Standard Operating Procedure (SOP) Template - OSAC … Trial SOP Drug... · · 2013-05-02STANDARD...

OSAC Trial SOP Drug Handling v1.0 (27 Mar 2013) FINAL VERSION Printed: Wed, 1 May 2013 UNCONTROLLED WHEN PRINTED of 28

www.osactrial.org.uk

STANDARD OPERATING PROCEDURE FOR:

OSAC (Oral Steroids for Acute Cough) Trial

DRUG HANDLING

SOP Details:

Number: SOP-OSAC-0001 Version: 1.0

Author(s): Harriet Downing

Title: OSAC Trial Manager

Date: 27 Mar 2013

Authorised by: Dr Alastair Hay

Title: Chief Investigator

Date: 27 Mar 2013

Authorised by: Dr Birgit Whitman

Title: Sponsor

Date: 27 Mar 2013

Date operational: 1 May 2013

Date to be reviewed: 1 November 2013

Review History:

Review Date: Reviewed By:

Review amendments:

Amended date: Amended by:

Authorised date: Authorised by:

SOP-OSAC-0001 CONFIDENTIAL: UNAUTHORISED COPYING PROHIBITED

G:\Studies\OSAC Trial\SOPs\Drug_Handling (completed)\Current version\Complete SOP\OSAC Trial SOP Drug Handling

v1.0 (27 Mar 2013) FINAL VERSION.docx

Printed: Wed, 1 May 2013 UNCONTROLLED WHEN PRINTED of 28

Contents

1 Document History ......................................................................................................................................... 2

2 Background ................................................................................................................................................... 3

3 Purpose .......................................................................................................................................................... 3

4 Scope ............................................................................................................................................................. 3

5 Definitions & Abbreviations ......................................................................................................................... 3

6 Pre-Requisites ............................................................................................................................................... 3

6.1 Pre-Requisite Knowledge & Training ................................................................................................... 3

6.2 Pre-Requisite Equipment & Systems .................................................................................................... 3

7 Roles & Responsibilities ............................................................................................................................... 3

8 Procedure ...................................................................................................................................................... 4

8.1 Procedure Diagram................................................................................................................................ 4

8.2 Procedure Narrative .............................................................................................................................. 4

8.2.1 Receipt of OSAC Trial IMP by UH Bristol Pharmacy ........................................................................ 4

8.2.2 OSAC Trial IMP Storage at UH Bristol Pharmacy .............................................................................. 4

8.2.3 Randomisation ..................................................................................................................................... 5

8.2.4 Production of Patient Packs and delivery to UH Bristol Pharmacy ..................................................... 5

8.2.5 Allocation of IMP to Patient Packs by UH Bristol Pharmacy .............................................................. 6

8.2.6 Risk assessment of OSAC trial IMP storage locations at trial centres ................................................. 6

8.2.7 Risk Assessment Procedure ................................................................................................................. 6

8.2.8 Issue of OSAC Trial Patient Packs by UH Bristol Pharmacy to OSAC Trial Centres ......................... 7

8.2.9 Temperature Monitoring Procedure ..................................................................................................... 8

8.2.10 Significant Temperature Variations Reporting Procedure ............................................................ 8

8.2.11 Significant Temperature Variations Management Procedure ....................................................... 9

8.2.12 Issue of OSAC Trial Patient Packs to recruiting GP sites by OSAC Trial Centres ...................... 9

8.2.13 Issue of OSAC Trial Patient Packs to eligible, consented patients by recruiting GP sites ......... 10

8.2.14 Re-allocation of OSAC Trial Patient Packs from one recruiting GP site to another .................. 10

8.2.15 Return of any unused medication and empty medicine packs from patients to the Bristol trial

centre 10

8.2.16 Return of any unused Patient Packs from recruiting GP practices to the trial centres ................ 11

8.2.17 Management of any unused Patient Packs and medicine packs at the Bristol trial centre .......... 11

8.2.18 Shipment of any unused Patient Packs and medicine packs to UH Bristol for destruction ........ 11

9 Quality Control Measures ........................................................................................................................... 11

10 Related Documents ..................................................................................................................................... 12

11 Additional Guidelines ................................................................................................................................. 14

12 Appendices .................................................................................................................................................. 14

1 Document History

Revision Date Author Changes

1.0 27 Mar 2013 Harriet Downing None, this is the first draft





2 Background

This document describes all of the procedures to be followed in the OSAC trial for the handling and

management of the IMP (Prednisolone or matched placebo).

3 Purpose

This is the reference document for the trial and should be used by all members of research and administrative

staff working on the trial.

4 Scope

The document refers to IMP management for the OSAC trial only.

5 Definitions & Abbreviations

IMP Investigational Medicinal Product

N/A Not Applicable

PID Patient Identification number

PP Patient Pack

PTF Pharmacy Trial File

RF Recruitment Folder

TMF Trial Master File

TSF Trial Site File

UHB University Hospitals Bristol NHS Foundation Trust

UoB University of Bristol

6 Pre-Requisites

None.

6.1 Pre-Requisite Knowledge & Training

Good Clinical Practice.

6.2 Pre-Requisite Equipment & Systems

None.

7 Roles & Responsibilities

Who What & Why

Chief Investigator Authorises this SOP.

Principal Investigator Ensures that this SOP is adhered to in all local sites. Delegates certain

activities to local researchers; all delegated activities documented on the

trial Delegation Log.

Piramal Healthcare / Mode Pharma Manufactures the IMP to quality standards, and delivers it to UH Bristol

Pharmacy in two equal batches in 2012/13 and in 2013/14. The second

batch is stored by Piramal until 2013/14.

Bristol Randomised Trials

Collaboration

Produces the randomisation schedule and sends this to UH Bristol

Pharmacy. Unblinds the trial data for review by the Data Monitoring

Committee.

UH Bristol Pharmacy Reviews this SOP and advises on content. Receives and stores the IMP

prior to dispatch to centres. Allocates the IMP to Patient Packs in line

with the Randomisation Schedule. Dispatches the IMP in blocks of four,

initially in batches of 44 Patient Packs to the trial centres.

Trial Sponsor (UoB) Reviews this SOP and approves content.

Trial Manager Updating of this SOP and adherence to content in all trial operations.

Trial Research Nurse Adherence to content of this SOP in all trial operations.





Who What & Why

Trial Administrator Adherence to content of this SOP in all trial operations.

GP Practices Adherence to content of this SOP in all recruitment activity.

UH Bristol Monitor Monitors site adherence to this SOP within the monitoring plan.

8 Procedure

8.1 Procedure Diagram

See OSAC Trial Medicine Flow diagram (Appendix 1).

8.2 Procedure Narrative

Each of the stages through which the IMP will move during the progress of the trial are described below in

sequence.

8.2.1 Receipt of OSAC Trial IMP by UH Bristol Pharmacy

1. The trial medication will be shipped from Piramal Healthcare (Logistics Department, Piramal Healthcare,

Whalton Road, Morpeth, Northumberland, NE61 3YA, Tel: 01670 562 400) to UH Bristol Pharmacy

(Pharmacy Trials Unit, c/o Pharmacy Stores, Level 3 King Edward Building, Bristol Royal Infirmary,

Marlborough Street, Bristol, BS2 8HW, United Kingdom, Tel: 0117 342 3324).

2. The medicines will be transported in line with standard clinical shipping practice in the country of

manufacture of the 20mg prednisolone tablets (Germany). The manufacturer has confirmed that their

prednisolone is shipped under ambient conditions and that ICH stability data states that the 20mg

prednisolone tablets (Galen) can be stored at a temperature of up to 40°C and a relative humidity of 75% for

6 months, therefore short-term deviation from the normal storage temperature (15-25°C) is not critical and

thus short-term storage of up to 30°C is possible without any loss of quality.

3. The QP batch certificate will be sent to UH Bristol Pharmacy and stored in the pharmacy trial file. UH

Bristol Pharmacy will receive the delivery of IMPs. Prednisolone and placebo medicine packs to be in

separate, clearly labelled boxes. Each medicine pack shipped from Piramal to UH Bristol Pharmacy (which

will remain independent and unblinded throughout the trial) will be labelled with the MHRA-approved

labelling and carry a unique Medicine ID Number, which will also be printed onto three detachable stickers.

During the recruitment interview, these medicine ID number stickers will be removed from the medicine

pack (within the patient pack) by the Recruiting Clinician and affixed to (1) the completed Consent Form,

(2) the Trial Prescription which has been completed and authorised by the Responsible Clinician, and (3)

the Trial Participation Card.

4. Upon arrival at UH Bristol the contents of the delivery will be checked in line with UH Bristol’s Standard

Operating Procedure CT 2 01 (CT 2 01 Receipt and Recording of the safe delivery of Clinical Trial

Material).

5. The receipt of the medication and the completion of the UH Bristol checking procedure will be confirmed

to the trial centre by e-mail from UH Bristol Pharmacy to the OSAC Trial Manager.

6. UH Bristol Pharmacy will store the IMPs as per section 8.2.2.

8.2.2 OSAC Trial IMP Storage at UH Bristol Pharmacy

1. At UH Bristol, the trial medication will be stored below 25⁰C in the Pharmacy Trials Unit, pending the

allocation of medicine packs to the Patient Packs, and temperature monitoring will be carried out in line





with the UH Bristol Safe Handling and Storage of Room Temperature Clinical Trial Material in Pharmacy

Trials Unit (CT 3 01).

8.2.3 Randomisation

1. A list detailing the contents of each medicine pack (active Prednisolone vs. Placebo), known as the

unblinded list, will be sent by Piramal Healthcare to UH Bristol following shipment of the IMP.

2. UH Bristol Pharmacy will record the medicine numbers of the medicine packs onto trial-specific Inventory

Logs for Active Medication and Placebo (Appendix 2).

3. An independent statistician from the Bristol Randomised Trials Collaboration will deliver to UH Bristol a

Randomisation Schedule of Participant ID numbers. This document, as well as the unblinded list and the

completed Inventory Logs, will be kept in the secure Pharmacy Trial File at UH Bristol.

4. No copies of any of the randomisation data will be kept at the trial centre (though a copy will be retained by

the Bristol Randomised Trials Collaboration). This is in order to ensure that the blinding of all of the trial

research team is maintained.

8.2.4 Production of Patient Packs and delivery to UH Bristol Pharmacy

5. Strips of 12 small yellow OSAC trial Patient ID labels will be prepared for each of the Patient ID numbers

generated by the Oxford clinical database programmer.

6. The following contents will be placed in the OSAC patient pack box by a member of the OSAC trial team:

a. Peak flow meter

b. £5 High Street Voucher in a thank you card

c. OSAC pen

d. Sheet of 12 Patient ID labels

e. OSAC trial canvas shopping bag

(The following patient pack items will be supplied to GP sites in the separate recruitment folder, and transferred

from the recruitment folder to the patient pack by the Recruiting Clinician during the recruitment interview:

f. Full Patient Information Booklet

g. Summary Patient Information Sheet

h. Consent form

i. Trial participation card)

j. Symptom diary

k. Laminated instruction sheet for using the peak flow meter

l. 1 padded freepost envelope (for the return of the trial medication packet)

m. 1 large freepost envelope (for the return of the symptom diary)

7. The contents of the box will be checked by a second member of the OSAC trial team, who will affix one of

the 12 Patient ID labels to the front of the Patient Pack, and return the remaining 11 to the box.

8. The assembled patient packs will be stored in sequential number order in the specified, risk-assessed

storage location. For each day of storage at the trial centre, the storage temperature will be monitored in line

with section 8.2.9.

9. The patient packs will be personally delivered to UH Bristol Pharmacy by a member of the trial team.





8.2.5 Allocation of IMP to Patient Packs by UH Bristol Pharmacy

1. UH Bristol Pharmacy will receive the assembled Patient Packs from the Bristol trial centre.

2. UH Bristol Pharmacy will allocate the uniquely numbered medicine packs to the uniquely identified Patient

Packs according to the BRTC Randomisation Schedule for the corresponding centre, and in line with the

UH Bristol OSAC Trial Dispensing Procedure, inserting 1 medicine pack into each patient pack

accordingly.

3. For each Patient Pack, UH Bristol will affix one of the 12 small yellow Patient ID labels (included in the

Patient Pack) to the Medicine Pack, and write the appropriate number on the Drug Accountability Log.

4. UH Bristol Pharmacy will complete the UH Bristol OSAC Trial Pharmacy Drug Accountability Log

(Appendix 3). This is a record of matched Patient Pack ID Numbers to Medicine Pack Numbers, a copy of

which will be retained in the Pharmacy Trial File for unblinding purposes. No copy of this log will be held

at the trial centre, in order to maintain blinding for all research staff.

5. The fully assembled Patient Packs will be sealed and stored at UH Bristol Pharmacy Trials Unit, in

sequential number order and by centre, under the same conditions as the trial medicine packs (as the

medicine packs are now contained within the Patient Packs) pending distribution to the OSAC trial centres.

8.2.6 Risk assessment of OSAC trial IMP storage locations at trial centres

1. Prior to receiving any of the Patient Packs, each OSAC trial centre will be required to complete a risk

assessment, with reference to the proposed storage location. The aim of the risk assessment is to ensure that

clinical trial materials stored outside the UH Bristol Pharmacy are handled and stored in accordance with

applicable good manufacturing practice (GMP) and good clinical practice (GCP) regulations and as

specified by the sponsor. The OSAC trial protocol states that the “storage environment will be secure” (i.e.

a locked cabinet or room) “with access limited to members of the practice team recorded as being involved

in the trial. If sites have medication storage which is temperature monitored the trial medicines should be

stored there. Otherwise, the trial centre will ensure GP sites have minimum/maximum thermometers

available to monitor the temperature. The GP sites will check the temperature weekly and prior to issuing

medicines to recruited patients, recording the temperature on the temperature log and notifying the trial

centre if the temperature has exceeded 25°C.”

2. The IMP should be stored separately from other medication. If stored in the same area, the storage spaces

should be clearly distinguished.

3. Access to the locked storage area should be restricted to those persons with authority to handle the IMP as

stated on the OSAC Trial Centre Delegation Log.

4. Regular temperature monitoring of the storage facility must be undertaken (see section 8.2.9) and the local

OSAC trial centre team contacted if the temperature falls outside the specified range.

5. The OSAC trial IMP should be used only in accordance with the approved trial protocol.

8.2.7 Risk Assessment Procedure

1. The OSAC Trial IMP Storage Risk Assessment Form should be used to complete the risk assessment

(Appendix 4).





2. The risk assessment should be carried out prior to the IMP arriving at the trial centre, and prior to the trial

opening at the recruiting GP practice.

3. The risk assessment should be completed by a member of the OSAC trial research team (for GP sites, this is

to minimise the burden on the practice team).

4. A named member of the OSAC trial research team (at the trial centre) or of the GP Practice team (at the

recruiting site) should take responsibility for the clinical trial material while it is stored outside pharmacy

and be responsible for temperature monitoring the clinical trial material and reporting temperature

deviations to the local trial centre (GP sites) and/or Bristol trial centre (trial centres). The name of this

person must be recorded in the OSAC Trial Delegation Log.

5. The local (centre or site) Principal Investigator must sign the completed form to acknowledge and confirm

that they are satisfied with the outcomes of the risk assessment.

6. The completed risk assessment forms should be filed in the centre/site trial file. A copy of any form

recording a ‘high’ or ‘medium’ risk, unacceptable storage location or actions to be taken should be faxed to

the Bristol trial centre who will arrange review, if appropriate, by an appropriately trained member of the

UH Bristol Pharmacy Clinical Trials Unit. Appropriate measures will then be taken in order to reduce the

level of risk to low.

7. The completed form must be filed in the centre or site OSAC trial file.

8. If any factors change during the trial, a new risk assessment must be carried out and a new assessment form

completed.

8.2.8 Issue of OSAC Trial Patient Packs by UH Bristol Pharmacy to OSAC Trial Centres

1. OSAC trial Patient Packs will be issued from UH Bristol directly to the four trial centres on completion of

Section1 the OSAC Trial Patient Pack Requisition and Transfer form (Appendix 5) by the Trial

Manager, who will send this to UH Bristol Pharmacy.

2. UH Bristol Pharmacy will confirm release of the patient packs in line with their standard internal processes.

Initially, 44 Patient Packs (in bundles of 4) will be sent to the requesting centre using the OSAC trial

courier, of which details are provided in Appendix 6 (towards the end of the trial, fewer patient packs may

need to be sent to centres depending on the progress of recruitment and the number of patient packs

remaining at UH Bristol Pharmacy). The courier pick-up will be arranged by the OSAC trial centre. The

Pharmacy will receive notification of the safe delivery of the patient packs to the trial centre, by the centres

faxing the signed transfer form to UH Bristol Pharmacy (0117 432 4304). The Pharmacy will store this

notification in the pharmacy trial file.

3. Trial patient packs will be issued to recruiting trial centres in sequential order of Patient Pack ID number, as

the medicine has been randomised to the patient packs prior to receipt of completed patient packs by the

trial centres. The Pharmacy will summarise the specific patient pack numbers to be issued in Section 2 of

the Requisition, Transfer and Receipt form. A hard copy of all the form will be sent with the Patient Pack

Shipment to the trial centre. For patient pack deliveries to the Oxford, Southampton and Nottingham

centres, a copy of the Requisition, Transfer and Receipt form will also be sent to the Bristol trial centre.

4. Upon receipt of the Patient Packs at the trial centre, a member of the Research team will check the contents

of the Shipment, complete Section 4 and fax a copy to the Bristol trial centre.





5. The Trial Manager will double-check that all sections of the form are consistent and complete, in order to

confirm that the specific patient packs issued match those that have been received at the trial centres, and

enter the Patient Pack transfer data onto the Trial management database.

6. The Patient Packs will be transferred to the designated, risk assessed storage area (see section 8.2.6).

7. The temperature of the storage area will be monitored on a weekly basis as per the procedure outlined in

8.2.9.

8.2.9 Temperature Monitoring Procedure

1. The designated member of staff will monitor the storage temperature of the trial medication weekly and

record the findings on the OSAC Trial Temperature Monitoring Log (Appendix 7).

2. Temperatures should be read on the first working day of every week (preferably first thing in the morning).

3. Record the minimum and maximum temperature from the calibrated digital thermometer (see Appendix 8

for details of the model to be used) in the IMP storage area.

4. Reset the thermometer by pressing the reset button.

5. Complete all sections of the temperature monitoring log.

6. File completed temperature logs in the OSAC trial file.

7. If for any week the minimum or maximum temperature falls outside the accepted range (15⁰C to 25⁰C),

OSAC trial centres should fax a copy of the log to the Bristol trial centre. (GP Practices should fax their log,

in the case of temperature deviations, to their local trial centre).

8. The Bristol trial team will enter all site temperature monitoring data onto the Trial Management Database.

8.2.10 Significant Temperature Variations Reporting Procedure

1. The Bristol Centre will keep a cumulative log of the number of weeks on which significant temperature

variations have occurred for any trial centre. OSAC trial centres will keep a cumulative log of the number

of weeks on which significant temperature variations have been reported for any participating GP site.

These variations will be recorded on the OSAC Trial Significant Temperature Variations Log

(Appendix 10).

2. Should a temperature variation be recorded for any single site on more the 15 weeks, this will be taken by

the trial team to represent, cumulatively, a significant percentage of the 6 month period covered by the

Galen stability data (Appendix 9).

3. If this happens for any participating GP practice, the Significant Temperature Variations Log will be faxed

by the local trial centre to UH Bristol Pharmacy, with a copy to the Bristol trial centre. UH Bristol

Pharmacy will then follow the Significant Temperature Variations Management Procedure (see section

8.2.11).





8.2.11 Significant Temperature Variations Management Procedure

1. The OSAC trial centre or GP site about which the significant temperature variations report has been made

will be asked by the Bristol trial centre (OSAC trial centres) or by the local trial centre (GP Practices) to

clearly mark all OSAC patient packs with “IN QUARANTINE. DO NOT USE” and inform all members of

staff involved in the trial (trial centres) or in recruiting patients and issuing the Patient Packs (GP Practices).

2. UH Bristol Pharmacy will decide, on the basis of all available information, whether or not the OSAC trial

IMPs are fit or unfit for use. The Pharmacy may need to contact Piramal for advice.

3. If the clinical trial material is deemed unfit for use, the affected stock should remain in quarantine and

replacement stock should be ordered. OSAC trial centres should contact the Bristol Centre to arrange

transfer of the quarantined stock back to UH Bristol Pharmacy for destruction.

4. Quarantined stock must be stored separately from “active” stock.

5. If the clinical trial material is deemed fit for use, remove the stock from quarantine. Inform all members of

staff involved in the trial (trial centres) or in recruiting patients and issuing the Patient Packs (GP Practices).

6. Ensure you have written confirmation from UH Bristol pharmacy confirming whether the stock is fit or

unfit for use. File this in the OSAC centre / site trial file.

8.2.12 Issue of OSAC Trial Patient Packs to recruiting GP sites by OSAC Trial Centres

1. A member of the OSAC trial research team responsible for setting up the GP site should carry out the

OSAC Trial IMP Storage Risk Assessment, for the proposed storage location, on behalf of the GP Practice

(see section 8.2.7), prior to the delivery of Patient Packs to the site.

2. GP Practices will be provided with OSAC trial calibrated digitial minimum / maximum thermometers (see

Appendix 8 for details) either before or at the same time as the first delivery of Patient Packs to the site.

3. At the start of recruitment each participating GP practice will be provided with 4 Patient Packs and

associated Recruitment Folders. Prior to shipment, the local trial centre will complete Section 2 of the

Requisition, Transfer and Receipt Log.

4. A printed copy of the Requisition, Transfer and Receipt Log will be included with the delivery of Patient

Packs.

5. The local trial centre will record the details of which patient packs have been sent to which GP site in the

OSAC Trial Centre Patient Pack Accountability Log (Appendix 11), and check this prior to any Patient

Packs leaving the trial centre.

6. A nominated member of staff at the recruiting GP Practice will check the ID numbers of the Patient Packs

they receive, and acknowledge and sign for these in Section 4 of the Requisition, Transfer and Receipt

Form, a copy of which will be faxed back to the local trial centre.

7. The designated member of staff at the GP practice will also complete the OSAC Trial GP Practice Patient

Pack Accountability Log (Appendix 12).

8. The designated member of staff will follow the weekly IMP Storage Temperature Monitoring Procedure

(see section8.2.9).





9. Staff at the local trial centre will check that the Patient Pack numbers on the Requisition, Transfer and

Receipt Form match those that have been received, and record this in the Trial Site File.

10. If the recruiting GP Practice needs more packs, they will complete the Requisition section of the

Requisition, Transfer and Receipt Form and send this to their local trial centre. The local trial centre will

then issue the GP Practice with a further 4 packs, which will be recorded on issue and on receipt as

described above.

11. The local trial team will receive copies of all centre Requisition, Transfer and Receipt forms by secure fax

after each transfer, and enter the data onto the Trial Management Database.

8.2.13 Issue of OSAC Trial Patient Packs to eligible, consented patients by recruiting GP sites

1. Patient packs will be allocated to patients for whom a GCP-trained GP has authorised the OSAC trial

prescription, and from whom written consent has been obtained by a GCP-trained clinician, in sequential

number order.

2. GP practices will record the allocation of patient packs to patients by updating the OSAC Trial GP

Practice Patient Pack Accountability Log (Appendix 12).

3. The Bristol centre will use this data to update the OSAC Trial Master Patient Pack Accountability Log

(Appendix 13) and will enter these data electronically into the Trial Management Database.

8.2.14 Re-allocation of OSAC Trial Patient Packs from one recruiting GP site to another

1. OSAC Trial Patient Packs must not be re-allocated or transferred to another site. In exceptional

circumstances a decision may be taken by the Trial Management Group, with the agreement of the Sponsor,

to arrange for re-allocation in a manner which maintains the integrity of the randomisation.

8.2.15 Return of any unused medication and empty medicine packs from patients to the Bristol trial

centre

1. Patients are asked to return unused trial medication, and/or the empty medicine packs from the Patient Pack,

to the trial centre by post using the OSAC Trial prepaid addressed return medicine packaging. The patient

will be advised of this requirement in the following ways:

1) During the training for follow-up provided by the recruiting clinician as they administer the patient

pack to the patient. The return envelope will be contained in the Recruitment Folder, and passed by the

recruiting clinician to the patient during the recruitment process. The physical handover of the

medicine return packaging from the recruitment folder to the patient – who will be asked to store it

within their patient pack – will help to emphasise the importance of this part of the patient training

process and lessen the possibility of this being overlooked or forgotten by the clinician or the patient.

2) The requirement is specified as an action after Day 5 within the Patient Symptom and Recovery Diary.

3) The patient will be reminded of this requirement by the Research Nurse during the Day 7 follow-up

telephone call, and asked to return the medicine packet (and any unused medication) if they have not

already done so.

2. GP Practices will be provided with a few spare pre-paid envelopes (the same as those provided to the

patients for returning the medication) in case any patients give any unused trial medication back to the GP

practice. This could then be returned directly by the GP practice to the Bristol trial centre.





3. The Bristol trial centre will count and record all returned medicine packets and unused medicines in the

Master Patient Pack Accountability Log and electronically in the Trial Management Database.

4. The empty medicine packets and unused medicines will be stored, separately from the unused trial

medication to be dispensed for recruitment, until the end of the recruitment period.

5. When each sheet of the Master Patient Pack Accountability Log is complete, the Bristol trial team will

arrange for this to be signed off by the Chief Investigator and by the UH Bristol Pharmacy, to confirm that

all trial medication is accounted for.

8.2.16 Return of any unused Patient Packs from recruiting GP practices to the trial centres

1. GP sites will be required to return any unused Patient Packs to the local trial centre at the end of their

involvement in recruitment.

2. The Patient Packs to be returned will be recorded by the GP sites on the Requisition, Transfer and Receipt

form and sent to the local trial centre, who will record receipt of the transferred material on their Receipt

section of the form and check this against the Centre Patient Pack Accountability Log to ensure that all

Patient Packs provided to the recruiting site have been accounted for (either as issued to a patient, or as

returned to the local centre.

3. Unused patient packs will be stored at the local trial centres until a decision is made by the TMG as to

whether the IMPs will need to be reallocated (in this case all unused patient packs will be returned to UH

Bristol Pharmacy].

8.2.17 Management of any unused medicines and empty medicine packs at the Bristol trial centre

1. Once recruitment is complete, all empty medicine packs will be destroyed. Either all empty packaging will

be placed into University of Bristol confidential waste disposal system, or the label containing the Patient

Identification Number will be removed and placed in confidential waste, and the remainder disposed of as

domestic waste. The Master Patient Pack Accountability Log will be updated to record that the packaging

has been destroyed.

2. All unused medications will be delivered by the Bristol trial centre to UH Bristol Pharmacy. The

medications will be accompanied by a copy of the Master Patient Pack Accountability Log which will

account for all of the Patient Packs which have been issued from UH Bristol Pharmacy (via the trial centres

and GP practices) during the trial. As the Master Patient Pack Accountability Log contains patient

information, this must be transferred to the Pharmacy by secure courier or by hand delivery by a member of

the OSAC trial research team.

8.2.18 Destruction of unused medication

1. The Pharmacy will update the UH Bristol OSAC Trial Pharmacy Drug Accountability Log to account

for all trial tablets, and arrange for the medicine to be destroyed line with their standard procedure (CT 4 01

Return and Disposal of Unused Clinical Trial Material).

9 Quality Control Measures

All centres will go through the trial sponsor Green light Process before the trial is initiated at any recruiting site.

The OSAC trial monitoring plan will include checking that the above processes are being followed.



10 Related Documents

Document name Document owned

by

Version no. /

date

Appended to this

document

For use by Filing / Storage

Summary of medicinal product characteristics (120903

Prednisolone Galen 20mg SmPC English FINAL (03

September 2012)

Piramal 3 September

2012

No Investigators TMF

Piramal Healthcare Certificate of Confirmity (Certificate

of Confirmance OSAC trial IMPs CofC B03404 (sent by

Gillian Nicholson 20 Dec 2012)

Piramal N/A No Piramal TMF

Piramal Healthcare Distribution Instructions and Order

Acknowledgement Form (SOP-000570)

Piramal 15.0 No Piramal TMF

OSAC Trial Centre Piramal Drug Request Form v1.0 (21

December 2012)

OSAC Trial

Centre (adapted

from Piramal

template)

1.0 (21

December 2012)

No OSAC trial centre

(Bristol)

TMF

UH Bristol Standard Operating Procedure CT 2 01

Receipt and Recording of the safe delivery of Clinical

Trial Material

UH Bristol 2.0 (17 August

2010)

No UH Bristol Pharmacy PTF

UH Bristol Standard Operating Procedure for Safe

Handling and Storage of Room Temperature Clinical

Trial Material in Pharmacy Trials Unit (CT 3 01)

UH Bristol 3.0 (05 Nov

2012)

No UH Bristol Pharmacy PTF

Piramal OSAC Trial Unblinded List Piramal N/A No UH Bristol Pharmacy PTF

UH Bristol OSAC Trial Inventory Logs, blank (ACTIVE

and PLACEBO)

UH Bristol N/A Appendix 2 UH Bristol Pharmacy PTF

OSAC Trial Randomisation Schedule BRTC N/A No UH Bristol Pharmacy PTF, BRTC

UH Bristol OSAC Trial Dispensing Procedure UH Bristol 1 (22/03/2013) No UH Bristol Pharmacy PTF

UH Bristol OSAC Trial Pharmacy Drug Accountability

Log

UH Bristol N/A Appendix 3 UH Bristol Pharmacy PTF

UH Bristol SOP CT 1 04 Risk assessment for storing

clinical trial material outside of pharmacy version 2 (used

as reference source for sections 8.2.6-7 and for the risk

assessment form in Appendix 4)


2012)

No UH Bristol Pharmacy TMF

OSAC Trial GP Practice Delegation Log OSAC Trial

Centre

1.0 No OSAC trial centres

(all centres)

TMF


G:\Studies\OSAC Trial\SOPs\Drug_Handling (completed)\Current version\Complete SOP\OSAC Trial SOP Drug Handling v1.0 (27 Mar 2013) FINAL VERSION.docx


Document name Document owned

by

Version no. /

date

Appended to this

document

For use by Filing / Storage

OSAC Trial Centre Delegation Log OSAC Trial

Centre

1.0 No OSAC trial centres

(all centres)

TMF

UH Bristol CT 4 01 Return and Disposal of Unused

Clinical Trial Material version 3


2012)

No Pharmacy PTF



11 Additional Guidelines

None other than those referred to in section 10 (Related Documents).

12 Appendices

Appendix 1 OSAC Trial Medicine Flow Diagram

Appendix 2 UH Bristol OSAC Trial Inventory Logs (active and placebo)

Appendix 3 UH Bristol OSAC Trial Accountability Log for Patient Packs

Appendix 4 OSAC Trial IMP Storage Risk Assessment Form

Appendix 5 OSAC Trial Patient Pack Requisition, Transfer and Receipt Form

Appendix 6 Details of courier service used for OSAC patient pack distribution

Appendix 7 OSAC Trial IMP Storage Temperature Monitoring Log

Appendix 8 Details of thermometer used to monitor IMP storage temperature

Appendix 9 Stability data communicated by GALENpharma GmbH regarding the Prednisolone to be used

in the OSAC trial

Appendix 10 OSAC Trial Significant Temperature Variations Log

Appendix 11 OSAC Trial Centre Patient Pack Accountability Log

Appendix 12 OSAC Trial GP Practice Patient Pack Accountability Log

Appendix 13 OSAC Trial Master Patient Pack Accountability Log

OSAC Trial SOP: IMP Handling Appendix 1: Trial Medicine Flow Diagram


Dev elop placebo Acquire prednisolone f rom within the EU MANUF AC TURING

COMPAN Y

Package as per IMP spec

Send IMP test samples to SSCM

3 months prior to deliv ery

Send code break scratch

cards to UH Bristol

Deliv er half of total tender to UHB (equal

packs of Prednisolone and placebo)

Test IMP (activ e and placebo) f or similarity and quality

Second half of tender stored at

manuf acturing company

As needed, put relev ant medicine pack in patient packs as per randomisation schedule

UH Bristol complete label

section with patient number

UH Bristol keep record of matching patient pack and

medicine pack numbers to store with code break card

UH Bristol sign off and log which patient packs are sent

BRTC send randomisation

schedule to UH Bristol UH BRISTOL

Order sent through to

UH Bristol via SSCM

BRTC

Send 44 packs (in bundles of 4) to

SSCM f or f irst recruiting season

Send 44 packs (in bundles of 4) to each of the

study centres f or second recruiting season

Send 4 patient packs

to GP practice

TRI AL

CENTRES

Centre to log which patient packs

are sent to which GP practice

Storage of packs at recruiting centres

Deliv ery organised through

centre co-ordinator

Storage of packs at UH Bristol

Centre has suffi-

cient packs? YES

NO

GP practice sign f or and acknowledge receipt of patient

packs (e-mail patient pack numbers to recruiting centre)

Patient packs (including IMPs) av ailable

at GP practice f or clinicians to dispense

RECRUITING GP

PR ACTICES

GP practice has only

1 patient pack left

Practice sends through

order f orm to trial centre

Patient packs to be stored in secure

env ironment with access limited to trial

staff as per delegation log

Weekly temperature check and log

Report any weekly temperature

dev iations to the local trial centre

Responsible Clinician checks patient is eligible by

completing CRF 1 and 2

GP arranges f or patient to see Recruiting Clinician

Responsible Clinician authorises trial prescription

Recruiting clinician will: (1) Consent patient; (2) Give them their trial participation card (after hav -

ing attached the PID and med ID stickers); (3) explain all contents of the patient pack including the trial

medication; (4) ensure that all documents are correctly labelled with the PID and medicine ID stickers

as per recruitment protocol; (5) enter data onto the secure online database

Ask patients to return any unused IMP to Bristol

centre in prepaid return env elope prov ided

Any unused IMP returned by patient to SSCM f or counting

At the end of recruitment, all unused packs to be returned, v ia trial

centres, to SSCM f or counting, and to UH Bristol f or destruction

Emergency unblinding to be

done v ia contact with UH Bristol

UH Bristol to record reason f or

unblinding in online sy stem

If any cause to require unblinding, GP or pa-

tient to call number on trial participation card

UH

BRISTOL

OSAC Trial SOP: IMP Handling Appendix 2: Inventory Logs for Active and Placebo Medication


OSAC Trial SOP: IMP Handling Appendix 3: UH Bristol Pharmacy Drug Accountability Log


OSAC Trial SOP: IMP Handling Appendix 4: OSAC Trial IMP Storage Risk Assessment Form


1. A member of the OSAC trial research team should complete this form for each storage location (trial centre or recruiting GP

practice) of the fully assembled (i.e. containing the IMP) patient packs in line with the procedure described in section 8.2.6.

Please complete all unshaded parts of the form.

2. NB: OSAC trial IMP cannot be stored outside of the UH Bristol Pharmacy unless a risk assessment has been conducted, the

sponsor is in agreement and the investigator has authorised the risk assessment form.

3. File the completed form in the centre/site trial file and fax a copy to the Bristol trial centre on 0117 938 7341.

Title of study protocol OSAC (Oral Steroids for Acute Cough)

Protocol Name / Number 12/SW/0180

EudraCT Number 2012-000851-15

Sponsor University of Bristol (sponsor ref: 1581)

Chief Investigator Dr Alastair Hay, University of Bristol

Reason for assessment Proposed storage of OSAC trial patient packs containing the trial IMPs in line with the

trial protocol.

Local trial centre

Bristol Oxford Nottingham Southampton

(Please place a cross in the appropriate box)

Storage at trial centre or at GP

practice?

Trial centre GP Practice

If GP Practice, name of site

Proposed location for the clinical trial material

Security (limited access, designated lockable

fridge/cupboard)

Description of trial material Patient packs [insert dimensions] containing patient materials including medicine packs

which contain the trial IMP (10 x Prednisolone 20mg or Placebo-to-match tablets)

Storage requirements for the clinical trial material (fridge,

freezer, ambient) Ambient

Acceptable storage temperature range

(2 - 8°C, -20 +/- 5°C, 15 – 25°C, 15 – 30°C) 15 – 25°C

Details of the temperature monitoring device (e.g.

calibrated min/max thermometer)

OSAC trial calibrated min/max thermometer. Weekly temperature

monitoring. Fax log to trial centre if temperature falls out of range

within any one week.

Person(s) responsible for temperature monitoring and

reporting deviations As per centre / site OSAC Trial Delegation Log

Date risk assessment conducted

_ _ / _ _ / _ _ _ _ (dd / mm / yyyy)

Assessment conducted by:

(sign /print name)

Outcome of risk assessment

High Medium Low

Storage location acceptable

YES NO

Actions/Comments:

Authorised by (Principal Investigator at

trial centre or recruiting GP practice)

(sign /print name)

Date risk assessment authorised

_ _ / _ _ / _ _ _ _ (dd / mm / yyyy)

OSAC Trial SOP: IMP Handling Appendix 5: OSAC Trial Patient Pack Requisition, Transfer and Receipt Form


PAGE 1 OF 2

SECTION 1: Requesting OSAC Trial Centre / GP Practice to complete to order Patient Packs:

OSAC Trial Centre / GP Site

Name:________________________________________________________________________

Request supply of:

Quantity Investigational Medicinal Product

___________ (multiple of 4)

OSAC Trial Patient Packs containing Prednisolone 20mg or Placebo tablets X 10

Requested by (signature): ____________________ Print name:________________________________________________

Date: ___ / ___ / _____ (dd / mm / yyyy) Telephone Number: _________________________________________

Requesting GP practices: please fax Page 1 of this form to your local trial centre. File the original in your site trial file.

Requesting OSAC trial centres: please fax Page 1 of this form to the Bristol trial centre. File the original in your centre

trial file.

Bristol trial centre: please fax this form to UH Bristol Pharmacy. File the original in the TMF.

SECTION 2: UH Bristol Pharmacy / Issuing OSAC Trial Centre to complete on issue of Patient

Packs to the requesting trial centre / site:

OSAC Trial Centre (name) or UH Bristol

Pharmacy:___________________________________________________________

Number of OSAC Trial Patient Packs issued: ______________________ (multiple of 4)

Patient Identification Numbers of the packs issued: ___________________ to ___________________ (must be

consecutive)

Dispensed by: _____________________________________________________ Date: ___ / ___ / _____ (dd / mm /

yyyy)

Checked by: _______________________________________________________ Date: ___ / ___ / _____ (dd / mm /

yyyy)

Transfer from (name storage location): ____________________________________________________________________

While the investigational medicinal product has been held at the above storage location I can confirm that it has been stored

according to the recommended conditions and the packaging is intact prior to transfer.

Released by (signature): ____________________ Print name:_________________________________________________

On date: ___ / ___ / _____ (dd / mm / yyyy) At time: ____ : ____ (24 hour clock)

UH Bristol Pharmacy: Take a copy of this form and send with the Shipment. File original in pharmacy file.

Issuing OSAC trial centres: Take a copy of this form and send with the Shipment. File original in the trial file.

UH Bristol and issuing centre: When the courier company arrives to collect the Shipment, ensure that the courier

completes section 3 of this form (on Page 2).

OSAC Trial SOP: IMP Handling Appendix 5: OSAC Trial Patient Pack Requisition, Transfer and Receipt Form

G:\Studies\OSAC Trial\SOPs\Drug_Handling (completed)\Current version\Complete SOP\OSAC Trial SOP Drug Handling v1.0 (27 Mar 2013)

FINAL VERSION.docx


PAGE 2 OF 2

SECTION 3: Courier Company to complete on collection of Patient Packs:

Transferred by (Courier Company):_______________________________________________________________________

Accepted by (signature): _____________________________ Print name:________________________________________


SECTION 4: Receiving OSAC Trial Centre / GP practice to complete on receipt of Patient Packs:

Transferred to OSAC Trial Centre (name) / GP Site (name of site):

_______________________________________________

Received by (signature): ___________________________ Print

name:___________________________________________


State of Study Medication: Acceptable / Not Acceptable (please circle)

Please provide details: _________________________________________________________________________________

____________________________________________________________________________________________________

Signature: _________________________________________

Receiving GP practices: Take a copy of this form and fax to your local trial centre. File original in site file.

Receiving OSAC trial centres: Take a copy of this form and fax to the Bristol trial centre. File original in the centre trial

file.

Receiving GP practices and OSAC trial centres: Place OSAC Treatment Packs in the designated and risk-assessed

storage location.

OSAC Trial SOP: IMP Handling Appendix 6: OSAC Trial Courier (used to transport Patient Packs)


Details to be added.

OSAC Trial SOP: IMP Handling Appendix 7: OSAC Trial IMP Storage Temperature Monitoring Log


The designated member of the OSAC research team (trial centres) or GP practice team (recruiting sites), as recorded on

the OSAC Trial Delegation Log, should complete this temperature log at the beginning of each working week during

which the site is involved in the OSAC trial.

Date on which

Patient Packs

received:

____ / ____ / _______ (dd/mm/yyyy) Patient Packs to be stored at room temperature,

below 25°C

Name of trial centre

or recruiting GP

practice:

Risk assessment

completed and

authorised? (yes/no)

Date

(dd/mmm/yy)

Time

(24hr format)

Minimum

Temperature (°C)

Accepted minimum =

15°C

Maximum

Temperature (°C)

Accepted maximum

= 25°C

Pass / Fail Initials

: °C °C

: °C °C

: °C °C

: °C °C

: °C °C

: °C °C

: °C °C

: °C °C

: °C °C

: °C °C

: °C °C

: °C °C

: °C °C

: °C °C

: °C °C

: °C °C

: °C °C

GP Practices: Please report any temperature deviations (“Fail”) by faxing this form to your local trial centre.

OSAC trial centres: Please report any temperature deviations (“Fail”) by faxing this form to the Bristol trial centre.

OSAC Trial SOP: IMP Handling Appendix 8: Details of the thermometer used for monitoring IMP storage temperature in the OSAC trial


OSAC Trial SOP: IMP Handling Appendix 9: Stability data communicated by GALENpharma GmbH regarding Prednisolone used in the OSAC trial


From: "Oliver Gupta" <[email protected]>

To: "'Harriet Downing'" <[email protected]>

Cc: "Rima Gupta" <[email protected]>,

<[email protected]>,

"'JASON KNIGHT'" <[email protected]>

Subject: RE: OSAC trial - storage of Prednisolone above 25deg C

Date: Tue, 28 Aug 2012 11:25:43 +0100

Dear Harriet,

I am forwarding an email response from GalenPharma (the marketing authorisation holder of the Prednisolone 20mg) below. It is in German but

the translation is as follows:

"According to the current ICH stability data for our prednisolone 20 mg GALEN, tablets storage at a temperature of 40°C and a relative

humidity of 75% for 6 months is possible. It follows that a short-term deviation from the normal storage temperature (25°C) is not critical, ie

short-term storage of up to 30°C is possible without any loss of quality. The above mentioned ICH stability data will be presented to the

licensing authority in the foreseeable future, and with this the existing storage conditions will be removed."

I hope this clarifies any doubts about the temporary storage of the active product at temperatures above 25degC.

Best wishes,

Oliver

MODEPHARMA - Medication and Services for Clinical Trials

Phone: +44 207 0432 442

Mobile: +44 774 070 1015

www.modepharma.com

-----Original Message-----

From: Neujahr (GALENpharma) [mailto:[email protected]]

Sent: 28 August 2012 11:19

To: '[email protected]'

Subject: AW: Prednisolon 20 mg GALEN, Tabletten

Sehr geehrter Herr Gupta,

gemäß den aktuellen ICH-Stabilitätsdaten für unsere Prednisolon 20 mg GALEN, Tabletten ist die Lagerung bei einer Temperatur von 40°C und

einer relative Luftfeuchtigkeit von 75% über 6 Monate möglich. Daraus ergibt sich, dass eine kurzfristige Abweichung von der üblichen

Lagertemperatur (bis 25°C) unkritisch ist, d.h. eine kurzfristige Lagerung bis zu 30°C ohne Qualitätseinbußen möglich ist. Die o.g. ICH-

Stabilitätsdaten werden wir der Zulassungsbehörde in absehbarer

Zeit anzeigen; damit entfällt der bisherige Lagerhinweis.

Freundliche Grüße

Hans Neujahr

_________________________

Dr. Hans Neujahr

Med.-Wiss., IB § 74a AMG

GALENpharma GmbH

Wittland 13

D- 24109 Kiel

Tel.: +49 (0) 431/58 518 16

Fax: +49 (0) 431/58 518 516

e-Mail: [email protected]

Geschäftsführer: Jan Paul Paulsen

Handelsregister: Nr. 5 HRB 2237

Amtsgericht Kiel

OSAC Trial SOP: IMP Handling Appendix 10: Significant Temperature Variations Log


The designated member of the OSAC research team (Oxford, Nottingham, Southampton and Bristol trial centres), as recorded on the OSAC Trial Delegation Log, should complete this log

whenever a significant temperature variation is reported (by means of faxing the IMP Storage Temperature Monitoring Log). When the number of weeks for which a significant temperature

variation is reported for any single site, this log should be faxed to UH Bristol Pharmacy who will then follow the Significant Temperature Variations Management Procedure.

Date of

temperature

variation report

(dd/mm/yyyy)

Name of site (name of

OSAC trial centre or GP

practice)

Type of variation:

Positive = > 25 ⁰C;

Negative = < 15 ⁰C

Maximum

temperature

reported (⁰C)

Cumulative number of weeks

for which significant

temperature variation reported

for this site (up to 15 weeks)

Reported to UH

Bristol Pharmacy

(at 15 weeks)

Name of person making

report to UH Bristol

Pharmacy

The local centre PI

should sign here to

confirm that

appropriate action has

been taken

OSAC Trial SOP: IMP Handling Appendix 11: OSAC Trial Centre Patient Pack Accountability Log


FOR COMPLETION BY OSAC TRIAL CENTRES

Trial: OSAC (Oral Steroids for Acute Cough) Sponsor: University of Bristol

Chief Investigator: Dr Alastair Hay EudraCT Number: 2012-000851-15

IMP: Prednisolone 20mg or Placebo tablets x 10

Name of OSAC trial centre:

RECEIVED AT TRIAL CENTRE ISSUED TO GP PRACTICES

Date

(dd/mm/yyyy)

Participant ID

number

Received by

(initials)

Date

(dd/mm/yyyy)

Name of GP Practice Issued by

(initials)

Please keep a copy of this accountability log in your centre trial file.

OSAC Trial SOP: IMP Handling Appendix 12: OSAC Trial GP Practice Patient Pack Accountability Log


FOR COMPLETION BY PARTICIPATING GP PRACTICES

CONFIDENTIAL: PATIENT INFORMATION Do not store or transmit other than by approved data protection methods. Please contact your local trial centre

with any queries.

Trial: OSAC (Oral Steroids for Acute Cough) Sponsor: University of Bristol

Chief Investigator: Dr Alastair Hay EudraCT Number: 2012-000851-15

IMP: Prednisolone 20mg or Placebo tablets x 10

Name of GP Practice:

RECEIVED BY GP PRACTICE ISSUED TO PATIENTS

Date

(dd/mm/yyyy)

Participant

ID number

Received by

(initials)

Date of issue

(dd/mm/yyyy)

Medicine ID

number

Patient

initials

Patient date

of birth

(dd/mm/yyyy)

Issued by

(initials)

Please keep a copy of this accountability log in your site file.

OSAC Trial SOP: IMP Handling Appendix 13: OSAC Trial Master Patient Pack Accountability Log


TO BE COMPLETED BY BRISTOL TRIAL CENTRE FOR ALL OSAC PATIENT PACKS ISSUED BY UH BRISTOL PHARMACY

CONFIDENTIAL: PATIENT INFORMATION Do not store or transmit other than by approved data protection methods.

Participant

ID

Medicine

ID

Issued to

patient on

date

(dd/mm/yyyy)

Patient

D.O.B.

(dd/mm/yyyy)

Patient

initials

Name of issuing GP

Practice

Medicine

pack

returned to

Bristol

centre?

(tick)

Date on

which

medicine

pack

returned to

Bristol centre

(dd/mm/yyyy)

Contents

of

medicine

pack

(number of

tablets)

Initials of

person

counting

the tablets

Date on which

any unused

medications

transferred to UH

Bristol for

destruction

(dd/mm/yyyy)

Date on which

destruction

confirmed by

UH Bristol

(dd/mm/yyyy)

When complete, this form should be signed off by the Chief Investigator and a member of staff at UH Bristol Pharmacy.

I confirm that all IMPs issued for the OSAC trial as listed in the above patient packs have been accounted for:

Signature of Chief

Investigator:

Print name: Date

(dd/mm/yyyy)

Signature of representative

of UH Bristol Pharmacy:

Print name: Date

(dd/mm/yyyy)

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