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Investigational Medicinal Product Management
Lead Author Liz Hartshorne, CTU Trial Manager
Signed hard copy stored in approved
SOP file with Research Integrity
Office
12-Jul-2018
Reviewer Emma Skinner, Research Integrity
Manager
Signed hard copy
stored in approved
SOP file with
Research Integrity
Office
12-Jul-2018
Effective date 19-July-2018
Next review date 19-July-2020
Applicability This SOP is applicable to all involved in the development of processes
affecting IMP handling and oversight in CTIMPs.
Disclaimer
Once printed from PDF, this document is an unofficial copy.
All SOPs and associated documents must only be accessed through the dedicated SOP area of
the Keele University Research Toolkit webpage to ensure the correct version is being used. The
user must ensure that they are working to the current version of this document.
Document type Keele University Health and Social Care QMS: Standard Operating Procedure
Version No. 3.0 Version
Date 19-July-2018
SOP
index
number HSCR-SOP-19
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Version History Log
Version Date Reason for change Implementation plan
1.0 30/04/2015 Approval of version 1.0
2.0 05-Nov-2015 Transfer to new SOP Template
Removal of detail around device trials, new title IMP Management
Clarification that IMP also refers to placebo
Clarification of operational delegation from Sponsor to CI
Removal of site level responsibilities
Details relating to use of generic products
Reference to blinded trials added
Clarification that trial cannot start until specific information is received
Requirement to notify CTU Director and QA Office where IMP license status does not meet set criteria
Clarification that process should be followed for all CTU studies unless external sponsor requires otherwise
Insertion of IMP management summary table as appendix 1
All RI staff will be notified of the revised SOP. Staff are expected to read the updated version of the SOP when it is released, as applicable to their role. The updated procedures are to be implemented from the SOP effective date.
3.0 12-Jul-2018 Re-write to bring in line with new
SOP format and Project Research Integrity Office re-structure as a result of RaISE
Addition of responsibilities for trial specific labelling of marketed products
Addition of potential requirement for accountability for IMP not prescribed under normal practice
Addition of recall section
References to associated SOPs and QCDs updated
Inclusion of a Clinical Trials Pharmacist (CTP) / Pharmacy Lead role
Additional detail added around IMP supply
Withdrawal of WI07 IMP Management Summary Table as this has been incorporated into the SOP
This SOP release will be notified via email. Staff are expected to read the SOP when it is released, as applicable to their role. The procedures are to be implemented from the SOP effective date for all studies which have yet to develop their IMP management procedures. A targeted training session will be held for those members of staff responsible for developing IMP management procedures for active CTIMPs.
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Contents
Section A Scope and Applicability .............................................................................................. 4
Section B Introduction ................................................................................................................ 4
Section C Responsibilities ......................................................................................................... 5
Section D Procedure ................................................................................................................. 6
IMP Management Summary Table .................................................................................... 6
Trial Set-up ....................................................................................................................... 8
During the trial ................................................................................................................ 10
After the trial ................................................................................................................... 12
Section E References ............................................................................................................. 12
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Section A Scope and Applicability
A1 This SOP applies to Clinical Trials of Investigational Medicinal Products (CTIMPs) only.
A2 This Standard Operating Procedure (SOP) describes the process for management and
oversight of Investigational Medicinal Products (IMPs) placebos and comparators for clinical
trials, and may be used in conjunction other SOPs including External or trial-specific
Pharmacy SOPs where applicable.
A3 This SOP outlines the related activities that Keele University CTU may have delegated
responsibility for concerning IMPs in clinical trials.
Section B Introduction
B1 The Medicines for Human Use (Clinical Trials) Regulations SI 2004 No. 1031 (as amended by
Statutory Instruments SI 2006 No. 1928, SI 2006 No. 2984 and SI 2008 No. 941) define the
responsibilities of the Sponsor, delegate(s) and Investigators in relation to handling of
Investigational Medicinal Products (IMPs).
B2 IMP(s) must be used only in strict accordance with the protocol and Clinical Trial Authorisation
(CTA).
B3 Definitions used in this SOP according to the UK Medicines for Human use (Clinical Trials)
Regulations 2004 (SI 2004/1031)
Investigational Medicinal Product (IMP) – “a pharmaceutical form of an active
ingredient or placebo being tested, or to be tested, or used, or to be used, as a reference
in a clinical trial, and includes a medicinal product which has a marketing authorisation,
but is, for the purposes of the trial; used or assembled (formulated or packaged) in a way
different from the form of the product authorised under the authorisation, used for an
indication not included in the summary of product characteristics under authorisation for
that product, or used to gain further information about the form of that product as
authorised under the authorisation.”
Clinical Trial [of an Investigational medicinal Product (CTIMP)] – “any investigation
in human subjects, other than a non-interventional trial intended to discover or verify the
clinical, pharmacological or other pharmacodynamic effects of one or more medicinal
products, to identify any adverse reactions to one or more such products or to study
absorption, distribution, metabolism and excretion of one or more such products with the
object of ascertaining the safety or efficacy of those products.”
Manufacture – “in relation to an investigational medicinal product, includes any process
carried out in the course of making the product, but does not include dissolving or
dispersing the product in, or diluting it or mixing it with, some other substance used as a
vehicle for the purposes of administering it”
Assembly – “(a) enclosing the product (with or without other medicinal products of the
same description) in a container which is labelled before the product is sold or supplied,
or used in a clinical trial, or (b) where the product (with or without other medicinal
products of the same description) is already contained in the container in which it is to be
sold or supplied, or used in a clinical trial, labelling the container before the product is
sold or supplied, or used in a clinical trial, in that container.”
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Section C Responsibilities
Chief Investigator (CI)
Oversight of development of processes for IMP management
Completion of trial IMP risk assessment
Monitoring and oversight of IMP handling at participating sites
Completion and submission of an application for a Clinical Trial Authorisation (SOSOP01: Sponsorship, Regulatory Approvals and Green Light)
Project Assurance
Research Integrity
(PARI)
Identification of contracts relating to IMP supply and handling (SOSOP01:
Sponsorship, Regulatory Approvals and Green Light)
CTU Trial Manager Supporting development of documentation for IMP management
procedures in accordance with trial-specific requirements
Liaising with local Principal Investigators (PIs) and Clinical Trial
Pharmacists/teams to monitor compliance with IMP handling processes
Clinical Trials Pharmacist (CTP) / Pharmacy Lead (where applicable)
Specific delegated pharmaceutical roles and responsibilities related to the management and handling of study drugs as applicable to the specific trial, delegated by the CI.
As Trial Management Group (TMG) member, will advise about any study-specific trial supply/management issues regarding the clinical trial.
HSCR SOP19_V3.0_ddmonyyyy
Section D Procedure
IMP Management Summary Table
D1.1 The table below summarises usual expectations for IMP supply and handling. However, the details of the trial protocol and risk assessment
must be taken into account and the details below applied accordingly.
Table 1.
IMP
License
Status
Supply CTA
Supporting
Documents
Labelling
Ordering Storage Prescriptions Dispensing $Accountability
Destruction
Fo
r u
se w
ith
in m
ark
eti
ng
au
tho
risati
on
‘li
cen
sed
’(in
clu
de
s o
ff l
ab
el
us
e w
here
co
mm
on
pra
cti
ce)
#Commercial
off-shelf stock
Participating site’s own supply
SmPC
No additional clinical trial labelling required.
Responsibility of local site. Use usual pre-existing stock. Possible cost re-imbursement to participating site or participant
As per local practice and in accordance with SmPC
Standard NHS prescription
As per local site policy for research
As per local site policy
OR
*If reimbursement, as per trial
contract or Sponsor’s requirements (detailed in protocol / pharmacy manual / working instruction)
As per local policy
Community Pharmacy
Stock control as per standard practice Possible cost re-imbursement of prescription cost to participant
Standard local practice
Standard local practice
OR
*If reimbursement, as per trial
contract or Sponsor’s requirements (detailed in protocol / Working Instruction)
Standard local practice
*Trial-specific supplies direct
to local Investigator’s Pharmacy (trial stock)
No additional clinical trial labelling required. In accordance main supply contract
Order from supplier as per trial contract (detailed in protocol / Working Instruction) Options: Per patient supply Per site bulk supply
Ring-fencing usually required by trial contract (detailed in protocol / Working Instruction). Storage as per local policy and in accordance with SmPC
As per local site policy
As per local policy
OR
As per trial contract (detailed in protocol / Working Instruction)
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*Trial specific stock supplied
to contracting party, e.g. packaging company, prior to supply to local Investigators Pharmacy (trial stock)
No additional clinical trial labelling required.
OR
Additional labelling may be required e.g. for blinding purposes. Labelling must be compliant with Annex 13.
Order from supplier as per trial contract (detailed in protocol / Working Instruction)
Storage as per local policy
OR
As per trial contract (detailed in protocol / Working Instruction/ Pharmacy manual). Storage in accordance with SmPC.
Trial specific prescription
OR
Detailed on patient drug prescription chart
As per trial contract (detailed in protocol / Working Instruction/ Pharmacy manual)
As per trial contract (detailed in protocol / Working Instruction/ Pharmacy manual)
As per local policy
OR
As per trial contract (detailed in protocol / Working Instruction/ Pharmacy manual)
Off
lab
el U
se
an
d N
OT
pa
rt o
f co
mm
on
pra
cti
ce
As above for licensed use
SmPC
OR
IB
Additional labelling required. Labelling must be compliant with Annex 13.
As above for licensed use
As above for licensed use
Trial specific prescription
As above for licensed use
As above for licensed use
As above for licensed use
Un
licen
sed
*Clinical trial supplies IB with IMPD
Annex 13 compliant labelling required
Order from supplier as per trial contract (detailed in protocol / Working Instruction)
As per trial contract (detailed in protocol / Working Instruction/ Pharmacy manual)
Trial specific prescription
As per trial contract (detailed in protocol / Working Instruction/ Pharmacy manual)
As per trial contract (detailed in protocol / Working Instruction/ Pharmacy manual). Usually full accountability
As per trial contract (detailed in protocol / Working Instruction/ Pharmacy manual).
# If IMP can be supplied as a generic product, where different brands of IMP may be dispensed to different trial participants, the risk of variability must be assessed. This must be documented in the trial Risk
Assessment (SOP 40: Risk Assessment) and identified in the CTA application. If only specific brands or makes of generics can be used within the trial, an approved list of brands to be used must be provided
to site and pharmacy staff.
$ If IMP is being provided to the participating site specifically for use in the trial, the level of accountability required may be determined by;
any contractual requirements,
the end-point of the trial and how the result will be used (for example, to support a change in prescribing practice)
if the participant or a carer is administering the IMP
*Requires a trial contract (SOP 41: Vendor Assessment and Oversight)
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Trial Set-up
D2.1 The CI must use the MHRA’s Clinical Trial Algorithm to confirm the trial’s status as a
CTIMP (SOSOP 01: Sponsorship, Regulatory Approvals and Green Light) and
document this in the Study Master File (SMF) (SOP 06: Essential Documents (previously
SOP 6: Study Master File)).
D2.2 The CI (or delegate) must undertake a trial-specific IMP Risk Assessment (SOP 40: Risk
Assessment), and ensure:
D2.2.1 Confirmation of the IMP risk category in accordance with the MRC/DH/MHRA Joint
Project Risk adapted approaches to the management of clinical trials of
investigational medicinal products including reviewing the Summary of Product
Characteristics (SmPC) to confirm the license status of the IMP(s) in relation to the
trial population and objectives (most SmPCs are available through
https://www.medicines.org.uk/emc).
D2.2.2 The CTP/ Pharmacy Lead (where applicable) is engaged at protocol design stage to
discuss the study drugs and any issues prior to grant submission. Where applicable,
the CI/Trial Manager must work closely with and take guidance from the CTP/
Pharmacy Lead throughout the study lifecycle to ensure adequate management of,
and accountability for, study drugs.
D2.2.3 Development of the trial protocol in accordance with the HRA’s Protocol guidance
and template for use in a Clinical Trial of an Investigational Medicinal Product
(CTIMP).
D2.2.4 Processes are put in place for IMP management including, but not limited to (as
required, see Table 1):
ordering
shipment
storage
dispensing
destruction
(this may be delegated to CTP/Pharmacy Lead)
D2.2.5 Any trial-specific dispensing procedures are detailed in the trial protocol and/or trial
specific working instruction/Pharmacy manual.
D2.2.6 Preparation of IMP accountability forms as required. These forms must allow for the
documentation of full drug accountability from arrival of the IMP at the participating
site, storage, dispensing and return from trial participants through to destruction of
used / unused supplies, as applicable for the trial.
D2.2.7 Procedures are put in place for monitoring IMP compliance where required (SOP
14: Monitoring).
D2.2.8 Sites are trained in any trial-specific IMP management procedures (SOP 05: Site
Management (formerly SOP 5: Site Initiation))
D2.3 Arranging IMP Supply (see Table 1).
D2.3.1 The IMP may come directly from a standard commercial supply available at the
participating sites, or provided to the Investigator from a pharmaceutical company or
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another Marketing Authorisation Holder (MAH). A third party vendor may be
employed for IMP management purposes
D2.3.2 The CTP/ Pharmacy Lead may be delegated responsibility for the sourcing the IMP
on behalf of the CI (including making sure the IMP has a suitable expiry date for the
length of the study).
D2.3.3 If the IMP requires manufacture and/or assembly (see section B3) by an external
party, the external party must hold a Manufacturers Authorisation for Investigational
Medicinal Products (MIA (IMP)).
D2.3.3.1 Regulations require the IMP manufacturer to comply with the principles
and guidelines of GMP and the Medicines for Human Use (Clinical Trials)
Regulations 2004. They are required to have the services of a Qualified
Person (QP) who is responsible for certifying that production batches are
of adequate quality. IMPs must not be released by the manufacturer until
the QP has certified that the requirements of Directive 2001/20/EC have
been met.
D2.3.3.2 Where applicable, a technical agreement must be in place between the
Sponsor and the supplier (vendor) to document respective responsibilities
and must include quality standards that will be adhered to (SOP 41:
Vendor Assessment and Oversight). Where this agreement is not in
place, this may be initiated by Project Assurance Research Integrity
(PARI) during review (SOSOP 01: Sponsorship, Regulatory Approvals
and Green Light).
D2.3.4 Financial responsibilities around IMP supply for the study must be detailed in the
relevant study contract(s) for example the Sponsor delegation of functions (SOP 41:
Vendor Assessment and Oversight).
D2.4 Labelling
D2.4.1 Where a trial uses marketed product within the terms of its marketing licence (or
within well-established clinical practice) the adapted provisions allowable by Article
14 of the European Clinical Trials Directive 2001/20/EC may be applied provided the
following conditions are met:
The product does not require particular manufacturing or packaging processes
The product has a Marketing Authorisation (MA)
The subjects participating in the trial have the same characteristics as those
covered by the indication specified in the MA (i.e. as identified in the SmPC)
The product is dispensed to a subject in accordance with a prescription given by
a healthcare professional
As per standard dispensing practice, a dispensing label is applied as a minimum
in accordance with Schedule 5 to The Medicines for Human Use (Marketing
Authorisations etc.) Regulations 1994
D2.4.2 Where the above adapted provision described in D2.4.1 is applied, no trial-specific
labelling is required. A justification for the decision not to use trial-specific labels
must be documented in the trial risk assessment and included in the CTA
application (GUI 11: Regulatory Submission).
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D2.4.3 If trial specific labelling is required, e.g. to maintain the blind of a study with
marketed products being used within the terms of their marketing licence (or within
well-established clinical practice), the contract between the Sponsor and any
relevant subcontractor must detail who has responsibility for label design and
labelling of IMP (SOP 41: Vendor Assessment and Oversight). Labels must be
compliant with Annex 13: Manufacture of investigative medicinal products (Volume 4
of The Rules Governing Medicinal Products in the EU: Good Manufacturing
Practices).
D2.5 Packaging
D2.5.1 If IMP is a marketed product, in most cases, it may be used in its original packaging.
D2.5.2 If secondary packaging of a marketed product is required, e.g. for blinding
purposes, appropriate contracts detailing responsibilities must be in place between
the Sponsor and supplier (vendor) who will complete the secondary packaging
(SOP 41: Vendor Assessment and Oversight).
D2.5.3 Suppliers of trial-specific IMPs must have a specific MA issued by the licensing
authority before they can manufacture, assemble or import an IMP for use in a
clinical trial. However, an exemption exists in the UK Clinical Trial Regulations
(section 37), which permits the assembly of an IMP in the pharmacy or locally within
the trial site, by a doctor or pharmacist or person acting under the supervision of a
Pharmacist. This exemption only applies when the IMP is assembled exclusively for
use within that hospital or health centre participating site or any other hospital or
health centre which is a trial site for the clinical trial in which the IMP is to be used.
This exemption means that a pharmacy can re-package, re-label or dispense
batches of IMPs after they have been sourced and obtained for use in a CTIMP.
During the trial
D3.1 A Clinical Trial Authorisation (CTA) (GUI 11 Regulatory Approvals) must be in place
before any protocol-defined activity takes place. For details on how to prepare and, obtain
sponsor authorisation for and submit a CTA refer to SOSOP 01: Sponsorship, Regulatory
Approvals and Green Light.
D3.2 Where applicable, IMP is not permitted to be supplied to individual sites until the
following conditions are met:
Technical release: Certification by a QP that the IMP is suitable for use in the trials
Regulatory release: required regulatory approvals and agreements are in place (CTA,
favourable REC opinion, local R&D approval, Sponsor-participating site and all other
agreements for the trial in place)) and Sponsor Regulatory Green Light has been given
(SOSOP 01: Sponsorship, Regulatory Approvals and Green Light)
D3.3 Prescribing
D3.3.1 Only qualified and registered medical practitioners or health care professionals who
are supplementary prescribers and who are detailed on the Delegation of Duties
Log (TEM 71: Delegation of Duties Log or equivalent) are permitted to prescribe
IMPs.
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D3.4 Dispensing
D3.4.1 Only suitably qualified members of staff listed on the Delegation of Duties Log
(TEM71: Delegation of Duties Log or equivalent) and authorised by the local
Principal Investigator (PI) are permitted to dispense IMPs. Where community
pharmacies are dispensing commercial stock in accordance with usual practice
against a standard NHS prescription, Delegation of Duties Logs are not applicable.
D3.5 Monitoring and accountability
D3.5.1 The CI must ensure that monitoring of IMP accountability and storage is conducted
as per the trial specific monitoring plan and in accordance with the protocol.
D3.5.2 If participating sites are following normal prescribing practice (where IMP and
comparator are used within their authorisation) then there may be no requirement
for participating sites to retain trial-specific detailed accountability records. The
appropriate level of accountability must be considered for each trial and decisions
recorded on the trial risk assessment.
D3.6 IMP Recall
D3.6.1 For IMPs supplied specifically for the trial, responsibilities for product recall must be
included in the Technical Agreement (or equivalent) with the IMP supplier. Trial-
specific requirements for product recall should be included in a trial pharmacy
manual / working instruction. Responsibility falls to the Sponsor or Manufacturer with
responsibility documented in the technical agreement.
D3.6.2 For IMPs sourced from participating site commercial stock, IMP recall should be
managed in accordance with local participating site policy. The CI (or their delegate)
should notify PARI at [email protected] at the earliest opportunity.
D3.6.3 Where a recall is initiated, the Research Integrity Office must be notified at
[email protected] at the earliest opportunity (ideally within 24hours
of the notification). The Research Integrity Manager should then liaise with the
Chief Investigator (or their delegate) and agree a course of action, which may
include contacting the MHRA Clinical Trials Unit and/or Defective Medicines Support
Centre for advice (https://www.gov.uk/guidance/contact-mhra#clinical-trials-of-
medicines).
D3.7 Transfer of IMP between sites
D3.7.1 The transfer of IMP between sites is only allowed in exceptional circumstances (as
per Article 47 of Annex 13). Note that a lack of oversight of IMP supply does not
satisfy this condition, and that timely restocking of IMP is paramount.
D3.7.2 If transfer is necessary, a formal process must be put in place, and must be
documented clearly, including:
Details of what has been transferred (including batch numbers and quantities of IMPs involved)
Evidence that the storage conditions of the IMP were maintained at the originating site and during shipment to the receiving site.
D3.8 For trials where the IMP is a marketed product, the current version of the Summary of
Product characteristics used for the trial should be reviewed in line with SOP 20: Safety
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Reporting and Pharmacovigilance. Any updates to the SmPC used within a trial must be
sent to participating sites as applicable.
After the trial
D4.1 At the end of the trial, the CI must ensure;
D4.1.1 IMP reconciliation is performed as appropriate and as per the monitoring plan for the
trial.
D4.1.2 Returned, unused or part-used IMP must be destroyed (where required) after
sponsor authorisation and documents relating to the destruction are retained in the
pharmacy trial file.
D4.1.3 Documents are passed to archive in accordance with SOP 17: CTU Archiving and
Destruction.
Section E References
Annex 13 Manufacture of investigative medicinal products (Volume 4 of The Rules Governing
Medicinal Products in the EU: Good Manufacturing Practices)
Professional Guidance on Pharmacy Services for Clinical Trials 2013 (Royal Pharmaceutical
Society of Great Britain)
Volume 10 of "EudraLex - The rules governing medicinal products in the European Union",
Clinical Trials Chaper III: Quality of the Investigational Medicinal Product
Clinical Trials Tool Kit (http://www.ct-toolkit.ac.uk/)
CT-1 Detailed guidance on the request to the competent authorities for authorisation of a clinical
trial on a medicinal product for human use, the notification of substantial amendments and the
declaration of the end of the trial
Risk adapted approaches to the management of clinical trials of Investigational Medicinal
Products – MRC/DH/MHRA Joint Project.
Article 40: Directive 2001/83/EC:
http://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural_guidelin
e/2009/10/WC500004481.pdf
Electronic Medicines Compendium (eMC) https://www.medicines.org.uk/emc