title: The concordance between nonclinical and phase I clinical cardiovascular assessment from a cross-company data sharing initiative.
abstract: It is widely accepted that more needs to be done to bring new, safe, and efficacious drugs to the market. Cardiovascular toxicity detected both in early drug discovery as well as in the clinic, is a major contributor to the high failure rate of new molecules. The growth of translational safety offers a promising approach to improve the probability of success for new molecules. Here we describe a cross-company initiative to determine the concordance between the conscious telemetered dog and phase I outcome for 3 cardiovascular parameters. The data indicate that, in the context of the methods applied in this analysis, the ability to detect compounds that affect the corrected QT interval (QTc) was good within the 10-30x exposure range but the predictive or detective value for heart rate and diastolic blood pressure was poor. These findings may highlight opportunities to refine both the animal and the clinical study designs, as well as refocusing the assessment of value of dog cardiovascular assessments beyond phase 1. This investigation has also highlighted key considerations for cross-company data sharing and presents a unique learning opportunity to improve future translational projects.
authors.affiliation: *AstraZeneca R&D Mölndal, Pepparedsleden 1, 431 83, Mölndal, Sweden, GlaxoSmithKline, Park Road, Ware, Hertfordshire, SG12 ODP, UK, Novartis Pharma AG, PO Box, CH-4002, Basel, Switzerland, Amgen, Inc, One Amgen Center Drive, Thousand Oaks, CA 91320, Janssen Research & Development, a division of Janssen Pharmaceutica NV, Turnhoutseweg 30, B-2340 Beerse, Belgium, Novartis Institutes for BioMedical Research, One Health Plaza, East Hanover, NJ 07936, Eli Lilly and company, Indianapolis, IN 46285, Association of the British Pharmaceutical Industry, 105 Victoria Street, London SW1E 6QT, UK, Pfizer Inc., Eastern Point Road, Groton, CT 06340 and Safety Pharmacology consultant, Sandwich, Kent, UK lorna.ewart@astrazeneca.com.
authors.forename: Lorna
authors.initials: L
authors.lastname: Ewart
authors.affiliation: *AstraZeneca R&D Mölndal, Pepparedsleden 1, 431 83, Mölndal, Sweden, GlaxoSmithKline, Park Road, Ware, Hertfordshire, SG12 ODP, UK, Novartis Pharma AG, PO Box, CH-4002, Basel, Switzerland, Amgen, Inc, One Amgen Center Drive, Thousand Oaks, CA 91320, Janssen Research & Development, a division of Janssen Pharmaceutica NV, Turnhoutseweg 30, B-2340 Beerse, Belgium, Novartis Institutes for BioMedical Research, One Health Plaza, East Hanover, NJ 07936, Eli Lilly and company, Indianapolis, IN 46285, Association of the British Pharmaceutical Industry, 105 Victoria Street, London SW1E 6QT, UK, Pfizer Inc., Eastern Point Road, Groton, CT 06340 and Safety Pharmacology consultant, Sandwich, Kent, UK.
authors.forename: Mike
authors.initials: M
authors.lastname: Aylott
authors.affiliation: *AstraZeneca R&D Mölndal, Pepparedsleden 1, 431 83, Mölndal, Sweden, GlaxoSmithKline, Park Road, Ware, Hertfordshire, SG12 ODP, UK, Novartis Pharma AG, PO Box, CH-4002, Basel, Switzerland, Amgen, Inc, One Amgen Center Drive, Thousand Oaks, CA 91320, Janssen Research & Development, a division of Janssen Pharmaceutica NV, Turnhoutseweg 30, B-2340 Beerse, Belgium, Novartis Institutes for BioMedical Research, One Health Plaza, East Hanover, NJ 07936, Eli Lilly and company, Indianapolis, IN 46285, Association of the British Pharmaceutical Industry, 105 Victoria Street, London SW1E 6QT, UK, Pfizer Inc., Eastern Point Road, Groton, CT 06340 and Safety Pharmacology consultant, Sandwich, Kent, UK.
authors.forename: Mark
authors.initials: M
authors.lastname: Deurinck
authors.affiliation: *AstraZeneca R&D Mölndal, Pepparedsleden 1, 431 83, Mölndal, Sweden, GlaxoSmithKline, Park Road, Ware, Hertfordshire, SG12 ODP, UK, Novartis Pharma AG, PO Box, CH-4002, Basel, Switzerland, Amgen, Inc, One Amgen Center Drive, Thousand Oaks, CA 91320, Janssen Research & Development, a division of Janssen Pharmaceutica NV, Turnhoutseweg 30, B-2340 Beerse, Belgium, Novartis Institutes for BioMedical Research, One Health Plaza, East Hanover, NJ 07936, Eli Lilly and company, Indianapolis, IN 46285, Association of the British Pharmaceutical Industry, 105 Victoria Street, London SW1E 6QT, UK, Pfizer Inc., Eastern Point Road, Groton, CT 06340 and Safety Pharmacology consultant, Sandwich, Kent, UK.
authors.forename: Mike
authors.initials: M
authors.lastname: Engwall
authors.affiliation: *AstraZeneca R&D Mölndal, Pepparedsleden 1, 431 83, Mölndal, Sweden, GlaxoSmithKline, Park Road, Ware, Hertfordshire, SG12 ODP, UK, Novartis Pharma AG, PO Box, CH-4002, Basel, Switzerland, Amgen, Inc, One Amgen Center Drive, Thousand Oaks, CA 91320, Janssen Research & Development, a division of Janssen Pharmaceutica NV, Turnhoutseweg 30, B-2340 Beerse, Belgium, Novartis Institutes for BioMedical Research, One Health Plaza, East Hanover, NJ 07936, Eli Lilly and company, Indianapolis, IN 46285, Association of the British Pharmaceutical Industry, 105 Victoria Street, London SW1E 6QT, UK, Pfizer Inc., Eastern Point Road, Groton, CT 06340 and Safety Pharmacology consultant, Sandwich, Kent, UK.
authors.forename: David J
authors.initials: DJ
authors.lastname: Gallacher
authors.affiliation: *AstraZeneca R&D Mölndal, Pepparedsleden 1, 431 83, Mölndal, Sweden, GlaxoSmithKline, Park Road, Ware, Hertfordshire, SG12 ODP, UK, Novartis Pharma AG, PO Box, CH-4002, Basel, Switzerland, Amgen, Inc, One Amgen Center Drive, Thousand Oaks, CA 91320, Janssen Research & Development, a division of Janssen Pharmaceutica NV, Turnhoutseweg 30, B-2340 Beerse, Belgium, Novartis Institutes for BioMedical Research, One Health Plaza, East Hanover, NJ 07936, Eli Lilly and company, Indianapolis, IN 46285, Association of the British Pharmaceutical Industry, 105 Victoria Street, London SW1E 6QT, UK, Pfizer Inc., Eastern Point Road, Groton, CT 06340 and Safety Pharmacology consultant, Sandwich, Kent, UK.
authors.forename: Helena
authors.initials: H
authors.lastname: Geys
authors.affiliation: *AstraZeneca R&D Mölndal, Pepparedsleden 1, 431 83, Mölndal, Sweden, GlaxoSmithKline, Park Road, Ware, Hertfordshire, SG12 ODP, UK, Novartis Pharma AG, PO Box, CH-4002, Basel, Switzerland, Amgen, Inc, One Amgen Center Drive, Thousand Oaks, CA 91320, Janssen Research & Development, a division of Janssen Pharmaceutica NV, Turnhoutseweg 30, B-2340 Beerse, Belgium, Novartis Institutes for BioMedical Research, One Health Plaza, East Hanover, NJ 07936, Eli Lilly and company, Indianapolis, IN 46285, Association of the British Pharmaceutical Industry, 105 Victoria Street, London SW1E 6QT, UK, Pfizer Inc., Eastern Point Road, Groton, CT 06340 and Safety Pharmacology consultant, Sandwich, Kent, UK.
authors.forename: Philip
authors.initials: P
authors.lastname: Jarvis
authors.affiliation: *AstraZeneca R&D Mölndal, Pepparedsleden 1, 431 83, Mölndal, Sweden, GlaxoSmithKline, Park Road, Ware, Hertfordshire, SG12 ODP, UK, Novartis Pharma AG, PO Box, CH-4002, Basel, Switzerland, Amgen, Inc, One Amgen Center Drive, Thousand Oaks, CA 91320, Janssen Research & Development, a division of Janssen Pharmaceutica NV, Turnhoutseweg 30, B-2340 Beerse, Belgium, Novartis Institutes for BioMedical Research, One Health Plaza, East Hanover, NJ 07936, Eli Lilly and company, Indianapolis, IN 46285, Association of the British Pharmaceutical Industry, 105 Victoria Street, London SW1E 6QT, UK, Pfizer Inc., Eastern Point Road, Groton, CT 06340 and Safety Pharmacology consultant, Sandwich, Kent, UK.
authors.forename: Haisong
authors.initials: H
authors.lastname: Ju
authors.affiliation: *AstraZeneca R&D Mölndal, Pepparedsleden 1, 431 83, Mölndal, Sweden, GlaxoSmithKline, Park Road, Ware, Hertfordshire, SG12 ODP, UK, Novartis Pharma AG, PO Box, CH-4002, Basel, Switzerland, Amgen, Inc, One Amgen Center Drive, Thousand Oaks, CA 91320, Janssen Research & Development, a division of Janssen Pharmaceutica NV, Turnhoutseweg 30, B-2340 Beerse, Belgium, Novartis Institutes for BioMedical Research, One Health Plaza, East Hanover, NJ 07936, Eli Lilly and company, Indianapolis, IN 46285, Association of the British Pharmaceutical Industry, 105 Victoria Street, London SW1E 6QT, UK, Pfizer Inc., Eastern Point Road, Groton, CT 06340 and Safety Pharmacology consultant, Sandwich, Kent, UK.
authors.forename: Derek
authors.initials: D
authors.lastname: Leishman
authors.affiliation: *AstraZeneca R&D Mölndal, Pepparedsleden 1, 431 83, Mölndal, Sweden, GlaxoSmithKline, Park Road, Ware, Hertfordshire, SG12 ODP, UK, Novartis Pharma AG, PO Box, CH-4002, Basel, Switzerland, Amgen, Inc, One Amgen Center Drive, Thousand Oaks, CA 91320, Janssen Research & Development, a division of Janssen Pharmaceutica NV, Turnhoutseweg 30, B-2340 Beerse, Belgium, Novartis Institutes for BioMedical Research, One Health Plaza, East Hanover, NJ 07936, Eli Lilly and company, Indianapolis, IN 46285, Association of the British Pharmaceutical Industry, 105 Victoria Street, London SW1E 6QT, UK, Pfizer Inc., Eastern Point Road, Groton, CT 06340 and Safety Pharmacology consultant, Sandwich, Kent, UK.
authors.forename: Louise
authors.initials: L
authors.lastname: Leong
authors.affiliation: *AstraZeneca R&D Mölndal, Pepparedsleden 1, 431 83, Mölndal, Sweden, GlaxoSmithKline, Park Road, Ware, Hertfordshire, SG12 ODP, UK, Novartis Pharma AG, PO Box, CH-4002, Basel, Switzerland, Amgen, Inc, One Amgen Center Drive, Thousand Oaks, CA 91320, Janssen Research & Development, a division of Janssen Pharmaceutica NV, Turnhoutseweg 30, B-2340 Beerse, Belgium, Novartis Institutes for BioMedical Research, One Health Plaza, East Hanover, NJ 07936, Eli Lilly and company, Indianapolis, IN 46285, Association of the British Pharmaceutical Industry, 105 Victoria Street, London SW1E 6QT, UK, Pfizer Inc., Eastern Point Road, Groton, CT 06340 and Safety Pharmacology consultant, Sandwich, Kent, UK.
authors.forename: Nick
authors.initials: N
authors.lastname: McMahon
authors.affiliation: *AstraZeneca R&D Mölndal, Pepparedsleden 1, 431 83, Mölndal, Sweden, GlaxoSmithKline, Park Road, Ware, Hertfordshire, SG12 ODP, UK, Novartis Pharma AG, PO Box, CH-4002, Basel, Switzerland, Amgen, Inc, One Amgen Center Drive, Thousand Oaks, CA 91320, Janssen Research & Development, a division of Janssen Pharmaceutica NV, Turnhoutseweg 30, B-2340 Beerse, Belgium, Novartis Institutes for BioMedical Research, One Health Plaza, East Hanover, NJ 07936, Eli Lilly and company, Indianapolis, IN 46285, Association of the British Pharmaceutical Industry, 105 Victoria Street, London SW1E 6QT, UK, Pfizer Inc., Eastern Point Road, Groton, CT 06340 and Safety Pharmacology consultant, Sandwich, Kent, UK.
authors.forename: Andy
authors.initials: A
authors.lastname: Mead
authors.affiliation: *AstraZeneca R&D Mölndal, Pepparedsleden 1, 431 83, Mölndal, Sweden, GlaxoSmithKline, Park Road, Ware, Hertfordshire, SG12 ODP, UK, Novartis Pharma AG, PO Box, CH-4002, Basel, Switzerland, Amgen, Inc, One Amgen Center Drive, Thousand Oaks, CA 91320, Janssen Research & Development, a division of Janssen Pharmaceutica NV, Turnhoutseweg 30, B-2340 Beerse, Belgium, Novartis Institutes for BioMedical Research, One Health Plaza, East Hanover, NJ 07936, Eli Lilly and company, Indianapolis, IN 46285, Association of the British Pharmaceutical Industry, 105 Victoria Street, London SW1E 6QT, UK, Pfizer Inc., Eastern Point Road, Groton, CT 06340 and Safety Pharmacology consultant, Sandwich, Kent, UK.
authors.forename: Phil
authors.initials: P
authors.lastname: Milliken
authors.affiliation: *AstraZeneca R&D Mölndal, Pepparedsleden 1, 431 83, Mölndal, Sweden, GlaxoSmithKline, Park Road, Ware, Hertfordshire, SG12 ODP, UK, Novartis Pharma AG, PO Box, CH-4002, Basel, Switzerland, Amgen, Inc, One Amgen Center Drive, Thousand Oaks, CA 91320, Janssen Research & Development, a division of Janssen Pharmaceutica NV, Turnhoutseweg 30, B-2340 Beerse, Belgium, Novartis Institutes for BioMedical Research, One Health Plaza, East Hanover, NJ 07936, Eli Lilly and company, Indianapolis, IN 46285, Association of the British Pharmaceutical Industry, 105 Victoria Street, London SW1E 6QT, UK, Pfizer Inc., Eastern Point Road, Groton, CT 06340 and Safety Pharmacology consultant, Sandwich, Kent, UK.
authors.forename: Willi
authors.initials: W
authors.lastname: Suter
authors.affiliation: *AstraZeneca R&D Mölndal, Pepparedsleden 1, 431 83, Mölndal, Sweden, GlaxoSmithKline, Park Road, Ware, Hertfordshire, SG12 ODP, UK, Novartis Pharma AG, PO Box, CH-4002, Basel, Switzerland, Amgen, Inc, One Amgen Center Drive, Thousand Oaks, CA 91320, Janssen Research & Development, a division of Janssen Pharmaceutica NV, Turnhoutseweg 30, B-2340 Beerse, Belgium, Novartis Institutes for BioMedical Research, One Health Plaza, East Hanover, NJ 07936, Eli Lilly and company, Indianapolis, IN 46285, Association of the British Pharmaceutical Industry, 105 Victoria Street, London SW1E 6QT, UK, Pfizer Inc., Eastern Point Road, Groton, CT 06340 and Safety Pharmacology consultant, Sandwich, Kent, UK.
authors.forename: Ard
authors.initials: A
authors.lastname: Teisman
authors.affiliation: *AstraZeneca R&D Mölndal, Pepparedsleden 1, 431 83, Mölndal, Sweden, GlaxoSmithKline, Park Road, Ware, Hertfordshire, SG12 ODP, UK, Novartis Pharma AG, PO Box, CH-4002, Basel, Switzerland, Amgen, Inc, One Amgen Center Drive, Thousand Oaks, CA 91320, Janssen Research & Development, a division of Janssen Pharmaceutica NV, Turnhoutseweg 30, B-2340 Beerse, Belgium, Novartis Institutes for BioMedical Research, One Health Plaza, East Hanover, NJ 07936, Eli Lilly and company, Indianapolis, IN 46285, Association of the British Pharmaceutical Industry, 105 Victoria Street, London SW1E 6QT, UK, Pfizer Inc., Eastern Point Road, Groton, CT 06340 and Safety Pharmacology consultant, Sandwich, Kent, UK.
authors.forename: Karel
authors.initials: K
authors.lastname: Van Ammel
authors.affiliation: *AstraZeneca R&D Mölndal, Pepparedsleden 1, 431 83, Mölndal, Sweden, GlaxoSmithKline, Park Road, Ware, Hertfordshire, SG12 ODP, UK, Novartis Pharma AG, PO Box, CH-4002, Basel, Switzerland, Amgen, Inc, One Amgen Center Drive, Thousand Oaks, CA 91320, Janssen Research & Development, a division of Janssen Pharmaceutica NV, Turnhoutseweg 30, B-2340 Beerse, Belgium, Novartis Institutes for BioMedical Research, One Health Plaza, East Hanover, NJ 07936, Eli Lilly and company, Indianapolis, IN 46285, Association of the British Pharmaceutical Industry, 105 Victoria Street, London SW1E 6QT, UK, Pfizer Inc., Eastern Point Road, Groton, CT 06340 and Safety Pharmacology consultant, Sandwich, Kent, UK.
authors.forename: Hugo M
authors.initials: HM
authors.lastname: Vargas
authors.affiliation: *AstraZeneca R&D Mölndal, Pepparedsleden 1, 431 83, Mölndal, Sweden, GlaxoSmithKline, Park Road, Ware, Hertfordshire, SG12 ODP, UK, Novartis Pharma AG, PO Box, CH-4002, Basel, Switzerland, Amgen, Inc, One Amgen Center Drive, Thousand Oaks, CA 91320, Janssen Research & Development, a division of Janssen Pharmaceutica NV, Turnhoutseweg 30, B-2340 Beerse, Belgium, Novartis Institutes for BioMedical Research, One Health Plaza, East Hanover, NJ 07936, Eli Lilly and company, Indianapolis, IN 46285, Association of the British Pharmaceutical Industry, 105 Victoria Street, London SW1E 6QT, UK, Pfizer Inc., Eastern Point Road, Groton, CT 06340 and Safety Pharmacology consultant, Sandwich, Kent, UK *AstraZeneca R&D Mölndal, Pepparedsleden 1, 431 83, Mölndal, Sweden, GlaxoSmithKline, Park Road, Ware, Hertfordshire, SG12 ODP, UK, Novartis Pharma AG, PO Box, CH-4002, Basel, Switzerland, Amgen, Inc, One Amgen Center Drive, Thousand Oaks, CA 91320, Janssen Research & Development, a division of Janssen Pharmaceutica NV, Turnhoutseweg 30, B-2340 Beerse, Belgium, Novartis Institutes for BioMedical Research, One Health Plaza, East Hanover, NJ 07936, Eli Lilly and company, Indianapolis, IN 46285, Association of the British Pharmaceutical Industry, 105 Victoria Street, London SW1E 6QT, UK, Pfizer Inc., Eastern Point Road, Groton, CT 06340 and Safety Pharmacology consultant, Sandwich, Kent, UK.
authors.forename: Rob
authors.initials: R
authors.lastname: Wallis
authors.affiliation: *AstraZeneca R&D Mölndal, Pepparedsleden 1, 431 83, Mölndal, Sweden, GlaxoSmithKline, Park Road, Ware, Hertfordshire, SG12 ODP, UK, Novartis Pharma AG, PO Box, CH-4002, Basel, Switzerland, Amgen, Inc, One Amgen Center Drive, Thousand Oaks, CA 91320, Janssen Research & Development, a division of Janssen Pharmaceutica NV, Turnhoutseweg 30, B-2340 Beerse, Belgium, Novartis Institutes for BioMedical Research, One Health Plaza, East Hanover, NJ 07936, Eli Lilly and company, Indianapolis, IN 46285, Association of the British Pharmaceutical Industry, 105 Victoria Street, London SW1E 6QT, UK, Pfizer Inc., Eastern Point Road, Groton, CT 06340 and Safety Pharmacology consultant, Sandwich, Kent, UK.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Valentin
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D066126:Cardiotoxicity; D017321:Clinical Trials, Phase I as Topic / Q000379:methods / Q000592:standards / Q000706:statistics & numerical data*; D004285:Dogs; D004353:Drug Evaluation, Preclinical / Q000379:methods / Q000592:standards / Q000706:statistics & numerical data*; D004345:Drug Industry / Q000592:standards*; D064420:Drug-Related Side Effects and Adverse Reactions / Q000209:etiology* / Q000503:physiopathology; D004562:Electrocardiography; D064368:Healthy Volunteers; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D011237:Predictive Value of Tests; D012680:Sensitivity and Specificity; D013686:Telemetry; D057170:Translational Research, Biomedical / Q000379:methods* / Q000592:standards / Q000706:statistics & numerical data
keywords: cardiovascular system; concordance; phase I; safety pharmacology; statistical analysis; translational safety