investigational medicinal product management€¦ · investigational medicinal product (imp) –...

HSCR-SOP19_V3.0_19-Jul-2018

TEM06_HSCR SOP01_V7.0_16-Apr-2018 of 12 Copyright © Keele University

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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


OR

*If reimbursement, as per trial

contract or Sponsor’s requirements (detailed in protocol / Working Instruction)


*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 local policy

OR


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.







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). 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

https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/317952/Algothrim.pdf

https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/343677/Risk-adapted_approaches_to_the_management_of_clinical_trials_of_investigational_medicinal_products.pdf


https://www.medicines.org.uk/emc

https://www.hra.nhs.uk/planning-and-improving-research/research-planning/protocol/





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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.

https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-4/2009_06_annex13.pdf



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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

mailto:[email protected]

mailto:[email protected]

https://www.gov.uk/guidance/contact-mhra%23clinical-trials-of-medicines

https://www.gov.uk/guidance/contact-mhra%23clinical-trials-of-medicines



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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

https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-4/2009_06_annex13.pdf

https://ec.europa.eu/health/documents/eudralex/vol-4_en


https://www.rpharms.com/Portals/0/RPS%20document%20library/Open%20access/Hospital%20Pharmacy%20Hub/professional-guidance--n-pharmacy-services-for-clinical-trials-141013.pdf



http://www.ct-toolkit.ac.uk/

https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-10/2010_c82_01/2010_c82_01_en.pdf





http://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural_guideline/2009/10/WC500004481.pdf

http://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural_guideline/2009/10/WC500004481.pdf

https://www.medicines.org.uk/emc