Standard Operating Procedure
Title
Researchers guide to Notification of Amendments for
UoL / LTHT Sponsored CTIMPs
Scope
Describes the process that the researcher follows when notifying and submitting
amendments from CTIMPs being sponsored by the LTHT / UoL
Version
1.0
Date
20/05/2016
SOP ID
QCRES_03
Details:
Author: Razwan Mahroof - QA Clinical Trials Monitor
SOP Pages:
12
Version No. of replaced SOP:
N/A
Effective date of replaced SOP:
N/A
Approval:
Version No:
of the SOP
being
approved.
Name of person
approving this SOP.
Date
Signature of the person approving this SOP.
Clare Skinner
Faculty Head of Research and
Innovation Support
Faculty of Medicine & Health
University of Leeds
1.0
Louise Brook
QA Manager
Research and Innovation
University of Leeds / Leeds Teaching
Hospitals Trust
1.0
Distribution & Storage:
Distribution to
Chief Investigators, Principal Investigators and to all members of staff working on CTIMPs sponsored by University of Leeds or
Leeds Teaching Hospital Trust
Location of Document
Paper:
Quality Assurance, Research and Innovation, Leeds General Infirmary
Electronic:
I:\QA\1_SPONSOR_LEEDS_DOCUMENTS\SOPs
Page 1 of 12
Standard Operating Procedure
Title
Researchers guide to Notification of Amendments for
UoL / LTHT Sponsored CTIMPs
Scope
Describes the process that the researcher follows when notifying and submitting
amendments from CTIMPs being sponsored by the LTHT / UoL
Version
1.0
Date
20/05/2016
SOP ID
QCRES_03
CONTENTS
SECTION A INTRODUCTION………………………………………………………….3
SECTION B APPLICABILITY…………………………………………………………..3
SECTION C LTHT / UoL SPONSORED CTIMP AMENDMENTS…………………4
Non-Substantial (minor) Amendments…………………………..………….....4
Substantial Amendments………………………….…………………………….4
Reporting to Sponsor QA - completing the CTT05 Form.…………………...4
Changes to the Original Clinical Trials Application Form / EudraCT Form..6
Obtaining REC and HRA Approval for Amendments....………………….…..6
Obtaining MHRA Approvals for Amendments ….…………………………….7
Obtaining NHS Permission for Amendments………………………………….8
Post Approval Process…………………………………………………………..9
SECTION D ACRONYMS…………………………………………………………........9
SECTION E REFERENCES…………………………………………………….….....10
SECTION F APPENDICES..…………………………………………………….….....11
Page 2 of 12
Standard Operating Procedure
1.
Section A
Title
Researchers guide to Notification of Amendments for
UoL / LTHT Sponsored CTIMPs
Scope
Describes the process that the researcher follows when notifying and submitting
amendments from CTIMPs being sponsored by the LTHT / UoL
Version
1.0
Date
20/05/2016
SOP ID
QCRES_03
Introduction
1.1
This Standard Operating Procedure (SOP) outlines the procedure for the
management of amendments for Clinical Trials of Investigational Medicinal Products
(CTIMPs) being sponsored by the Leeds Teaching Hospitals NHS Trust (LTHT) or
University of Leeds (UoL).
1.2
Amendments are changes made to a research study after a favourable ethical
opinion by Research Ethics Committee (REC) / Health Research Authority (HRA) or
approval by the Medicines and Healthcare products Regulatory Agency (MHRA) has
been given. Changes can be made to the protocol, associated documentation or any
aspects of the trial’s arrangements.
1.3
An amendment to a Clinical Trial can be either Substantial (major) or Nonsubstantial (minor) in nature. This assessment must be made by the trial Sponsor.
1.4
All amendments, regardless of Investigator opinion (e.g. if considered NonSubstantial or Substantial) must be reported to the Sponsor QA office (via
completion of a CTT05_LTHT UoL Sponsor Notification of CTIMP Amendment
form) for review and approval prior to submitting to the MHRA, REC and/or HRA.
1.5
This SOP outlines the Sponsor amendment process, the forms that need to be
completed and who researchers need to contact to make an amendment to a
CTIMP.
2.
2.1
Section B
Applicability
This SOP is applicable to all staff / researchers involved in the clinical trial
amendment process for trials sponsored by either Leeds Teaching Hospitals Trust
(LTHT) or the University of Leeds (UoL).
Page 3 of 12
Standard Operating Procedure
3.
3.1
Title
Researchers guide to Notification of Amendments for
UoL / LTHT Sponsored CTIMPs
Scope
Describes the process that the researcher follows when notifying and submitting
amendments from CTIMPs being sponsored by the LTHT / UoL
Version
1.0
Section C
LTHT
Amendments
Date
/
20/05/2016
UoL
SOP ID
Sponsored
QCRES_03
CTIMP
Non-Substantial (minor) Amendments
A minor amendment can be defined as a change to the details of a study which will have
no significant implications for participants or for the conduct, management or scientific
value of the study.
3.1.1
Non substantial amendments do not need to be submitted to the REC or the MHRA,
but must still be submitted to the QA office for review, categorisation and approval
prior to implementation.
3.1.2
From April 2016, all non-substantial amendments must be submitted to the HRA for
their information and categorisation (please see section 3.5)
3.2
Substantial Amendments
A Substantial Amendment can be defined as an amendment to the protocol or any other
supporting documentation that is likely to affect to a significant degree:
 The safety or physical or mental integrity of the subjects of the trial;
 The scientific value of the trial;
 The conduct or management of the trial; or
 The quality or safety of any Investigational Medicinal Product used in
the trial.
3.2.1
Amendments categorised as substantial may require submission the REC only, the
MHRA only (with a notification to the HRA) or to both organisations, depending on
the nature of the amendment. All amendments must be submitted to the QA office
for review and approval.
3.2.2
The QA team will inform the researcher as to which authority the amendment needs
to be submitted.
3.2.3
It is the regulatory responsibility of the Sponsor and CI to ensure that authorisation
from the appropriate regulatory bodies is obtained before allowing any substantial
amendments to be implemented.
3.3
Reporting to Sponsor QA - Completing the CTT05 Form
3.3.1
Once the researcher has identified the need for an amendment, a CTT05_LTHT
UoL Sponsor Notification of CTIMP Amendment form must be completed.
Page 4 of 12
Standard Operating Procedure
Title
Researchers guide to Notification of Amendments for
UoL / LTHT Sponsored CTIMPs
Scope
Describes the process that the researcher follows when notifying and submitting
amendments from CTIMPs being sponsored by the LTHT / UoL
Version
1.0
Date
20/05/2016
SOP ID
QCRES_03
3.3.2
This form must summarise the rationale for the amendment including the
researchers opinion as to whether the amendment is substantial or non-substantial.
3.3.3
Section 1(a-h) of the CTT05 must be completed by an authorised member of the
research team as follows:

For part d) Amendment Reference use format Substantial/Non-Substantial
Amendment XX / Document v X / mm-yy (Date when submitted to QA) e.g.
Substantial Amendment 1/ Protocol v2.0/ 03-2016 or Substantial Amendment 2/
GP letter v3.0 / 03-2016. If the amendment relates to multiple documents please
list the most significant document changed as the amendment reference.

For part e) Amendment Details, provide a brief summary of the amendment
detailing the main changes made (e.g. “amendment to address minor clarifications
and a substantial change to the inclusion criteria”).

For part f) ensure an updated version number is added to the header / footer of the
amended documents. Queries regarding version control should be directed to QA.

If the amendment relates to changes to REC approved trial documents e.g.
Protocol, Patient Information Sheet, Consent Forms, GP letters, Patient ID cards
and Patient Invitation Letters, copies of tracked changed versions of the
documents must be sent the Sponsor QA office along with the CTT05 form.

A list of each and every change is not required providing a tracked changed
version of the document accompanies the submission.
3.3.4
Once complete, the CTT05 form should be emailed to the Sponsor QA monitors for
review (Please send to all E-mail addresses listed on CTT05 template form).
3.3.5
If submitting a substantial amendment, a Notification of Substantial Amendment
form (NSAF) must be completed and a draft copy sent to the Sponsor QA monitors
with the CTT05 form for review. The NSAF can be found on the Integrated
Research Application System (IRAS)
https://www.myresearchproject.org.uk/Signin.aspx. Once logged in, highlight the
relevant IRAS form, select the Amendment tab and follow the instructions provided.
3.3.6
The Sponsor QA Monitoring team or a delegated member of staff will confirm
receipt, usually within 3 working days.
3.3.7
The Sponsor QA reviewer will review the CTT05 and request any further required
information, within 5 working days of receipt.
Page 5 of 12
Standard Operating Procedure
Title
Researchers guide to Notification of Amendments for
UoL / LTHT Sponsored CTIMPs
Scope
Describes the process that the researcher follows when notifying and submitting
amendments from CTIMPs being sponsored by the LTHT / UoL
Version
1.0
Date
20/05/2016
SOP ID
QCRES_03
3.3.8
Once fully reviewed and approved (signed) by the Sponsor QA reviewer, the form
will be emailed to the initial sender detailing action to be taken.
3.3.9
Where the Sponsor QA reviewer classification detailed on the form differs from that
of the researchers (e.g. when the research team deems the amendment nonsubstantial, but QA believes it to be substantial), the Sponsor QA opinion overrides
that of the researchers and must be followed.
3.3.10
For substantial amendments, the authorised member of the research team can
send the NSAF to the Sponsor Representative once they have received a signed
CTT05. The Sponsor representative will electronically sign the form prior to
submission to the REC and / or MHRA.
3.3.11
The research team must forward on the final documents, cover letter, notification of
amendment form and any REC, HRA and MHRA correspondence to Sponsor QA
office in real time.
3.4
Changes to the Original REC Application Form / EudraCT Form
3.4.1
If changes to the original REC Application form and/or EudraCT form are also
required as part of the amendment, Sponsor QA must be notified of all changes
and a draft copy of the amended forms must be sent to Sponsor QA along with the
CTT05. (For reporting to Sponsor QA please see section 3.3).
3.4.2
Once Sponsor QA have approved the changes, the authorised member of the
research team can forward the revised form to the Sponsor Representative who will
add their electronic signature ready for submission.
3.5
Obtaining REC and HRA Approval for Amendments
3.5.1
The QA signed CTT05 form will specify if the amendment needs to be submitted to
the REC (for substantial amendments) or to the HRA (for non-substantial
amendments).
Submission to REC:
3.5.2
For REC, the Notification of Substantial Amendment Form (created in IRAS as per
point 3.3.5) must be submitted to the REC via email. The QA reviewer must be
copied in to this submission. REC will then share this information internally with
the HRA (please see appendix D).
3.5.3
The REC will give an opinion within a maximum of 35 days of the date of receipt of
the proposed amendment.
Page 6 of 12
Standard Operating Procedure
Title
Researchers guide to Notification of Amendments for
UoL / LTHT Sponsored CTIMPs
Scope
Describes the process that the researcher follows when notifying and submitting
amendments from CTIMPs being sponsored by the LTHT / UoL
Version
1.0
Date
20/05/2016
SOP ID
QCRES_03
3.5.4
The REC will initially issue a letter of acknowledgement confirming if the application
is valid.
3.5.5
The REC may request further information or changes to be made. Sponsor QA
must be notified of any modifications made to the initial amendment via email prior
to resubmission. A new CTT05 form is not required to be completed.
3.5.6
A written notification should be sent to the REC within 14 days of receiving an
‘unfavourable opinion’ letter, using the same NSAF used for the initial notification
and indicating/highlighting the modifications that have been made.
3.5.7
Once the REC have approved the amendment, a ‘favourable opinion’ (approval)
letter is issued. Please forward this onto the Sponsor QA assistant within 1 working
day.
Submission to HRA
3.5.8
Non-Substantial amendments which do not require REC review must instead be
submitted to the HRA by completing a Notification of non-substantial amendment
form. http://www.hra.nhs.uk/documents/2014/11/notification-non-substantialminoramendmentss-nhs-studies.docx.
3.5.9
The Non Substantial Amendment Form must be signed by the Sponsor
representative and then emailed to the HRA at [email protected]. The QA
reviewer must be copied in to this submission.
3.5.10
The HRA will categorise the amendment and inform the applicant within 5 working
days of any further action required.
3.5.11
All interim correspondence and HRA letters must be forwarded to the Sponsor QA
assistant within 1 working day.
3.6
Obtaining MHRA Approval for Amendments
3.6.1
For up to date information regarding submitting amendments to the MHRA please
use the guidance summarised on the MHRA website.
https://www.gov.uk/guidance/clinical-trials-for-medicines-manage-yourauthorisation-report-safety-issues
Submission to the MHRA
3.6.2
Following 3.3.10, the application to the MHRA for a substantial amendment must be
made using the NSAF available through the link in section 3.6.1.
Page 7 of 12
Standard Operating Procedure
Title
Researchers guide to Notification of Amendments for
UoL / LTHT Sponsored CTIMPs
Scope
Describes the process that the researcher follows when notifying and submitting
amendments from CTIMPs being sponsored by the LTHT / UoL
Version
1.0
Date
20/05/2016
SOP ID
QCRES_03
3.6.3
NSAF submissions must be made through the Common European Submissions
Platform (CESP), with the QA reviewer copied into the amendment submission.
Please contact the QA assistant for login details.
3.6.4
Amendments being submitted to the MHRA but not the REC, must also be sent to
the HRA via email ([email protected]) for their information. (Please note if
an amendment is to be submitted to both the MHRA and REC, the information will
be shared internally between the REC and HRA therefore the HRA do not need to
be notified separately).
3.6.5
The MHRA will issue an acknowledgement letter and assess the amendment within
35 days of the submission date.
3.6.6
Post review, the MHRA will issue one of the following letters:
• Acceptance of amendment
• Acceptance of amendment subject to conditions
• Grounds for non-acceptance of the amendment (usually requiring a resubmission of the amendment).
3.6.7
Any MHRA letters or correspondence must be forwarded to the QA assistant within
1 working day of receipt.
3.6.8
The Sponsor QA monitor, who dealt with the initial amendment submission, must be
notified of re-submissions via email with a clear explanation/justification of the
changes made, prior to resubmitting to the MHRA. A new CTT05 form is not
required to be completed for a resubmission.
3.7
Obtaining NHS Permission for Amendments
3.7.1
Once all required approvals have been received and forwarded to Sponsor QA, the
QA assistant or named delegate will confirm the Sponsor amendment process is
complete via email to the PI / research team.
3.7.2
ONLY once this confirmation has been received can the amendment be
implemented.
3.7.3
The trial has to continue on the basis of the current approved documentation until
an NHS R&I permission email has been received.
Page 8 of 12
Standard Operating Procedure
Title
Researchers guide to Notification of Amendments for
UoL / LTHT Sponsored CTIMPs
Scope
Describes the process that the researcher follows when notifying and submitting
amendments from CTIMPs being sponsored by the LTHT / UoL
Version
1.0
Date
20/05/2016
SOP ID
QCRES_03
3.8
Post Approval Process
3.8.1
The amended documentation must be communicated to all members of the
research team.
3.8.2
Previous versions of documents must be clearly marked as superseded in the TMF
and removed from any working files.
3.8.3
Once all approvals have been received, it is the responsibility of the research team
to notify all local departments associated with the trial (e.g. pharmacy, radiology,
pathology etc.) of the amendment(s) made.
3.8.4
Local departments associated with the trial must confirm if any of the changes affect
their trial specific duties or willingness to support the trial activity e.g labs, pharmacy
and radiology etc.
3.8.5
All correspondence between the research team and the local departments
pertaining to the amendment must be printed and filed in the TMF.
3.8.6
It is advisable to create an amendment tracker log to keep a record of all
amendments made to the trial (See appendix C). Such logs must be maintained in
real time and filed in the TMF.
Section D
CI
CTIMP
HRA
IB
IRAS
LTHT
MHRA
NSAF
QA
REC
R&I
SmPC
TMF
UoL
Acronyms
Chief Investigator
Clinical Trial of an Investigational Medicinal Product
Health Research Authority
Investigator Brochure
Integrated Research Application System
Leeds Teaching Hospitals NHS Trust
Medicines and Healthcare products Regulatory Agency
Notification of Substantial Amendment Form
Quality Assurance
Research Ethics Committee
Research & Innovation Department, Leeds Teaching Hospitals NHS Trust
Summary of Product Characteristics
Trial Master File
University of Leeds
Page 9 of 12
Standard Operating Procedure
Section E
Title
Researchers guide to Notification of Amendments for
UoL / LTHT Sponsored CTIMPs
Scope
Describes the process that the researcher follows when notifying and submitting
amendments from CTIMPs being sponsored by the LTHT / UoL
Version
1.0
Date
20/05/2016
SOP ID
QCRES_03
References
MHRA Good Clinical Practice Guide (Grey Guide)
The European Commission Guidance
Health Research Authority (HRA) http://www.hra.nhs.uk/
Section F
Appendices
Appendix A
Examples of Substantial amendments include but are not
restricted to
 changes to the design or methodology of the study, or to background
information affecting its scientific value; e.g. adding another trial arm;
 changes to the primary or secondary endpoints likely to have a significant
impact on the safety or scientific value of the trial;
 use of a new measurement of primary endpoint;
 changes to the inclusion and exclusion criteria;
 any change relating to the safety or physical or mental integrity of
participants, or to the risk/benefit assessment for the study e.g. new
toxicological or pharmacological data (or new interpretation of such data);
 significant changes to study documentation such as participant
information sheets, consent forms, questionnaires, letters of invitation,
letters to GPs or other clinicians, information sheets for relatives or
carers;
 a change of sponsor(s) or sponsor’s legal representative;
 appointment of a new chief investigator;
 a change to the insurance or indemnity arrangements for the study;
 inclusion of a new trial site (not listed in the original application);
 appointment of a new principal investigator at a trial site;
 temporary halt of a study to protect participants from harm (and the
planned restart of a study following a temporary halt);
 a change to the definition of the end of the study;
 any other significant change to the protocol or the terms of the REC or
CTA application.
 Changes to the Reference Safety Information (RSI). (e.g. if the SmPC or
IB containing the RSI submitted as part of the MHRA application is
amended)
Page 10 of 12
Standard Operating Procedure
Title
Researchers guide to Notification of Amendments for
UoL / LTHT Sponsored CTIMPs
Scope
Describes the process that the researcher follows when notifying and submitting
amendments from CTIMPs being sponsored by the LTHT / UoL
Version
1.0
Date
20/05/2016
SOP ID
QCRES_03
Appendix B
Examples of Non-substantial (minor) Amendments include but are
not restricted to:





minor changes to the protocol or other study documentation, e.g.
correcting errors, updating contact points, minor clarifications;
changes to the research team (other than the CI or PI) (does not need
reporting to Sponsor QA, but must be documented on the staff
authorisation / delegation log held in the Trial Master File (TMF);
changes in funding arrangements;
changes in the documentation used by the research team for recording
study data e.g. changes to source data collection sheets or Case Report
Forms (CRFs);
changes in the logistical arrangements for storing or transporting samples;
Appendix C
Example Amendment Tracker
Amendment
code
Date
CTT05
sent
Date
signed
CTT05
received
Date
amendment
Submitted
to
authorities
MHRA
approval
(Date on
letter)
Page 11 of 12
HRA
approval
(Date on
letter)
REC
approval
(Date on
letter)
R&I
permission
Standard Operating Procedure
Title
Researchers guide to Notification of Amendments for
UoL / LTHT Sponsored CTIMPs
Scope
Describes the process that the researcher follows when notifying and submitting
amendments from CTIMPs being sponsored by the LTHT / UoL
Version
1.0
Date
20/05/2016
Appendix D.
HRA Amendment Process
Page 12 of 12
SOP ID
QCRES_03