Conducting clinical trials from a clinical supplies ...€¦ · Clinical research –Drug development drug development …is a blanket term used to define the process of bringing

© 2019 Parexel International Corporation / CONFIDENTIAL

Conducting clinical

trials from a clinical

supplies perspectiveBettina Merz-Nideroest

07th June 2019


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


Clinical Research –

Drug Development –

Clinical Trial


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.

© 2019 Parexel International Corporation / CONFIDENTIAL5

Drug development

Phase II

Phase IV

drugdiscovery

preclinical studies

clinical studies

marketing approval


Drug development

Phase II

Phase IV

drugdiscovery

preclinical studies

clinical studies

marketing approval


Drug development

Phase II

Phase IV

drugdiscovery

preclinical studies

clinical studies

marketing approval


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


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


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


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

https://de.statista.com/statistik/daten/studie/513971/umfrage/anzahl-zugelassener-arzneimittel-in-deutschland-nach-verschreibungs-abgabestatus/


Although we have 1000s of drugs available, do we still need new ones?

Critical question ?

• oncologic

• metabolic

• infectious

• inflammatory

• neurodegenerative

dis

ea

se

s


collection of credible data relevant for marketing approval

safeguard participants rights, safety and wellbeing

assess safety and efficacy of the intervention

13

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 !


Key players in clinical research

responsibilities rights

processes documents

Ethics

Committees

Competent

Authorities

Sponsor

CRO

Subject

Investigator

legal framework


Legal Framework


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


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

17

General principles of international guidelines


ICH-GCP E6R2


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

http://www.ich.org/


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


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


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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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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EU Directives –

EU Regulation


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







EU






curre

nt le

gis

latio

n







EU






fro

m m

id 2

02

0?


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


from directives to the regulation

EU Directive 2001/20/EC


EU Directive ....

EU Regulation 536/2014


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

30

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


→ entire communication (applicant / MSs) via EU portal

Approval process acc. to EU Regulation 536/2014


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 of substance and its strenght or potency

pharmaceutical form, route of administration, quantity

batch or code number

clinical trial reference code

subject identification


directions for use


storage conditions


„Keep out of the reach of children“


EurdraLex Volume 4 GMP Annex 13


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


directions for use


storage conditions


„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 of substance and its strenght or potency

pharmaceutical form, route of administration, quantity

batch or code number

clinical trial reference code

subject identification


directions for use


storage conditions


„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


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


International Conference on Harmonization

International Council for Harmonization

International Committee for Harmonization

35

ICH ?


Good Clinical Practice

Good Communication Practice

General Confidentiality Proof

36

GCP ?


General Management Practice

Good Manufacturing Practice

Good Manufactured Products

37

GMP ?


1´000

10´000

15´000

38

Generally speaking: how many molecules must be tested

in the drug development process to finally get one

marketed drug ?


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?


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 ?


Falsified Medicines

Directive FMD

09Feb2019


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



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


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“)

43


EU Regulation 2016/161Unique

Identifier UI


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

44


EU Regulation 2016/161Anti-Tampering

Device ATD


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?



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


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




− 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!





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


Pharma / Manufacturer

Wholesaler

Pharmacies / Hospitals

48

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!)


Patient Centricity

Direct to Patient DtP


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

50

Patients in clinical trials

https://www.iqvia.com/blogs/2018/06/virtual-trials-a-more-direct-path-to-patients

https://www.iqvia.com/blogs/2018/06/virtual-trials-a-more-direct-path-to-patients


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


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


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)

53

Challenges for DtP studies


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.


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


Thank you

Documents

Conducting clinical trials from a clinical supplies ...€¦ · Clinical research –Drug development drug development …is a blanket term used to define the process of bringing