Izaak den Daas PhDPrincipal Scientist QPS Netherlands BV

Regulatory and Timeline Advantages for Early Clinical Research in

The Netherlands

16 October 2013 Confidential 1

Location of Clinical Studies: Global

Source: www.ClinicalTrials.gov

10/16/2013 Confidential 2

Location of Clinical Studies: Europe

Source: www.ClinicalTrials.gov10/16/2013 Confidential 3

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 4

Source: www.CIA.gov

Phase 1 CPUs in Western Europe

10/16/2013

QPS Netherlands BV

Biotech Center

Phase I clinic (34 beds)

Screening & Recruitment

Isotope lab

The Villa & Cascade building

Offices

Central Pharmacy

Bioanalytical Laboratories

University Medical Center Groningen

Centre of Innovations :

Phase I clinic (24 beds)

Trial Submission in The Netherlands

16 October 2013 Confidential 7

Obtaining EC and HA approval in NL

10/16/2013 Confidential 8

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 pre-advisors 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.

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

Independent EC

The EC is also the only IRB of the study submission

10/16/2013 Confidential 9

Project Time-Lines

Start-up (incl. CSP writing)

CTA submission

ApprovalClinicalphase

DB lock

(after LPLV)

Tables, graphs and

listings

First draft CSR

4 weeks 2 weeks varies 1 week 3 weeks 3 weeks

Documentation needed

10/16/2013 Confidential 11

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

GMP in EU – Clinical Trials

16 October 2013 Confidential 12

Pharmacy

GMP-compliant Pharmacy

Clinical Trial PharmacistPharmacy TechniciansManufacturer’s License for Investigational Medical ProductsAseptic production facilities

10/16/2013 Confidential 13

Guidelines

Applicable guideline:

EudraLex Volume 4 Good Manufacturing Practice (GMP) guidelines:

Annex 13: typical chaptersProduct Specification FileProduction

Manufacturing operations

Principles applicable to comparator product

Blinding

Randomisation

Packaging (Packed in individual way for each subject)

Labelling (in Dutch)

Release of batches

Labelling

Name, address and telephone number of the sponsor, CRO or PIPharmaceutical dosage form, route of administration, quantity of dosage unitsBatchnumberTrial reference codeTrial subject identification numberDirections for use“For clinical trial use only” or similar wordingStorage conditionsPeriod of use (use-by date, expiry date)“Keep out of reach of children”

Release of batches

Release of investigational medicinal products by QualifiedPerson (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 clinicaldrug study

Production process flow

Receipt

Quarantaine

Releasedbulk

product

CoABatch ReleaseIMPDCCMO/METc

IMP Receiptform

Bulk product IMP

• 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 conformanceProduction

Production process flow

Draft label specification

Final label specification

Labels

Labels forproduction

ProductionLabel reconciliation

• Labelspecification issued on

basis of clinical protocol

• QA involvement

• Sponsor representative

involvement if desired

Production process flow

Draft production

protocol

FinalProduction

protocol

Production Protocol

Production

• Production protocol issued

on basis of clinical protocol /

study operation manual /

TQA / other

• QA involvement

• Sponsor representative

involvement if desired

Protocol forproduction

Production process flow

Release of product

• Release on basis of

• Product

• Labels

• Production protocol

• Analysis of product

(optional)

• Release by QP or

Pharmacist

Protocol forproduction

Label reconciliation

Product

Analysis of product

CoA and release certificate of product

ReleasedProduct

Administration

Radioactive Studies in

The Netherlands

16 October 2013 Confidential 21

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

Human Mass Balance Study

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

Micro Dose Studies

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 APIIndividual Drug Preparation of 14C-labeled IMPReturn and/or Destruction of 14C-labeled IMP

Clinical Trial Pharmacy Clinical Trial Pharmacy of QPS Transport of 14C-labeled IMPPreparation of Individual Drug Preparation FormPreparation of Label Specifications according to GMP Annex 13

Clinical Pharmacology Unit Clinical Pharmacology Unit of QPS

Drug Administration of 14C-labeled IMPSample 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

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

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.

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 StudiesSample 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.

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.

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

16-10-2013 29

Thank you for your

attention!