101028 mode pharma imp presentation

8/8/2019 101028 Mode Pharma Imp Presentation

1/17

INVESTIGATIONAL MEDICINAL PRODUCTS:

Regulatory and Practical Considerations for Clinical TrialsNovember 2010


2/17

2010 MODEPHARMA www.modepharma.com

2

Investigational Medicinal Products

Introduction

EU and UK regulations relating to investigational medicinal products

Implications for undertaking clinical trials with IMPs

Common challenges acrossthe clinical trial lifecycle

Patient population factors and dosage forms

Imports from Non-EU countries

Labels

Expiry dates and stability

Technical agreements

Other common GMP related challenges

CTA

VAT

GMP: Behind the Scenes Overview of a clinical supply project

Introduction


3/17


3

About MODEPHARMA

Investigational Medicinal Products for clinical trials

Comprehensive sourcing and management of trial medication

MODEPHARMA is the only UK company to specialise

in clinical supplies for non-commercial clinical

trials

Full support around the IMP solution

Introduction

Advise, plan and coordinate on all aspects around the IMP

MANUFACTURING

Placebosto match

Tablets and capsules

Semi-solids

Injectables

Powders

Inhalers

Liquids

PACKAGING

Bulk supplies

Re-labelling

Patient kits

Ampoules

Sachets

Blisters

Bottles

Tubes

Vials

RELATED SERVICES

QP release

Imports

Randomisation

Regulatory support

Site monitoring

Pharmacy SOPs

IMP training


4/17


4

EU and UK Regulations Relating to Investigational Medicinal Products

EU Directives: Clinical Trials Directive 2001/20/EC

The principles of good manufacturing practice should be

applied to investigational medicinal products.

GMP Directive 2003/94/EC

Replaces original GMP Directive 91/356/EEC

GCP Directive 2005/28/EC

Additional principles and detailed guidelines with regards

to IMPs are specified to verify compliance of clinical trials

with the Clinical Trials Directive 2001/20/EC.

Transposed into Member State Laws:

UK: Statutory Instrument 2004/1031: The Medicines for Human Use (Clinical Trials) Regulations 2004 and itsamendments.

Despite harmonisation, differences remain between Member Statesin clinical trial requirements

Practical guidance:

GCP: ICH Guidelines for GCP

GMP: Eudralex Vol 4 (EU GMP Gu ide aka Orange Guide)

Annex 13: GMP for investigational products

Annex 16: QP responsibilities

See the MODEPHARMA Knowledge Centre: www.modepharma.com

Regulatory Aspects of IMPs


5/17


5

Implications for Undertaking Clinical Trials with IMPs

All IMPs must be manufactured according to GMP:

Requirement for appropriate IMP manufacturing/importauthorisation

Facility must be licensed for the dosage form & activities required

Qualified Person (QP):

Ensure compliance with EU GMP (for ownsites and contractors),the PSF, and the request for CTA

Responsible for the certification and release of batches of clinicaltrial material before they can be used in a clinical trial.

Exception: Regulation 37 in SI 2004/1031

Assembly (repacking, randomising and labelling)in ahospital/health centre under supervision of adoctor/pharmacist for use withinthatinstitution

No need for QP release butQC recommended

There are restrictions!

All facilities used for the manufacture or import ofIMPs aresubjectto aninspection by the competent authority

IfIMP manufactured outside EU, appropriate checks/retestsfor Import and before EU release

Regulatory Aspects of IMPs


6/17


7/17


7

Patient Population Factors and IMP Dosage Forms

Consider patient population factors and IMP hand-in-hand

Blinding mechanisms:

New dosage forms (e.g. Over-encapsulation for solid dosage

forms)

New packaging :

Formulation and development of placebo-to-match (e.g.tablets, liquids)

Repack into new packaging (e.g. sachets)

Other innovative solutions

Commonissues:

Chosen dosage form notthe most optimal for the trials

patient population

Not economically feasible to develop a placebo

Formulation work isnot a precise science

Poor quality placebos (e.g. taste,texture, colour, film-coating,

hardness, primary packaging)

IMP Considerations


8/17


8

Imports from Non-EU Countries

IMP manufactured outside EU: QP to verify thatthe IMP was manufactured to

GMP standards equivalentto EU GMP

QP may have to performssite audits

Additional analytical testing ofIMPs may be

required onimport to Europe

QP declaration on GMP equivalence to EU GMP

using the template available onthe MHRA website Signed by a QP named onthe manufacturers

authorisation ofthe importer

Should be trial and productspecific

Appliesto placebos as well

Common issues:

Lack ofsubstance behind QP declaration How doesthe QP know the actual site of

manufacture?

How doesthe QP assure EU GMP?

Transportation conditionsnot known

The QP certified animported IMP as free ofTransmissible Spongiform Encephalopathy (TSE) butno evidence was available to supportthis decision.

IMP Considerations


9/17


9

Technical Agreements Set Out the Roles and Responsibilities of Each Party

Common issues:

Non-existent

Essentially commercial innature

Agreementnotin place before manufacturing

commences

Lack of detail concerning GMP responsibilities:

Sourcing of materials

QP duties

Recall responsibilities

Approval and supply of relevant documents

Taking ofsamples/testing/retention

No requirement for signed QP certification

Refer to Appendicesthat do not exist

IMP Considerations

Responsibility Contract

Acceptor (CA)

Contract

Giver (CG)

Material safety of active substance and other

starting materialsR

Specifications R

Purchasing R

Qualification of the supplier R

Identification and analysis R

Release for processing R

Storage R

Reference Samples R

Stability study R

Enforcement of recalls R


10/17


10

Labels

GMP Directive 2003/94/EC:

Preamble 9: In order to protectthe human beingsinvolved inclinical trials and to ensure thatinvestigational medicinalproducts can be traced,specific provisions onthe labelling ofthose products are necessary.

Article 15 Labelling: Inthe case of aninvestigational medicinalproduct, labelling shall be such asto ensure protection ofthesubject and traceability,to enable identification ofthe productand trial, and to facilitate proper use ofthe investigationalmedicinal product.

Detailed guidance in Annex 13, paragraphs 26 to 33:

Paragraph 26 and Table 1 sets out 11 items ofinformationwhich should be included on labels

unless absence can be justified, e.g. use of a centralisedelectronic randomisationsystem

Paragraph 33 covers labelling to change use-by-dates

Commonissues:

Missing labels with CTA applications

Labels missing key information

Different batch numbers/expiry dates for active and placebo

IMP Considerations

AMAZING_TRIAL

FOR CLINICAL TRIAL USE ONLY

EudraCT No: 2007-00534-99

28 x Lisinopril 5mg Tablets or Placebo-to-Match

Patient Trial No: J789 Visit: _____ Dispensing Date: ________

Dose Instructions: Take ONE tablet orally once a day.

Batch No: 09B897 Expiry Date: 12/DEC/2010

Storage Instructions: Store below 25C.

KEEP OUT OF THE REACH OF CHILDREN

Professor XXXXX, SPONSOR NAME, Address, City,

Post Code, UK, Tel: 07979797979


11/17


12/17


12

Other Common GMP Issues

Creation and maintenance ofthe Product SpecificationFile:

Not available or incomplete

Lack ofstructure to the file

No system for updating the file following changesin

instructions, packaging etc.

Recall SOP

Insufficient detail with reference to recallsinstigated bymanufacturers of comparator products

No considerationthatthe IMP may identify defects with

comparator products during handling/use

Failure to notify the MHRA inthe event of a potential recall

situation being identified.

Transport and storage conditions

Lack of controlled storage

Temperature deviations

IMP Considerations


13/17


13

CTAs

Commonissues:

Invalid applications

Failure to supply an XML file

Missing sponsor authorisation letter

Non-machine readable PDFs

Password protected disks

Quality of applications

Section onIMPs (active and placebo)

left blank

Confusion on final EU site releasing

the IMP

Missing supporting documents: Sample labels

IMPD / IB / SmPCs

Manufacturing authorisations

TSE certificates

IMP Considerations


14/17


14

VAT

VAT

Clinical supplies for non-commercial trials are not

automatically VAT exempt

VAT exemptions only for trials funded by charitable sources

See www.modepharma.com/vatfor further guidance

IMP Considerations


15/17


15

Overview of a Clinical Supply Project

Client Enquiry andRequirement Definition

Confidential DisclosureAgreement

Proposal Acceptanceand Payment of Deposit

Technical Agreement

Project Manager andProject Plan

Documents for CTA including ProductSpecification Files

Label Designand Approval

Approval of Batch Manufacturing

Record

Procurement ofRaw Materials

Randomisation CodeClinical Manufacturing, Packaging and

QC TestingQP Release

StorageShipment on Demand InvoicingProject Close

Clinical Supply Manufacturing and Packaging Activities


16/17


16

Annex 13 Manufacture of IMPs

Sections on:

Principle

Glossary

Quality Management

Personnel

Premises and Equipment

Documentation

Production

Packaging materials Manufacturing operations

Principles applicable to comparator products

Blinding operations

Randomisation code

Packaging

Labelling

Quality Control

Release of Batches

Shipping

Complaints

Recalls and Returns

Destruction

Further Reading


17/17


17

h t t p : // w w w . m o d e p h a r m a . c o m

MODEPHARMA

Registered Office: Suite 16, BeaufortCourt,London E14 9XL, UK

Company No: 6332969 in England and Wales

VAT Registration: GB 909535016

Phone: +44 (0) 2070 432 442

Email: [email protected]

Contact

www.mode harma.com