title: Evidence-based clinical practice: Overview of threats to the validity of evidence and how to minimise them.
abstract: Using the best quality of clinical research evidence is essential for choosing the right treatment for patients. How to identify the best research evidence is, however, difficult. In this narrative review we summarise these threats and describe how to minimise them. Pertinent literature was considered through literature searches combined with personal files. Treatments should generally not be chosen based only on evidence from observational studies or single randomised clinical trials. Systematic reviews with meta-analysis of all identifiable randomised clinical trials with Grading of Recommendations Assessment, Development and Evaluation (GRADE) assessment represent the highest level of evidence. Even though systematic reviews are trust worthier than other types of evidence, all levels of the evidence hierarchy are under threats from systematic errors (bias); design errors (abuse of surrogate outcomes, composite outcomes, etc.); and random errors (play of chance). Clinical research infrastructures may help in providing larger and better conducted trials. Trial Sequential Analysis may help in deciding when there is sufficient evidence in meta-analyses. If threats to the validity of clinical research are carefully considered and minimised, research results will be more valid and this will benefit patients and heath care systems.
authors.affiliation: IRCCS Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy. Electronic address: silvio.garattini@marionegri.it.
authors.forename: Silvio
authors.initials: S
authors.lastname: Garattini
authors.affiliation: The Copenhagen Trial Unit, Centre for Clinical Intervention Research, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark; Department of Cardiology, Holbæk Hospital, Holbæk, Denmark. Electronic address: jcj@ctu.dk.
authors.forename: Janus C
authors.initials: JC
authors.lastname: Jakobsen
authors.affiliation: The Copenhagen Trial Unit, Centre for Clinical Intervention Research, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark. Electronic address: wetterslev@ctu.dk.
authors.forename: Jørn
authors.initials: J
authors.lastname: Wetterslev
authors.affiliation: IRCCS Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy. Electronic address: vittorio.bertele@marionegri.it.
authors.forename: Vittorio
authors.initials: V
authors.lastname: Bertelé
authors.affiliation: IRCCS Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy. Electronic address: rita.banzi@marionegri.it.
authors.forename: Rita
authors.initials: R
authors.lastname: Banzi
authors.affiliation: Orphanet, Institut National de la Santé et de la Recherche Médicale US14, Paris, France. Electronic address: ana.rath@inserm.fr.
authors.forename: Ana
authors.initials: A
authors.lastname: Rath
authors.affiliation: Faculty of Health, School of Medicine, Witten/Herdecke University, Campus Cologne, Germany. Electronic address: Edmund.Neugebauer@uni-wh.de.
authors.forename: Edmund A M
authors.initials: EA
authors.lastname: Neugebauer
authors.affiliation: Centre de Recherche en Nutrition Humaine, Rhône-Alpes, Univ de Lyon, Lyon, France. Electronic address: martine.laville@chu-lyon.fr.
authors.forename: Martine
authors.initials: M
authors.lastname: Laville
authors.affiliation: Centre de Recherche en Nutrition Humaine, Rhône-Alpes, Univ de Lyon, Lyon, France. Electronic address: yvonne.masson@clermont.inra.fr.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Masson
authors.affiliation: Centre de Recherche en Nutrition Humaine, Rhône-Alpes, Univ de Lyon, Lyon, France. Electronic address: virginie.hivert@inserm.fr.
authors.forename: Virginie
authors.initials: V
authors.lastname: Hivert
authors.affiliation: Institute for Research in Operative Medicine, Faculty of Health, School of Medicine, Witten/Herdecke University, Cologne, Germany. Electronic address: michaela.eikermann@uni-wh.de.
authors.forename: Michaela
authors.initials: M
authors.lastname: Eikermann
authors.affiliation: Department of Medical Pharmacology, School of Medicine, Dokuz Eylul University, Izmir, Turkey. Electronic address: burcaydin@gmail.com.
authors.forename: Burc
authors.initials: B
authors.lastname: Aydin
authors.affiliation: Orphanet, Institut National de la Santé et de la Recherche Médicale US14, Paris, France. Electronic address: sandra-nadia.ngwabyt-bikeye@inserm.fr.
authors.forename: Sandra
authors.initials: S
authors.lastname: Ngwabyt
authors.affiliation: Palliative Care Service, Portuguese Institute of Oncology, Porto, Portugal. Electronic address: cvm@aibili.pt.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Martinho
authors.affiliation: IRCCS Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy. Electronic address: chiara.gerardi@marionegri.it.
authors.forename: Chiara
authors.initials: C
authors.lastname: Gerardi
authors.affiliation: Department of Internal Medicine, Hypertension and Vascular Diseases, Medical University of Warsaw, Warsaw, Poland. Electronic address: cezary.szmigielski@wum.edu.pl.
authors.forename: Cezary A
authors.initials: CA
authors.lastname: Szmigielski
authors.affiliation: ECRIN (European Clinical Research Infrastructure Network), Paris, France. Electronic address: jacques.demotes@ecrin.org.
authors.forename: Jacques
authors.initials: J
authors.lastname: Demotes-Mainard
authors.affiliation: The Copenhagen Trial Unit, Centre for Clinical Intervention Research, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark. Electronic address: cgluud@ctu.dk.
authors.forename: Christian
authors.initials: C
authors.lastname: Gluud
mesh_terms: D019317:Evidence-Based Medicine; D055317:Evidence-Based Practice; D006801:Humans; D015201:Meta-Analysis as Topic; D016032:Randomized Controlled Trials as Topic; D015203:Reproducibility of Results; D012196:Review Literature as Topic
keywords: Evidence-based clinical practice; Evidence-based medicine; Meta-analysis; Randomised clinical trial; Systematic review; Trial Sequential Analysis