INVESTIGATIONAL MEDICINAL PRODUCTS:

Regulatory and Practical Considerations for Clinical Trials

November 2010
 Introduction 2

Investigational Medicinal Products

 Introduction

 EU and UK regulations relating to investigational medicinal products

 Implications for undertaking clinical trials with IMPs

 Common challenges across the 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

© 2010 MODEPHARMA www.modepharma.com

Introduction 3

About MODEPHARMA
MANUFACTURING
Placebos to match
Tablets and capsules
Investigational Medicinal Products for clinical trials Semi-solids
Injectables
Powders
Inhalers
Advise, plan and coordinate on all aspects around the IMP Liquids

PACKAGING
Bulk supplies
Comprehensive sourcing and management of trial medication Re-labelling
Patient kits
Ampoules
Sachets
MODEPHARMA is the only UK company to Blisters
Bottles
specialise in clinical supplies for non-commercial Tubes
clinical Vials
trials
RELATED SERVICES
Full support around the IMP solution QP release
Imports
Randomisation
Regulatory support
Site monitoring
Pharmacy SOPs
IMP training

© 2010 MODEPHARMA www.modepharma.com

Regulatory Aspects of IMPs 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 its
amendments.
 Despite harmonisation, differences remain between Member States in clinical trial requirements

 Practical guidance:
 GCP: ICH Guidelines for GCP
 GMP: Eudralex Vol 4 (EU GMP Guide aka “Orange Guide”)
» Annex 13: GMP for investigational products
» Annex 16: QP responsibilities

 See the MODEPHARMA Knowledge Centre: www.modepharma.com

© 2010 MODEPHARMA www.modepharma.com

Regulatory Aspects of IMPs 5

Implications for Undertaking Clinical Trials with IMPs

All IMPs must be manufactured according to GMP:

 Requirement for appropriate IMP manufacturing/import

authorisation
 Facility must be licensed for the dosage form & activities required

 Qualified Person (QP):

 Ensure compliance with EU GMP (for own sites and contractors),
the PSF, and the request for CTA
 Responsible for the certification and release of batches of clinical
trial material before they can be used in a clinical trial.
 Exception: Regulation 37 in SI 2004/1031
» Assembly (repacking, randomising and labelling) in a
hospital/health centre under supervision of a
doctor/pharmacist for use within that institution
» No need for QP release but QC recommended
» There are restrictions!

 All facilities used for the manufacture or import of IMPs are

subject to an inspection by the competent authority

 If IMP manufactured outside EU, appropriate checks/retests

for “Import” and before EU release

© 2010 MODEPHARMA www.modepharma.com

IMP Considerations 6

Common IMP Challenges Across the Clinical Trial Life-Cycle

Protocol Development Trial Setup Trial Implementation

Insufficient
Insufficient consideration
consideration of
of patient
patient Little or no experience with contract
Poor blinding
blinding of
of IMPs
IMPs
population factors manufacturers

Sub-optimal choice of active/placebo Hidden costs in quotes making them

Inadequate labelling of IMPs
dosage forms difficult to interpret and compare

Lack of awareness on regulatory

One-sided Technical Agreements Poor quality IMP and packaging
requirements
requirements for
for IMP
IMP manufacturing
manufacturing

IMP adversely
adversely affected
affected during
during storage
storage
Inaccurate budgeting of IMP costs Inadequate project planning
and transport

Risks: Risks: Risks:

•Non-compliance or high withdrawal rate • Poor IMP quality and design •Credibility of results
•Poor trial design / wastage of drug • Paying more than expected •Patient safety risk/regulatory non-compliance
•Regulatory approval delayed/failed • Sponsor’s responsibilities not adequately covered •Patient loss of confidence and drop-outs
•Insufficient funding for the trial to continue • Manufacturing delays • Early trial stop by Sponsor or MHRA

© 2010 MODEPHARMA www.modepharma.com

IMP Considerations 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

 Common issues:
 Chosen dosage form not the most optimal for the trial’s
patient population
 Not economically feasible to develop a placebo
 Formulation work is not a precise science
 Poor quality placebos (e.g. taste, texture, colour, film-coating,
hardness, primary packaging)

© 2010 MODEPHARMA www.modepharma.com

IMP Considerations 8

‘Imports’ from Non-EU Countries

 IMP manufactured outside EU:

 QP to verify that the IMP was manufactured to GMP
standards equivalent to EU GMP
 QP may have to performs site audits
 Additional analytical testing of IMPs may be
required on import to Europe
 QP declaration on GMP equivalence to EU GMP
using the template available on the MHRA website
 Signed by a QP named on the manufacturer’s
authorisation of the importer
 Should be trial and product specific
 Applies to placebos as well

 Common issues:
 Lack of substance behind QP declaration
» How does the QP know the actual site of
manufacture?
» How does the QP assure EU GMP?
 Transportation conditions not known
 The QP certified an imported IMP as free of
Transmissible Spongiform Encephalopathy (TSE) but
no evidence was available to support this decision.

© 2010 MODEPHARMA www.modepharma.com

IMP Considerations 9

Technical Agreements Set Out the Roles and Responsibilities of Each Party

Responsibility Contract Contract

Common issues:
Acceptor (CA) Giver (CG)  Non-existent
Material safety of active substance and other
starting materials
R  Essentially commercial in nature
Specifications R  Agreement not in place before manufacturing
Purchasing R commences
Qualification of the supplier R  Lack of detail concerning GMP responsibilities:
Identification and analysis R » Sourcing of materials
Release for processing R » QP duties
Storage R » Recall responsibilities
Reference Samples R » Approval and supply of relevant documents
Stability study R » Taking of samples/testing/retention
Enforcement of recalls R
» No requirement for signed QP certification
… … …
 Refer to Appendices that do not exist

© 2010 MODEPHARMA www.modepharma.com

IMP Considerations 10

Labels
 GMP Directive 2003/94/EC:
AMAZING_TRIAL
 Preamble 9: In order to protect the human beings involved in FOR CLINICAL TRIAL USE ONLY

clinical trials and to ensure that investigational medicinal EudraCT No: 2007-00534-99
28 x Lisinopril 5mg Tablets or Placebo-to-Match
products can be traced, specific provisions on the labelling of Patient Trial No: J789 Visit: _____ Dispensing Date: ________
those products are necessary. Dose Instructions: Take ONE tablet orally once a day.
Batch No: 09B897 Expiry Date: 12/DEC/2010
 Article 15 Labelling: In the case of an investigational medicinal Storage Instructions: Store below 25ºC.

product, labelling shall be such as to ensure protection of the KEEP OUT OF THE REACH OF CHILDREN
subject and traceability, to enable identification of the product Professor XXXXX, SPONSOR NAME, Address, City,
and trial, and to facilitate proper use of the investigational Post Code, UK, Tel: 07979797979
medicinal product.

 Detailed guidance in Annex 13, paragraphs 26 to 33:

 Paragraph 26 and Table 1 sets out 11 items of information which
should be included on labels
» unless absence can be justified, e.g. use of a centralised
electronic randomisation system
 Paragraph 33 covers labelling to change use-by-dates

 Common issues:
 Missing labels with CTA applications
 Labels missing key information
 Different batch numbers/expiry dates for active and placebo

© 2010 MODEPHARMA www.modepharma.com

IMP Considerations 11

Expiry Dates and Stability

 IMP expiry date and stability information is the Sponsor’s responsibility!

 GCP Guideline 5.14.5 (a):

» Sponsor should take steps to ensure that the investigational product(s) are
stable over the period of use

 Annex 13 (§20):
» The expiry date stated for the comparator product in its original packaging
might not be applicable to the product where it has been repackaged in a
different container that may not offer equivalent protection, or be compatible
with the product.
» A suitable use-by date, taking into account the nature of the product, the
characteristics of the container and the storage conditions to which the article
may be subjected, should be determined by or on behalf of the sponsor.
» Such a date should be justified and must not be later than the expiry date of
the original package.
» There should be compatibility of expiry dating and clinical trial duration.

 Common issues:
 Not considering shelf-life of IMPs
 Having to commission additional [unplanned] manufacturing
 Cost of analytical method development, validation and stability studies

© 2010 MODEPHARMA www.modepharma.com

IMP Considerations 12

Other Common GMP Issues

 Creation and maintenance of the Product Specification File:

 Not available or incomplete
 Lack of structure to the file
 No system for updating the file following changes in
instructions, packaging etc.

 Recall SOP
 Insufficient detail with reference to recalls instigated by
manufacturers of comparator products
 No consideration that the IMP may identify defects with
comparator products during handling/use
 Failure to notify the MHRA in the event of a potential recall
situation being identified.

 Transport and storage conditions

 Lack of controlled storage
 Temperature deviations

© 2010 MODEPHARMA www.modepharma.com

IMP Considerations 13

CTAs

 Common issues:

 “Invalid” applications
» Failure to supply an XML file
» Missing sponsor authorisation letter
» Non-machine readable PDFs
» Password protected disks

 Quality of applications
» Section on IMPs (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

© 2010 MODEPHARMA www.modepharma.com

IMP Considerations 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/vat for further guidance

© 2010 MODEPHARMA www.modepharma.com

Clinical Supply Manufacturing and Packaging Activities 15

Overview of a Clinical Supply Project

Client Enquiry and Confidential Disclosure Proposal Acceptance Project Manager and
Requirement Definition Agreement and Payment of Deposit Project Plan

Label Design Procurement of Documents for CTA including Product

Technical Agreement
and Approval Raw Materials Specification Files

Approval of Batch Manufacturing Clinical Manufacturing, Packaging and

Randomisation Code QP Release
Record QC Testing

Project Close Shipment on Demand Storage Invoicing

© 2010 MODEPHARMA www.modepharma.com

Further Reading 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

© 2010 MODEPHARMA www.modepharma.com

Contact 17

http://www.modepharma.com

MODEPHARMA
Registered Office: Suite 16, Beaufort Court, London E14 9XL, UK
Company No: 6332969 in England and Wales
VAT Registration: GB 909535016
Phone: +44 (0) 2070 432 442
Email: info@modepharma.com

© 2010 MODEPHARMA www.modepharma.com