© 2019 Parexel International Corporation / CONFIDENTIAL Conducting clinical trials from a clinical supplies perspective Bettina Merz-Nideroest 07 th June 2019
© 2019 Parexel International Corporation / CONFIDENTIAL
Conducting clinical
trials from a clinical
supplies perspectiveBettina Merz-Nideroest
07th June 2019
© 2019 Parexel International Corporation / CONFIDENTIAL
Agenda
Clinical research – drug development – clinical trials
Legal framework
ICH-GCP: responsibilities
EU directives and EU regulation: labeling requirements
Falsified Medicines Directive FMD
Patient centricity, Direct to Patient DtP
2
Conducting clinical trials
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Clinical Research –
Drug Development –
Clinical Trial
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clinical research
…is a branch of healthcare science
that determines the safety and
effectiveness (efficacy) of
medications, devices, diagnostic
products and treatment regimens
intended for human use. These
may be used for prevention,
treatment, diagnosis or for relieving
symptoms of a disease.
4
Clinical research – Drug development
drug development
…is a blanket term used to define
the process of bringing a new drug
to the market once a lead compound
has been identified through the
process of drug discovery. It includes
pre-clinical research and clinical
trials (on humans) and may include
the step of obtaining regulatory
approval to market the drug.
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Drug development
Phase II
Phase IV
drugdiscovery
preclinical studies
clinical studies
marketing approval
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Drug development
Phase II
Phase IV
drugdiscovery
preclinical studies
clinical studies
marketing approval
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Drug development
Phase II
Phase IV
drugdiscovery
preclinical studies
clinical studies
marketing approval
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Clinical trial
1 clinical trial → 1 project → 1 question → 1 research approved protocol
PHASE I
20-50 healthy volunteers „probands“
human pharmacology, tolerability
PHASE II
50-200 „ideal“ patients
efficacy, safety, dose finding: therapeutic exploratory
PHASE III
100s-1000s „normal“ patients
efficacy, safety in comparison to marketed drugs: therapeutic
confirmatory
PHASE IV
100s-1000s patients
long-term efficacy, safety, interactions: therapeutic practice
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Clinical trial
1 clinical trial → 1 project → 1 question → 1 research approved protocol
More modern concept:
Adaptive trials include a prospectively planned
opportunity for modifications of one or more specified
aspects of the study design and hypotheses based on
analysis of data from subjects in the trial
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from molecule to marketed drug
Drug development process
How long does it take?
10-12-15 years
How many molecules make it from
molecule to marketed drug?
1 out of 10,000
How much does it cost?
more than 1 Mrd $
Source: ePharmacology.hubpages.com
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Germany 2018: marketed drugs
https://de.statista.com/statistik/daten/studie/513971/umfrage/anzahl-zugelassener-arzneimittel-in-deutschland-nach-verschreibungs-abgabestatus/ 22Jan2019
48.377 prescription drugs
103.787 marketed drugs in total
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Although we have 1000s of drugs available, do we still need new ones?
Critical question ?
• oncologic
• metabolic
• infectious
• inflammatory
• neurodegenerative
dis
ea
se
s
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collection of credible data relevant for marketing approval
safeguard participants rights, safety and wellbeing
assess safety and efficacy of the intervention
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Aims of clinical research / drug development
→prevention;
diagnosis and
treatment
→assess
safety and
effectiveness
→marketing
authorization
advancing medical knowledge and patient care
clinical research is highly regulated !
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Key players in clinical research
responsibilities rights
processes documents
Ethics
Committees
Competent
Authorities
Sponsor
CRO
Subject
Investigator
legal framework
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Legal Framework
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Overview clinical trial regulations
regional
country-
level
international
organi-
zational
WW
guideline
DoH*, GCP*
geographical /
regional regulations:
USA EU
21 CFR directives & regulations, GMP
country regulations
drug law, data protection laws, pharmacy laws, insurance, local requirements
application at organizations: SOPs, manuals, operating guidelines, user guides, etc.
*DoH: Declaration of Helsinki:
set of ethical principles issued
by World Medical Association
*GCP: Good Clinical
Practice: ethical and
scientific standard for
clinical research
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safeguard rights, safety and well-being of trial subjects
collect credible data
to bring efficient and safe drugs to the market
research protocol needs to be approved by the responsible Ethics Committee
before study start
trial participation is always voluntary („informed consent“)
quality assurance and quality control systems must be established
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General principles of international guidelines
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ICH-GCP E6R2
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ICH: International Council for Harmonization: www.ich.org
issues Efficacy, Safety, Quality, Multidisciplinary guidelines, like
GCP: Good Clinical Practice guidelines E6R2
THE international, ethical and scientific quality standard for
designing, conducting, recording and reporting
trials that involve human subjects.
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ICH-GCP E6R2
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ICH-GCP E6R2
Introduction
1) Glossary
2) Principles of ICH-GCP
3) Institutional review boards, independent ethics committees
4) Investigator
5) Sponsor
6) Clinical trial protocol and protocol amendments
7) Investigator´s brochure
8) Essential documents for the conduct of a clinical trial
general information
responsibilities
documentation
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5.12/13/14 SPONSOR:
information on IMP: ensure sufficient safety and efficacy data is available to support trial
manufacturing acc GMP
IMP coded, labeled, packaged in a manner that protects blinding, acc local regulations
coding systems that permit rapid identification in cases of emergencies
storage conditions
supplying IMP to investigators, when relevant documentation is available, in time
handling instructions
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Responsibilities on IMP
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4.6 INVESTIGATOR:
→ responsible for IMP at site (can be delegated to pharmacist)
IMP accountability: maintain records of product´s delivery to site, the inventory at site,
the use by each subject and return to sponsor
store as specified
use only acc to study protocol
explain correct use to participants
strictly follow randomization and unblinding procedures
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Responsibilities on IMP
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5.18.4 MONITOR:
→ act as main contact between sponsor and investigator
verify that,
storage times and conditions are acceptable
IMP are supplied only to subjects who are eligible to receive it
subjets are provided with necessary instructions
receipt, use, return of IMP are controlled and documented
disposition of unused IMP complies with regulatory requirements
investigator receives current documentation (e.g. IB)
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Responsibilities on IMP
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EU Directives –
EU Regulation
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EU binding legal acts
DIRECTIVEset out goals to be
implemented into national laws
facilitating the internal market in medicinal products within EU
simplifying / harmonizing provisions governing clinical trials
EU
results in a consistent and uniform law
in all member states MS
MS decides, how the content of the directive is implemented
into the national laws
REGULATIONdirect supranational law
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EU binding legal acts
DIRECTIVEset out goals to be
implemented into national laws
facilitating the internal market in medicinal products within EU
simplifying / harmonizing provisions governing clinical trials
EU
results in a consistent and uniform law
in all member states MS
MS decides, how the content of the directive is implemented
into the national laws
REGULATIONdirect supranational law
curre
nt le
gis
latio
n
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EU binding legal acts
DIRECTIVEset out goals to be
implemented into national laws
facilitating the internal market in medicinal products within EU
simplifying / harmonizing provisions governing clinical trials
EU
results in a consistent and uniform law
in all member states MS
MS decides, how the content of the directive is implemented
into the national laws
REGULATIONdirect supranational law
fro
m m
id 2
02
0?
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Study start:
approvals acc. to EU Directive 2001/20/EC
responsible EC and CA in each participating country
SPONSOR
Ethics Committee
Competent Authority
Ethics Committee
Competent Authority
Ethics Committee
Competent Authority
Ethics Committee
Competent Authority
Sponsor to submit to
all country ECs and
CAs; can start the CT in
a country where both
approvals are available
Ethics Committee
Competent Authority
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from directives to the regulation
EU Directive 2001/20/EC
EU Directive 2005/28/EC
EU Directive ....
EU Regulation 536/2014
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PART 1
GENERAL ASPECTS
evaluated and coordinated by one (sponsor-)
selected reporting Member State (rMS):
scientific documents
therapeutic benefit
risk-benefit assessement
investigational medicinal product
manufacturing and labeling of IMP
import – export arrangements
protocol, investigators brochure
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part 1 by one reporting MS, parts 2 by concerned MSS
Study start:
approvals acc. to EU Regulation 536/2014
PART 2
NATIONAL ASPECTS
country specific evaluation done by each
concerned MS (cMS): national documents
recruitment arrangements
patient information sheet and informed consent
information on suitability of investigators and sites
proof of insurance
financial agreements
data protection
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→ entire communication (applicant / MSs) via EU portal
Approval process acc. to EU Regulation 536/2014
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EurdraLex Volume 4 GMP Annex 13
name, address, phone no of main contact
pharmaceutical dosage form, route of
administration, quantity, in case of open trials:
name/identifier and strength/potency
batch and/or code number
trial reference code
trial subject identification
name of investigator
directions for use
„For clinical trial use only“
storage conditions
period of use (use-by date, expiry date)
„Keep out of the reach of children“32
not only the number of the Annex will change......
Labeling requirements
Regulation 536/2014 Annex 6
name, address, phone no of main contact
name of substance and its strenght or potency
pharmaceutical form, route of administration, quantity
batch or code number
clinical trial reference code
subject identification
name of investigator
directions for use
„For clinical trial use only“
storage conditions
period of use (use-by date, expiry date)
„Keep out of the reach of children“
© 2019 Parexel International Corporation / CONFIDENTIAL
EurdraLex Volume 4 GMP Annex 13
name, address, phone no of main contact
pharmaceutical dosage form, route of
administration, quantity, in case of open trials:
name/identifier and strength/potency
batch and/or code number
trial reference code
trial subject identification
name of investigator
directions for use
„For clinical trial use only“
storage conditions
period of use (use-by date, expiry date)
„Keep out of the reach of children“33
not only the number of the Annex will change......
Labeling requirements
Regulation 536/2014 Annex 6
name, address, phone no of main contact
name of substance and its strenght or potency
pharmaceutical form, route of administration, quantity
batch or code number
clinical trial reference code
subject identification
name of investigator
directions for use
„For clinical trial use only“
storage conditions
period of use (use-by date, expiry date)
„Keep out of the reach of children“
symbols and pictograms may be
included to clarify certain
information
particulars should appear in official
language(s) of the country in
which the IMP is to be usedprimary and
secondary
packaging
immediate
and outer
packaging
IMP and non-
IMP
IMP and auxillary
medicinal products
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What is the correct answer?
What do the abbreviations stand for?
What is the term describing?
Instructions:
you get three coloured cards
in the following slides, I will show you abbreviations / term
there are three possible answers given in the three different colours Y, R, B
shortly think: what is the correct answer?
raise your hand with the corresponding coloured card giving the correct answer
34
Short quiz
YELLOW
RED
BLUE
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International Conference on Harmonization
International Council for Harmonization
International Committee for Harmonization
35
ICH ?
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Good Clinical Practice
Good Communication Practice
General Confidentiality Proof
36
GCP ?
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General Management Practice
Good Manufacturing Practice
Good Manufactured Products
37
GMP ?
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1´000
10´000
15´000
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Generally speaking: how many molecules must be tested
in the drug development process to finally get one
marketed drug ?
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EU Directive
EU Regulation
EU Decision
39
Which of the following is a
EU binding legislative act that applies automatically and
uniformly to all EU countries in its entirety?
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Monitor
Investigator
Sponsor
40
Acc. to ICH-GCP: whose responsibility is it to
determine for the IMP acceptable storage temperatures,
conditions, times, reconstitution fluids and procedures ?
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Falsified Medicines
Directive FMD
09Feb2019
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to prevent falsified medicinal products from entering into the legal supply chain
an end-to-end verification system for medicinal products was introduced
the end-to-end verification is a medicines authentication system including
mandatory safety features and a repository that stores information for each
individual pack!!
medicinal products sold in the EU need to carry 2 safety features
must be entered into the repository system
must be verified and decommissioned before supplied to patients
42
EU Directive 2011/62/EC
EU Regulation 2016/161
Use this placeholder for any footnotes, references or sources. Multiple l ines will extend the box upwards
Unique
Identifier UI
Anti-Tampering
Device ATD+ =2 safety
features
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Unique Identifier UI
is a unique sequence carried by a two-dimensional barcode, consisting of
this SERIALISATION allows identification and authentication of each individual
pack on which it is printed! → „verification“
verification to be performed before supply to patients against a data depository
(„decommissioning“)
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EU Directive 2011/62/EC
EU Regulation 2016/161Unique
Identifier UI
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Anti-Tampering Device ATD
is a device allowing the verification of whether the packaging of the medicinal
product has been opened choice of most appropriate ATD is left to the
manufacturer
examples: tamper-evident seals/closures: transperant stickers, perforated
tapes
→ opening the package (legally or as manipulation) permanently distroys or
changes the package or label
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EU Directive 2011/62/EC
EU Regulation 2016/161Anti-Tampering
Device ATD
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medicinal products subject to
prescription - unless included in
Annex I to the Regulation (exceptions
e.g.: homeopathic medicinal products,
medicinal gases, solutions for
parenteral nutrition, advanced therapy
medicinal products which contain or
consist of tissues or cells)
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which medicinal products have to bear the safety features?
EU Directive 2011/62/EC
EU Regulation 2016/161
medicinal products not subject to
prescription which are included in
Annex II to the Regulation (currently
only Omeprazol 20/40 mg)
→ other medicinal products (like over-the-counter drugs OTC) can bear the
safety features, as long as the 2D barcode does NOT contain a serial
number! ATD is allowed
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authorized medicinal products
have to fulfil safety features, up
to the moment it becomes
known which batch/unit will be
used for research and
development trials. In practice,
there are two possible
situations:
46
which medicinal products have to bear the safety features?
EU Directive 2011/62/EC
EU Regulation 2016/161
− 1. the product is manufactured for known use
in a clinical trial: used and labelled as IMP:
excluded from safety features; used as
auxiliary product in a trial: must fulfill safety
features and decommissioned
− 2. the product is authorized and sourced from
the regulated supply chain: must be
decommissioned
medicinal Products intended for research and development trials and
not yet granted a marketing authorization are excluded from the rules of
the safety features!
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which medicinal products have to bear the safety features?
EU Directive 2011/62/EC
EU Regulation 2016/161
medicinal Products intended for research and development trials and
not yet granted a marketing authorization are excluded from the rules of
the safety features!
ISPE working group (Magali Busquet, Rachel Owen)
How regulation impacts packaging, labelling
and distribution of commercial products used
in clinical supply chain
Aims: create blog, guidance documents to
support decomissioning
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Pharma / Manufacturer
Wholesaler
Pharmacies / Hospitals
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End-to-end verification
MP packed and labeled with UI and ATD
upload into repository system
verify MP when receiving / returning
decommission from system in certain cases (dentists)
verify MP before dispense to patients (scan)
decommission from system (DISPENSE; SAMPLE;
EXPORT: possible only once!)
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Patient Centricity
Direct to Patient DtP
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without patients → no trials → no data → no new marketed drugs !
....but, traditional clinical trials pose obstacles to patients:
travel to site: US: as far as 50 miles and more
time commitment: high, especially if several visits are foreseen
enrollment rate? <5% of patients participate in CL
drop outs: ~ 50% of subjects drop out before their study end
„ patient centricity“ / „direct to patient“ / „virtual trials“
→ process of designing a service around the patient
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Patients in clinical trials
https://www.iqvia.com/blogs/2018/06/virtual-trials-a-more-direct-path-to-patients
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when enrolling, consider
language used, atmosphere when
informing patients
conditions of patients
weak points from previous trials,
understand patients needs
include other patients testimonials,
learn from their feedback
awareness: communicate on your
landing page / social media
51
Patient centricity
when retaining participants, consider
create protocol / schedule with
flexibility
make it easy to get / find the site
(different departments), remote visits!
create a communication toolkit in
layperson language
use modern technology: devices,
wearables, mobiles, conduct remote
visits, send (study) nurses and IMP to
the patients home (DtP)
understanding – meeting patients needs – connection - engagement
© 2019 Parexel International Corporation / CONFIDENTIAL
when enrolling, consider
language used, atmosphere when
informing patients
conditions of patients
weak points from previous trials,
understand patients needs
include other patients testimonials,
learn from their feedback
awareness: communicate on your
landing page / social media
52
Patient centricity
when retaining participants, consider
create protocol / schedule with
flexibility
make it easy to get / find the site
(different departments), remote visits!
create a communication toolkit in
layperson language
use modern technology: devices,
wearables, mobiles, conduct remote
visits, send (study) nurses and IMP to
the patients home (DtP)
understanding – meeting patients needs – connection - engagement
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Are regulations allowing DtP shipments? Under what conditions?
What if patients are traveling, visiting friends?
How can the patient´s privacy be protected? Confidentiality?
How to organize the processes? Study visits; technical systems (e.g. IRT)
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Challenges for DtP studies
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How to deal with the regulatory situation?
Clinical protocol including
DTP is submitted to country
MoH with explanation of
process, ethical considerations
and justification why DTP
supports patient’s safety and
treatment.
Case by case decision due to
lack of implementation in
country medicinal and
pharmacy laws
Trial based allowance for
hand-over of study drug to a
courier or homecare staff
instead of dispensing directly
to the patient by the
pharmacist or site staff.
Many countries are only
allowing a licensed pharmacy
to dispense medication.
Special procedures and site
staff involvement can be
requested.
In case of direct patient contacts
and patient documents ethics
committees approval must be
available.
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The why and how of DtP services
DTP Service
Studies requiring DTP DTP Material
• Supply chain including depots, DtPtrained couriers and homecare providers
• Adapted systems with patient data protection and shipment management
• Regulatory/Country feasibility
• Orphan drug clinical trials
• Patients unable/unwilling to travel
• Site-less, in-home clinical trials
• Clinical trials with remote activities
• Competitive trials with recruitment challenges
• Trial medication
• Heavy and/or temperature sensitive and/or dangerous goods
• Material for in-home usage
• medical devices, wearables, smart phones, lab kits
• Lab samples, unused drug
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Thank you