, ERBB2, FBXW7, FGFR2, FOXL2, GNAQ, GNAS, KIT, KRAS, MAP2K1, MET, MSH6, NRAS, PDGFRA, PIK3CA, PTEN, SF3B1, SMAD4, SRC, SRSF2, STK11, TP53, and U2AF1; copy numbers for EGFR, c-myc, FGFR, PLAG, c-met) were assessed. None of the patients had axillary lymph node involvement. In 13 cases, local recurrence developed after surgery (30.9 %). Distant metastasis occurred in seven patients (17 %; four after local recurrence). The most frequent genetic alteration was PIK3CA mutation (50 % of cases). None of the pathological parameters (size, grade, stage, Ki-67 labeling index) was significantly associated with disease-free survival (DFS) or overall survival (OS). PIK3CA mutation, especially the H1047R type, tended to adversely affect OS. Type of resection (mastectomy vs. breast-conserving therapy, width of margins) or adjuvant radiotherapy had no influence on DFS or OS, whereas in the group treated with radio-/chemotherapy, no local recurrence or metastasis and no death occurred. We conclude that the spindle cell type of MBC with myoepithelial features exhibits a higher frequency of PIK3CA mutation than other types of metaplastic or basal-like breast cancer and may benefit from combined radio-/chemotherapy. Classical pathological parameters are not helpful in identifying the high-risk tumors among this subgroup of MBC.

This study evaluated the diagnostic value of D-dimer, CRP, and leucocytes count to detect an underlying pulmonary embolism (PE) in patients with pneumonia. A predictive model of an underlying PE, based on laboratory markers and clinical symptoms, was our ultimate objective. Overall 100 patients underwent a computed tomography angiography (CTA) of the lung: 54 with coexistence of PE and pneumonia (cases) and 46 with pneumonia without PE (controls). Cases and controls were matched 1 : 1. Symptoms and paraclinical findings were registered on admission. Receiver operating characteristic (ROC) curves, search for an optimal threshold, and conditional logistic regression analysis were conducted. D-dimer has a moderate ability to detect PE in pneumonia. Sensitivity of D-dimer was estimated at 97.78% and specificity at 11.11%. No optimal cut-point has acceptable diagnostic ability. After excluding patients with sepsis, sensitivity was reduced to 96.97%, whereas specificity increased to 16.13%. Consolidation in chest X-ray and positive D-dimer predict better an underlying PE as D-dimer itself. Thus, discriminatory power of the prediction model (AUC of 0.740) is not much greater than D-dimer (AUC of 0.703). No threshold that could increase the diagnostic value of D-dimer or a prediction model which is significantly better than D-dimer itself was identified.