title: Who is a 'healthy subject'?-consensus results on pivotal eligibility criteria for clinical trials.
abstract: METHODS
  A discussion forum was hosted by the German not-for-profit Association for Applied Human Pharmacology (AGAH e.V.) to critically review key eligibility criteria and stopping rules for clinical trials with healthy subjects, enrolling stakeholders from the pharmaceutical industry, contract research organisations, academia, ethics committees and competent authority.
  
  
  RESULTS
  Pivotal eligibility criteria were defined for trials with new investigational medicinal products (IMPs) or with clinically established IMPs. In general, a pulse rate ranging between 50 and 90 beats/min is recommended for first-in-human (FIH) trials, while wider ranges seem acceptable for trials with clinically established IMPs, provided there are no indications of thyroid dysfunction. Hepatic laboratory parameters not to exceed the upper limit of normal (ULN) comprise ALT (alanine aminotransferase) and AST (aspartate aminotransferase) in FIH trials, whereas slight elevations (10% above ULN) seem acceptable in trials with clinically established IMPs without known hepatotoxicity. A normal renal function is required for any clinical trial in healthy subjects. A risk-adapted approach for stopping rules was adopted. Stopping rules for an individual subject are one adverse event of severe intensity or one serious adverse event. In case of a severe adverse event, some stakeholders demand a causal relationship with the IMP (i.e. an adverse reaction). Stopping rules for a cohort are one serious adverse reaction or ≥50% of subjects experiencing any adverse reaction of moderate or severe intensity.
  
  
  CONCLUSIONS
  The application of this consensus resulted in a reduction in protocol deficiencies issued by the competent authority.
authors.affiliation: -kbr- clinical pharmacology services, D-60431, Frankfurt am Main, Germany.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Breithaupt-Groegler
authors.affiliation: Institute of Clinical Chemistry and Clinical Pharmacology, University of Bonn, Sigmund-Freud-Str. 25, 53127, Bonn, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Coch
authors.affiliation: Institute of Clinical Chemistry and Clinical Pharmacology, University of Bonn, Sigmund-Freud-Str. 25, 53127, Bonn, Germany. martin.coenen@ukb.uni-bonn.de.
authors.forename: Martin
authors.identifier: http://orcid.org/0000-0002-1552-4726
authors.initials: M
authors.lastname: Coenen
authors.affiliation: SocraTec Research and Development GmbH, D-99084, Erfurt, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Donath
authors.affiliation: clinphase®, D-63454, Hanau, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Erb-Zohar
authors.affiliation: National Association of Statutory Health Insurance Funds, Medicinal Product Department, 10117, Berlin, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Francke
authors.affiliation: Gruenenthal GmbH, Gruenenthal Innovation-Development-Clinical Development-Clinical Pharmacology, D-52099, Aachen, Germany.
authors.forename: Karin
authors.initials: K
authors.lastname: Goehler
authors.affiliation: Boehringer Ingelheim Pharma GmbH & Co. KG, Translational Medicine and Clinical Pharmacology, D-88397, Biberach/Riss, Germany.
authors.forename: Mario
authors.initials: M
authors.lastname: Iovino
authors.affiliation: Boehringer Ingelheim Pharma GmbH & Co. KG, Translational Medicine and Clinical Pharmacology, D-88397, Biberach/Riss, Germany.
authors.forename: Klaus Peter
authors.initials: KP
authors.lastname: Kammerer
authors.affiliation: Department of Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, D-69120, Heidelberg, Germany.
authors.forename: Gerd
authors.initials: G
authors.lastname: Mikus
authors.affiliation: Gruenenthal GmbH, Gruenenthal Innovation-Research-Translational Science & Strategy-Early Clinical Science, D-52078, Aachen, Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: Rengelshausen
authors.affiliation: Sourgens Consulting, D-80797, Munich, Germany.
authors.forename: Hildegard
authors.initials: H
authors.lastname: Sourgens
authors.affiliation: vasopharm GmbH, D-97076, Würzburg, Germany.
authors.forename: Reinhard
authors.initials: R
authors.lastname: Schinzel
authors.affiliation: Federal Institute for Drugs and Medical Devices (BfArM), D-53175, Bonn, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Sudhop
authors.affiliation: Bayer Pharma AG, Pharmaceutical Division Clinical Pharmacology Cardiovascular/Hematology (Primary Care), D-42096, Wuppertal, Germany.
authors.forename: Georg
authors.initials: G
authors.lastname: Wensing
mesh_terms: D001794:Blood Pressure; D017321:Clinical Trials, Phase I as Topic; D032921:Consensus; D004562:Electrocardiography; D006304:Health Status; D064368:Healthy Volunteers; D006801:Humans
keywords: Healthy subject; Inclusion/exclusion criteria; Investigational medicinal product; Phase I; Safety parameters; Stopping rules