Traditionally, the Netherlands has a major role in the conduct of early stage clinical drug trials. The Netherlands perform well on approval time, quality and expertise; all key drivers for early clinical trial location choice. QPS Netherlands has its own state-of-the-art clinical pharmacology unit (CPU) with 58 beds, an advanced bioanalytical laboratory, radiochemistry laboratory, GMP pharmacy, and a medical recruitment and examination center. The company is strategically located at the University Medical Center Groningen (UMCG). The clinical pharmacology beds and bioanalytical laboratories are highly integrated, resulting in a very efficient operational environment. QPS Netherlands has several strategic partners that further support its operations. Cooperation with these strategic partners gives QPS Netherlands a clear competitive advantage in specific therapeutic fields such as Female Health Care, CNS, Pain and Pulmonary Medicine. Key customers include several global Top 10 pharmaceutical companies and all of the global Top 5 biotechnology companies. Numerous small and medium-sized pharmaceutical and biotechnology companies complete QPS Netherlands’ customer base. Projects at QPS Netherlands range from full-service Phase I/IIa drug development, including strategic consultancy, to dedicated single task projects with high value added.

1. Regulatory and Timeline Advantages
for Early Clinical Research in
The Netherlands
Izaak den Daas PhD
Principal Scientist QPS Netherlands BV
16 October 2013
Confidential
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2. Location of Clinical Studies: Global
Source: www.ClinicalTrials.gov
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Confidential
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3. Location of Clinical Studies: Europe
Source: www.ClinicalTrials.gov
10/16/2013
Confidential
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4. Facts of The Netherlands
Population: 16,805,037
Ethnicity:
Dutch 80.7%,
EU 5%,
Indonesian 2.4%,
Surinamese 2%,
Caribbean 0.8%,
Turkish 2.2%,
Moroccan 2%,
other 4.8%
Gross Domestic Product:
$718.6 billion (ranking 24 in the world)
per capita: $42,900
Ecellent health system
Excellent academic and technology system
10/16/2013
Confidential
Source: www.CIA.gov
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5. Phase 1 CPUs in Western Europe
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6. University Medical Center Groningen
QPS Netherlands BV
The Villa & Cascade building

Offices

Central Pharmacy

Bioanalytical Laboratories
Biotech Center

Phase I clinic (34 beds)

Screening & Recruitment

Isotope lab
Centre of Innovations :
Phase I clinic (24 beds)

7. Trial Submission in The Netherlands
16 October 2013
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8. Obtaining EC and HA approval in NL
Parallel submission to Health Authority (CCMO) and local Ethics Committee (EC)
resulting in Clinical Trial Approval within 14 days!
Substantial amendments: 48h turnaround time
CTA will be prepared and submitted by QPS
Two EC meetings per month (every 1st and 3rd Tuesday); Submission 11 days before
meeting
1 day before the meeting our PI receives a memo with the questions from the preadvisors of the EC; these questions can be answered by the PI during the EC meeting
The PI will join the meeting for answering questions, but will off course not attend the
voting process
CCMO will perform a so called marginal test (check of Eudravigilence and completeness
of CTA); no questions will be raised; approval within 14 days as well
From past experience 3 (proof of principal studies: CSF sampling; dry blood spot and
continuous CSF) out of 105 studies were not approved in the 1st review round.
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9. Independent EC
The EC is also the only IRB of the study submission
Independent foundation BEBO Assen
2 committees meeting every 2 weeks
Main task is to judge the acceptable exposure
of healthy subject or patient
Review time 10 days resulting in pre-advise
before EC meeting
Advise before start study possible
Interim reporting between dosing evaluated
by the chairman
Also for radio-active studies
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10. Project Time-Lines
Start-up
(incl. CSP
writing)
4 weeks
CTA
submission
Approval
2 weeks
Clinical
phase
varies
DB lock
(after LPLV)
1 week
Tables,
graphs and
listings
First draft
CSR
3 weeks
3 weeks

11. Documentation needed
Submission documents as part of the Clinical Trial
Application are:
Clinical Trial Protocol (CTP)
Investigator’s Brochure (IB)
Investigational Medical Product Dossier (IMPD)
Informed Consent Form (ICF)
IMPD + IB = IND
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12. GMP in EU – Clinical Trials
16 October 2013
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13. Pharmacy
GMP-compliant Pharmacy
Clinical Trial Pharmacist
Pharmacy Technicians
Manufacturer’s License for Investigational Medical Products
Aseptic production facilities
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14. Guidelines
Applicable guideline:
EudraLex Volume 4 Good Manufacturing Practice
(GMP) guidelines:
Annex 13: typical chapters
Product Specification File
Production
Manufacturing operations
Principles applicable to comparator product
Blinding
Randomisation
Packaging (Packed in individual way for each subject)
Labelling (in Dutch)
Release of batches

15. Labelling
Name, address and telephone number of the sponsor, CRO or PI
Pharmaceutical dosage form, route of administration, quantity of
dosage units
Batchnumber
Trial reference code
Trial subject identification number
Directions for use
“For clinical trial use only” or similar wording
Storage conditions
Period of use (use-by date, expiry date)
“Keep out of reach of children”

16. Release of batches
Release of investigational medicinal products by Qualified
Person (QP)
Duties of Qualified Person affected by different circumstances
Product manufactured within EU but not subject to an EU marketing
authorisation
Product sourced from the open market within EU and subject to an EU
marketing authorisation
Product imported directly from a 3rd country (including US(!))
At QPS the QP is the clinical trial pharmacist. He is there to help the
sponsor with all local procedures needed for a successfull clinical
drug study

17. Production process flow
Bulk product IMP
Receipt
Quarantaine
CoA
Batch Release
IMPD
CCMO/METc
IMP Receipt
form
Released
bulk
product
Production
• Storage in temperature
controlled / monitored area
• Release based on
documentation and product
• QP or CTP involvement
• Release criteria for bulk
product depends on origin
and market authorization y/n
• Identification forms
• Invoice
• Approved supplier
• IB/IMPD
• Approval METc / CCMO
• CoA
• Release certificate
• GMP conformance

18. Production process flow
Labels
Draft label
specification
Final label
specification
• Labelspecification issued on
basis of clinical protocol
• QA involvement
• Sponsor representative
involvement if desired
Labels for
production
Production
Label
reconciliation

19. Production process flow
Production Protocol
Draft
production
protocol
Final
Production
protocol
Production
Protocol for
production
• Production protocol issued
on basis of clinical protocol /
study operation manual /
TQA / other
• QA involvement
• Sponsor representative
involvement if desired

20. Production process flow
Release of product
Analysis of
product
Label
reconciliation
CoA and release
certificate of
product
Protocol for
production
Product
Released
Product
Administration
• Release on basis of
• Product
• Labels
• Production protocol
• Analysis of product
(optional)
• Release by QP or
Pharmacist

21. Radioactive Studies in
The Netherlands
16 October 2013
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22. Human Mass Balance Study
Human Mass Balance Studies with radiolabelled IMP
Objectives
To determine the rate and extent of excretion of total
radioactivity
To evaluate the extent of absorption of radioactivity
after dosing
To examine the blood and plasma concentration profiles
of total radioactivity
Metabolite identification and profiling
GCP
Samples – urine, feces, blood, plasma, expired air
Timelines:
Clinical Protocol Approval – 2 weeks
Total Radioactivity Recovery Results – 3 to 4 weeks
Metabolite Identification and Profiling Results – 3 to 4
months

23. Micro Dose Studies
Dosing low doses of radiolabeled test article to
healthy subjects or patients
Objectives
To assess absolute bioavailability
To study pharmacokinetic profile in sub
therapeutic level
To examine the blood and plasma
concentration profiles of total radioactivity
Metabolite identification and profiling
GCP
Samples – urine, feces, blood, plasma, expired air
Timelines:
Clinical Protocol Approval – 2 weeks
Accelerated mass spectrometry (AMS) Results
– 6 to 8 weeks

24. Functions Involved – Roles & Responsibilities
Functions
Physical location/affiliation
Roles & Responsibilities
Radio Synthesis
Selcia Ltd., Ongar Essex UK
GMP Preparation of 14 labeled API
Radio Pharmacy
Radio pharmacy of the UMCG
(contract between QPS and
UMCG)
Receipt and Release of 14C-labeled API
Individual Drug Preparation of 14C-labeled IMP
Return and/or Destruction of 14C-labeled IMP
Clinical Trial Pharmacy
Clinical Trial Pharmacy of QPS
Transport of 14C-labeled IMP
Preparation of Individual Drug Preparation Form
Preparation of Label Specifications according to GMP Annex
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Clinical Pharmacology Unit
Clinical Pharmacology Unit of
QPS
Drug Administration of 14C-labeled IMP
Sample Collection and Processing of Radioactive Human
Excreta (blood, urine, feces and expired air)
AMS Laboratory
TNO, Zeist The Netherlands
Measurement of the 14C-Radioactivity using accelerated mass
spectrometry
Biometrics
Biometrics Department of QPS
Determination of the total 14C-Radioactivity Recovery Rate

25. Ethics Committee & Competent Authority Submission
The application process for a radioactive phase I trial in the Netherlands is
essentially the same as for any other non-radioactive phase I trial
Written EC and CA approval is routinely obtained within 14 days after
submission of the Clinical Trial Application (CTA).
Submission documents as part of the Clinical Trial Application are:
o Clinical Trial Protocol (CTP)
o Investigator’s Brochure (IB)
o Investigational Medical Product Dossier (IMPD)
o Informed Consent Form (ICF)
o Human Dosimetry Calculation, Not required for Micro Dose
QPS has a standard set of calculations, which are based on MIRD
and ICRP recommendations to determine human radiation
dosimetry estimates

26. Drug Administration of 14C-labeled IMP
Compounding from API to IMP at QPS Pharmacy
Drug administration of the 14C-labeled study
medication is always done in the presence of an
authorized user (PI or a designated Research
Physician).
Circumstances are again essentially the same as for
any other non-radioactive phase I trial.
Additional hygienic measures are used to prevent
radioactive contamination of the CPU.

27. Collection, Sample Processing and Transport of Radioactive Human
Excreta
All necessary steps to ensure sample integrity (experience
gained from preclinical studies) will be taken from sample
collection, sample processing, storage, and shipping.
Collection of blood, urine, feces and expired air takes place in
the CPU.
Sample processing of collected blood, urine and expired air
samples takes place in the CPU as well.
For non Micro-dose Studies
Sample processing (i.e. homogenization and aliquoting) of collected
feces samples takes place in the radionuclide laboratory.
The volunteers are discharged from the clinic after at least 85 % (or
more if the study protocol requires to do so) of the total dose of
radioactivity has been recovered in the excreta from the volunteer.

28. Measurement of the 14C-Radioactivity in Human Excreta
Not for micro-dose studies
All necessary sample pretreatments after the samples
have been processed and aliquoted until the
measurement of 14C-radioactivity, are done by laboratory
technicians from the radionuclide laboratory who are
trained by in GLP and the particular Assays Instruction(s)
as required by the Bioanalytical Protocol of the concerned
study.
The measurement of 14C-radioactivity in human study
samples is performed on a beta-counter (Tricarb 2500) in
the radionuclide laboratory. Feces combusted in Oxidizer.

29. Publication of Clinical Studies
EMA regulations for clinical studies endorse the
publications of results
Particularly if there are side effects found which are
important for public health
Scientific relevant results published in agreement
with sponsor
Sponsor has influence on timelines but can not
withhold
QPS will only publish in full collaboration with
sponsor
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30. Thank you for
your
attention!