Beharrlichkeit und Bürde fehlgeschlagener Paradigmen in der Arzneimittelentwicklung: eine explorative Analyse der VEGF-Inhibition bei Brustkrebs

Background: Failures in cancer drug development impose heavy burdens on patients, researchers, industry, and funders. Burdens in targeted drug development could be mitigated if investigators efficiently integrated not only trial outcomes, but also evidence for underlying pathophysiological hypotheses of drugs tested. However, little is known about how clinical trials testing different drugs with the same targets learn from each other’s failures and successes. The goal of this project was: a) to map the total patient burden and benefit of trials testing one failed drug development paradigm that showed particular perseverance (Vascular Endothelial Growth Factor [VEGF]-inhibition in breast cancer), and b) to describe the production and uptake of evidence from related clinical trials and address why the research agenda persisted despite limited evidence. Methods: We searched in the Embase and MEDLINE databases on February 9, 2017 for clinical trials testing VEGF inhibitors against breast cancer. We measured risk using drug-related serious adverse events (SAEs) Grade 3 or higher, benefit by objective response rate (ORR) and survival advantage versus a comparator arm, as well as trial outcomes by whether studies met their primary endpoint with acceptable toxicity. We assessed citation bias by comparing the number of cited earlier reports with the number of overall citable earlier reports within the trial reports included. Results: Up to February 2017, the VEGF inhibition paradigm in breast cancer consisted of 146 trials of 19 drugs that enrolled 17,924 patients. 6,441 patients receiving a VEGF inhibitor experienced ORR (46% of intent-to-treat population, 95% confidence interval [CI]: 45.1% to 46.8%), 114 died from drug-related toxicities (0.64%, 95% CI: 0.53% to 0.77%), at least 5448 experienced Grade 3–4 SAEs (30.4%, 95% CI: 29.7% to 31.1%). No trial showed a survival advantage for any VEGF inhibitor. Risk and benefit remained stable over the course of the paradigm suggesting little treatment optimization. Trials cited on average 5.38 prior reports within the set (12.6% of those available). Patients in positive trials were 2.4 times more likely to be cited in the discussion sections of subsequent reports than patients in non-positive trials. Citation bias did not diminish over the course of the paradigm’s testing. Fifty-seven (39%) of the trials cited reports that tested a different VEGF inhibitor. Conclusion: The paradigm of VEGF inhibition in breast cancer posed substantial patient burdens and did not provide survival benefit. Citation bias and limited learning between trials of different drugs of the same class may have contributed to its perseverance.Hintergrund: Misserfolge bei der Entwicklung von Krebsmedikamenten belasten Patienten, Forschung, Industrie und Geldgeber erheblich. Diese Last könnte bei der Entwicklung von zielgerichteten Medikamenten reduziert werden, indem die Forschung nicht nur Studienergebnisse, sondern auch Erkenntnisse zu den pathophysiologischen Hypothesen der getesteten Arzneimittel effizient integriert. Es ist jedoch wenig darüber bekannt, wie klinische Studien, in denen verschiedene Medikamente mit dem gleichen Wirkmechanismus getestet werden, aus den Misserfolgen und Erfolgen von Studien der gleichen Klasse lernen. Das Ziel dieses Projekts war es: a) Patientenlast und -nutzen klinischer Studien einer gescheiterten Medikamentenklasse, die besondere Beharrlichkeit gezeigt hat (Vascular Endothelial Growth Factor [VEGF]-Inhibition bei Brustkrebs) zu quantifizieren b) die Produktion und Integration von Evidenz aus miteinander verwandten klinischen Studien zu beschreiben und zu erörtern, warum die Forschungsagenda trotz begrenzter Evidenz vorangetrieben wurde. Methoden: Am 9. Februar 2017 wurden die Datenbanken Embase und MEDLINE nach klinischen Studien durchsucht, die VEGF-Inhibitoren in Brustkrebs untersuchten. Patientenlast wurde anhand von Serious Adverse Events (SAEs) Grad 3 oder höher bestimmt, Patientennutzen anhand von Objective Response Rate (ORR) sowie Überlebensvorteil gegenüber einem Vergleichsarm. Studienerfolg wurde durch das Erreichen des primären Endpunktes bei akzeptabler Toxizität definiert. Zitationsbias wurde gemessen, indem die Anzahl der zitierten vorangegangenen Studien mit der Anzahl der insgesamt zitierfähigen Studien in dem eingeschlossenen Set verglichen wurden. Ergebnisse: Das Entwicklungsparadigma der VEGF-Inhibition bei Brustkrebs bestand bis Februar 2017 aus 146 Studien mit 19 Arzneimitteln die 17.924 Patienten einschlossen. 6441 Patienten, die einem VEGF-Inhibitor ausgesetzt wurden, zeigten Objective Response (46% der intent-to-treat population, 95% Konfidenzintervall [CI]: 45,1% bis 46,8%), 114 starben an arzneimittelbedingten Nebenwirkungen (0,64%, 95% CI: 0,53 % bis 0,77%) und mindestens 5448 erlitten medikamentenbedingte Nebenwirkungen Grad 3–4 (30,4%, 95% CI: 29,7% bis 31,1%). Keine Studie zeigte einen Überlebensvorteil für einen VEGF-Inhibitor. Risiko und Nutzen blieben im Verlauf des Entwicklungsparadigmas konstant, was darauf hindeutet, dass wenig Optimierung der Therapie stattfinden konnte. Studien zitierten durchschnittlich 5,38 frühere Studien innerhalb des Samples (12,6% der verfügbaren Studienberichte). Patienten in positiven Studien wurden in den Diskussionsabschnitten nachfolgender Studien 2,4-mal häufiger zitiert als Patienten in nicht-positiven Studien. Der Zitationsbias hat im Verlauf des Paradigmas nicht abgenommen. Siebenundfünfzig (39%) Studien zitierten frühere Studienberichte, in denen ein anderer VEGF-Inhibitor getestet wurde. Schlussfolgerung: Das Entwicklungsparadigma der VEGF-Inhibition bei Brustkrebs war mit einer erheblichen Patientenlast verbunden und zeigte keinen Überlebensvorteil für einen VEGF-inhibitor. Zitationsbias und eingeschränkter Erkenntnisgewinn aus Arzneimittelstudien mit anderen Substanzen derselben Klasse haben möglicherweise zu Beharrlichkeit des Paradigmas beigetragen

Reconstruction for Renal Artery Aneurysm and its Effect on Hypertension

AbstractObjectives: many renal artery aneurysms (RAA) are diagnosed incidentally in the course of investigations for hypertension and their management is controversial. Aim: to review the results of renal artery reconstruction for RAA. Methods: between January 1978 and December 1998 111 RAR were performed in 81 kidneys in 71 patients. Results: fifty-nine patients were hypertensive, three had a creatinine >2.0 mg/dl and one was on dialysis. The principal underlying pathology was fibromuscular dysplasia (39) and atherosclerosis (17). The mean RAA diameter was 2.2 (range 1–15) cm overall and 3.5 (range 2–10) cm in four patients who presented with rupture. Fifty-one patients had renal artery stenosis. Autogenous material was used in 105 RAR. There was no 30-day mortality and the morbidity rate was 16%. The 5-year cumulative patency rate was 69%. Hypertension was cured in 25% and improved in 39%.Conclusions: RAR tested for RAA treats hypertension and reduces the risk of rupture and distal embolisation

On the Auschwitz Lie

In the November 1986 issue of the Michigan Law Review, Professor Eric Stein addressed the then-recent German legislation prohibiting the Auschwitz lie. The Auschwitz lie refers to contemporary attempts to deny the historical truth of the Holocaust. In the time since his article was published, Professor Stein has corresponded with several European scholars on the issues raised by the 1985 legislation. That correspondence, though brief, highlights the contentious aspects of Professor Stein\u27s analysis; it suggests that the issues of restricting historical speech, promoting national consciousness, attributing collective guilt, and identifying the role of courts in punishing historical lies remain troublesome to German intellectuals. Excerpts from Professor Stein\u27s correspondence follow

Three study decades on irrigation performance and salt concentrations and loads in the irrigation return flows of La Violada irrigation district (Spain)

30 Pags., 3 Tabls., 9 Figs. The definitive version is available at: http://www.sciencedirect.com/science/journal/01678809Irrigation district salt balances identify the main sources and sinks of salts and quantify salt loads in irrigation return flows. Salt balances were performed in La Violada Irrigation District during the 80s (1982–1984), 90s (1995–1998) and 00s (2006–2008) decades. Total Dissolved Solids (TDS) and loads in irrigation return flows were related with changes in irrigation performance and infrastructures during these decades. TDS increased linearly to increases in Irrigation Consumptive Use Coefficient (ICUC) (P 66%, and decreased exponentially for values above and below these thresholds, respectively. Therefore, the key management strategy to reduce salt discharge to downstream areas is to decrease drainage volumes by improving irrigation management.This work was sponsored by the Spanish Ministry of Science and Education project AGL2006-11860/AGR, the European Regional Development Fund (FEDER) and the European Union project INCO CT-2005-015031.Peer reviewe

Interventional creation of an atrial septal defect and its impact on right ventricular function: An animal study with the pressure-volume conductance system

Background: The aim of our study was to assess the suitability of different interventional techniques to create an atrial septal defect (ASD) and to evaluate the short-term effects of right ventricular (RV) volume overload on RV contractility in the growing swine. Methods: Thirteen ASD and six control animals were studied. An ASD was created by balloon dilatation (BD) of the fossa ovalis (n = 4) or by implantation of a multi-perforated Amplatzer Septal Occluder (n = 4) or a patch-less nitinol device (n = 5). After 4.8 (3.9&#8211;6.0) weeks, the amounts of left-to-right shunting (Qp/Qs) and RV contractility (end systolic elastance &#8212; Ees) were assessed. Results: In the ASD group, a significant left-to-right shunt could be documented (Qp/Qs 1.5 &#177; &#177; 0.4). However, a shunt was absent in the BD subgroup (Qp/Qs 1.1 &#177; 0.1). In animals with devices implanted, a significant relationship between the post-mortem ASD area and Qp/Qs was found (r = 0.68, p < 0.05). Compared to controls, RV contractility was not significantly impaired at rest and during dobutamine in ASD animals (Ees: 0.40 &#177; 0.20 vs 0.54 &#177; 0.12 and 0.75 &#177; 0.29 vs 1.04 &#177; 0.24 mm Hg/mL, p = NS for both). Conclusions: Device implantation is necessary to create a patent ASD resulting in significant left-to-right shunting. In an experimental ASD model, a five week period of chronic RV volume overload does not alter RV contractility significantly. (Cardiol J 2011; 18, 3: 289&#8211;296