Research Data Management
Scientific integrity & Societal value
Prof. Dr. Meindert Danhof
Leiden Academic Centre for Drug Researchmission & objectives
LACDR is one of the leading academic centres in learning, in 
teaching, and in advancing innovative medicines research
• state of the art multidisciplinary medicines research 
• undergraduate education leading to the BSc and MSc degree
• graduate education leading to the PhD degree
• collaboration with the international (pharmaceutical) industry 
in strategic research projects
OH
OH
Synthetic opioidsRemifentanil versus GR 90291
Remifentanil GR 90291
• Ultra-short acting synthetic opioid for use in anesthesia
• Contribution of the metabolite GR90291 to the effect?
Pharmacokinetic-Pharmacodynamic Modeling of the 
Electroencephalogram Effect of Synthetic Opioids in the Rat: 
Correlation with the Interaction at the Mu-Opioid Receptor 
EUGENE H. COX, THOMAS KERBUSCH, PIETER H. VAN DER GRAAF and MEINDERT DANHOF 
Leiden/Amsterdam Center for Drug Research, Division of Pharmacology, University of Leiden, Sylvius Laboratory, P.O. 
Box 9503, 2300 RA Leiden, The Netherlands 
Accepted for publication November 13, 1997 This paper is available online at http://www.jpet.org
Synthetic opioidsthe key publication
From: Cox et al., J. Pharmacol. Exp. Ther. 284: 1095-1103 (1998)
Chronically instrumented rat models    plasma concentration & EEG effect
Intravenous infusion of alfentanilcharacteristic EEG changes
Cox  et al., J. Pharmacol. Toxicol. Meth. 38: 99-108 (1997)
change in delta 
frequeny band 
= 
surrogate for 
depth of 
anesthesia
Synthetic opiates  plasma concentration & EEG effect  
From: Cox et al., J. Pharmacol. Exp. Ther. 284: 1095-1103 (1998)
Synthetic opiates                             pharmacokinetic-pharmacodynamic model
Synthetic opiatesconcentration-effect relations in rats 
From: Cox et al., J. Pharmacol. Exp. Ther. 284: 1095-1103 (1998)
Biophase concentration
EEG
 eff
ect
EC50 = potency
ECmax = intrinsic 
effiacy
                   Emax . CN E =           EC50 + CN 
Concentration-effect relations of synthetic opioidsrats versus humans 
From: Cox et al., J. Pharmacol. Exp. Ther. 284: 1095-1103 (1998)
• protocol: animal ethics commitee approval?
• experimental animals: origin, strain, sex, body weight, health 
status?
• experimental procedures: surgery, recovery, drug 
administration, doses
• EEG recording and analysis:  technique, validation
• Bio-analytical techniques:  validation
• Data analysis: PK analysis, PKPD analysis
• Raw data: plasma concentrations, EEG effect measures
• Derived data: PK parameters, PD parameters
• ...... etc.
Synthetic opioidsthe GLP inspection 
Data managementcoding projects & experiments
12
Data managementdirectory tree and file names
Computer controlled infusion remifentanil and GR90291
From: E.H. Cox  et al, Anesthesiology 90: 535-544 (1999)
remifentanil GR90291
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●●●●●●●●●●●●●●●●
●
●●
●●●●●●●●●●●●●●
From: E.H. Cox et al, Anesthesiology 90: 535-544 (1999)
●  remifentanil
Concentration-effect relations of synthetic opioidsrats versus humans 
sufentanil
alfentanil
fentanyl
Concentration-effect synthetic opiates                                                receptor affinity versus potency 
From: E.H. Cox et al, Anesthesiology 90: 535-544 (1999)
●  
GR 90291
●  remifentanil
sufentanil
alfentanil
fentanyl
PKPD modeling platform
• University-industry consortium with 4 academic and 7 
industrial partners
• Dedicated infrastructure for data management, data analysis 
and reporting: sharing of data, models and biological system 
specific information
• Emphasis on key factors in the discovery/development and the 
clinical application of novel drugs
– Translational pharmacology (efficacy and safety)
– Developmental pharmacology (pediatrics, elderly)
– Disease system analysis (osteoporosis, COPD)
Medicines research                            collaborative drug and disease model building
Data Data Data
DrafModel
PooledData
Publication
Partner:
Platform:
Data manager:
Modeler:
Partner:
Public domain:
FinalModel
TI Pharma PKPD modeling platform           the information flow
Data analysis
TI Pharma PKPD modeling platform            the database system
• Two-stage approach
• Non-linear mixed effects modeling
– Stage 1: (Non)-compartmental analysis
– Stage 2: Statistical testing (t-test)
– Prerequisite: rich sampling
– Compartmental analysis
– Simultaneous analysis of all data
– Rich / sparse sampling
– Balanced / unbalanced data
– co-variate analysis
TIPharma PKPD modeling platforminterindividual variation in pharmacokinetics
  Data from clinical practice
Prediction of variation in the 
treatment population
TIPharma PKPD  modeling platform maturation of morphine clearance
• 250 children
− 70 preterm neonates
− 60 term neonates
− 60 infants 1 – 6 months
− 30 infants 1 – 12 months
− 30 children 1 – 3 years 
• Intravenous morphine 
• 1-4 samples/24h/patient
• Median body weight 2.8 kg
• ….. adults
Knibbe et al., (2009) Clin. Pharmacokinet. 48: 371-385 
Cle
ara
nce
 [m
l/m
in]
Body weight [kg]
• Individualized training and supervision program
– research          PhD thesis, publications
– education           personal & professional skills
– teaching             self evaluations
– data management          “RDM course” & “RDM plan”
– communication             press release
• Individual PhD Advisory Committee (PAC): PhD programme 
coordinator, (co) promotor(s), external advisor: 
– monitoring of progress              
– advice on all aspects of PhD program
– sounding board
PhD program organization & structure - 1
• PAC Meetings: 2 months, 9 months, 2 years, 3 years
– Start-up meeting (2 months)
– Admission meeting (9 months)
– Progress evaluation meeting (2 years)
– Finalization meeting (3 years)
• PAC meetings and reports are part of the R&O cycle
PhD program organization & structure - 2
• Learning objectives
– principles of good research data management (RDM) 
– policies concerning RDM & benefits of RDM 
– how to manage, document and share data  (safety, efficiency) 
– how to write a data management plan
• Outline
– MANTRA modules
– lectures & assignments
– presentation & discussion of research data management plans
Research Data Management (RDM) courselearning objectives
• Submission of a data management plan (DMP) addressing 
type, format, storage, location and back-up 
• Time lines: 
– Data management course afer 2 months 
– First version DMP at 9 months
– Presentation DMP at 9 months 
– Updated versions of DMP & progress check at 2 and 3 years
• Final check on data management results & implementation
Research Data Management (RDM) planobjectives
Research Data Management plantemplate
Contact information LACDR
Leiden Academic Centre for Drug Research (LACDR)
Leiden University, Gorlaeus Laboratories
Einsteinweg 55, 2333 CC  Leiden 
PO Box 9502, 2300 RA  Leiden 
The Netherlands
T: +31-71- 527 4341
E: office@lacdr.leidenuniv.nl