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SOP for the Recording, Management and Reporting of AEs by investigators JRO/INV/S05/07

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Standard Operating Procedure for the Recording, Management and Reporting of Adverse Events by

Investigators

SOP Number: JRO/INV/S05/07

Effective Date: 30/10/2016

Version Number & Date: V07, 17/10/16

Review Date: 30/10/19

SOP eDocument Kept: S:\_SLMS\RSC_ALL_STAFF\CLINICAL_TRIALS\SOPs\EFFECTIVE_SOPs_Guides\Investigator

SOP\INV_S05_SOP for the Recording Management and Reporting of AE by Inv\INV_S05_SOP for AE_SAE_Reporting by Inv_V07.docx



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Revision Chronology:

SOP ID Number: Effective

Date:

Reason for Change:

Author:

CRN/04/S05/00 09/09/2004 N/A Yvanne Enever

BRD/04/S05/01 20/04/2005

Administrative changes i.e. email address update. UCL CRN to UCL Biomedicine R&D Unit. Removal of UCL SAE Follow-up Form. Update of UCL SAE Reporting Form.

Yvanne Enever

BRD/04/S05/02 25/10/2005

Administrative changes i.e. UCL logo. Additional text P2 to clarify version number, plus addition of CI expectedness evaluation, changes in staff titles.

Yvanne Enever

JBRU/07/S07/00 18/06/2007

Implementation of the Joint UCL/UCLH Biomedical Research Unit, clarification of definitions, inclusion of pregnancy, unblinding, update SAE report form, overdose reporting and a new numbering system.

Farhat Gilani

JBRU/07/S07/01 20/12/2007

Update SOP in response to MHRA Inspection to ensure all AE/Rs are recorded and reported accordingly. In particular procedure for pregnancy reporting has been updated.

Farhat Gilani

JBRU/INV/S05/02

28/10/2008

To make SOP specific to investigator responsibilities and clarify reports on deaths. To implement a new JBRU numbering system as reflected in SOP on SOPs JBRU/INT/S01/02

Joanna Galea-Lauri

JBRU/INV/S05/03

10/01/2010

To amend the SAE form and provide alternatives in the absence of the Senior Pharmacovigilance Co. format amended in line with revised SOP on SOPs to incorporate a UCL logo only, an Acronyms table, eDocument file path, associated templates/log table, SOP dissemination and training and a signature page.

Anne Marie

Downey

JRO/INV/S05/04 11/01/2012

Update SOP to reflect current system including e-SUSAR reporting, SPC review, DSUR, Drug Alerts and Safety Warnings, Safety Management Plan, Overdose and Sponsor Oversight.

Farhat Gilani

JRO/INV/SO5/05 16/06/2012 Administration update and removal of forms from SOP.

Farhat Gilani

JRO/INV/SO5/06 Formatting and administration changes Farhat Gilani

JRO/INV/SO5/07 30/10/2016 Minor clarifications only Farhat Gilani



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ACRONYMS:

AE Adverse Event

AR Adverse Reaction

CI Chief Investigator

CRF Case Report Form

CTIMP Clinical Trial Investigational Medicinal Product

DSMC Data Safety Monitoring Committee

DSUR Development Safety Update Report

e-SUSAR MHRA Electronic SUSAR

GCP Good Clinical Practice

HRA Health Research Authority

IB Investigator’s Brochure

IDMC Independent Data Monitoring Committee

IMP Investigational Medicinal Product

IMPD Investigational Medicinal Product Dossier

ISF Investigator Site File

JRO Joint Research Office www.ucl.ac.uk/jro

NRES National Research Ethics Service

PI Principal Investigator

PV Pharmacovigilance

RSI Reference Safety Information

SAE Serious Adverse Event

SAR Serious Adverse Reaction

SI Statutory Instrument

SPC Summary of Product Characteristics

SOP Standard Operating Procedure

SRA Sponsor Regulatory Advisor

SUSAR Serious Unexpected Suspected Adverse Reaction

TMF Trial Master File



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Standard Operating Procedure for the Recording, Management and Reporting of Adverse Events by Investigators

1. PURPOSE This Standard Operating Procedure (SOP) has been written to describe the procedure to be used by the investigator for the recording, management and reporting of Adverse Events (AEs), Adverse Reactions (ARs), Serious Adverse Events (SAEs), Suspected Serious Adverse Reactions (SSARs) and Suspected Unexpected Serious Adverse Reactions (SUSARs) which occur in subjects participating in Clinical Trials of Investigational Medicinal Products (CTIMPs). It will further describe the procedure for safety reference document updates, safety alerts; drug recall, management of pregnancy and overdose reports. 2. JOINT RESEARCH OFFICE POLICY All JRO SOPs will be produced, reviewed and approved in accordance with the JRO SOP on SOPs. 3. BACKGROUND All SOPs are written in accordance with applicable GCP requirements as outlined in Directives 2001/20/EC and 2005/20/EC (in the UK, these Directives were transposed into UK law by SI 2004/1031, SI 2006/1928) and subsequent amendments and when applicable Regulation 536/2014 and subsequent relevant SIs. Where applicable it incorporates elements of ICH GCP tripartite guidelines (E6). To comply with the UK Regulations which set out the responsibilities of the sponsor, this SOP will focus on the trial site team procedures for the adequate recording, evaluation and reporting of AEs, ARs, SAEs, SARs and SUSARs in trials involving IMPs. It will further outline the Investigator’s responsibilities to ensure oversight and management of pharmacovigilance systems in UCL sponsored trials. For convenience, this document will use the term “UK Regulations” to cover the UK legislation and the EU Clinical Trials Directive (CT3). 3.1. DEFINITIONS The following definitions have been adapted from the UK regulations:

Adverse Event

Any untoward medical occurrence in a patient or clinical trial subject administered an Investigational Medicinal Product (IMP) and which does not necessarily have a causal relationship with this treatment. Therefore an AE can be any unfavourable or unintended change in the structure (signs), function (symptoms) or chemistry (laboratory data) in a subject to whom an IMP has been administered, including occurrences which are not necessarily caused by or related to that product.

Adverse Reaction (AR)

All untoward and unintended responses to an investigational medicinal product related to any dose administered This definition also covers medication errors and uses outside what is foreseen in the



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protocol, including misuse and abuse of the product. The definition implies a reasonable possibility of a causal relationship between the event and the IMP. This means that there are facts (evidence) or arguments to suggest a causal relationship.

Serious Adverse Event (SAE) or Serious Adverse Reaction (SAR)

Any adverse event or reaction in a trial subject that:

(a) results in death; or

(b) is life threatening; Note: places the subject, in the view of the investigator, at immediate risk of death from the experience as it occurred (this does not include an adverse experience that, had it occurred in a more severe form, might have caused death); or

(c) requires hospitalisation or prolongation of existing hospitalisation; Note: (hospitalisation is defined as an inpatient admission, regardless of length of stay), even if the hospitalisation is a precautionary measure for continued observation. Therefore, participants do not need to be hospitalised overnight to meet the hospitalisation criteria. Hospitalisation (including hospitalisation for an elective procedure) for a pre-existing condition (prior to study entry) which has not worsened does not constitute a serious event.

(d) Results in persistent or significant disability or incapacity Note: substantial disruption of one’s ability to conduct normal life functions; or

(e) consists of a congenital anomaly or birth defect Note: in offspring of subjects or their partners taking the IMP regardless of time of diagnosis.

Other Serious Adverse Events/Reactions

Important medical events that may not be immediately life-threatening or result in death or hospitalisation but may jeopardise the subject or may require intervention (medical or surgical) to prevent one of the other outcomes listed in the definition above should also be considered serious. Such events might include:

1. Overdoses (accidental or intentional) 2. Pregnancy (of subject or partner) 3. An alarming adverse experience 4. Specific Adverse events and/or laboratory abnormalities which are listed in the

trial protocol as critical to safety evaluations and requiring reporting

Suspected Serious Adverse Reaction (SSAR)

An adverse reaction that is classed in nature as serious and which is consistent with the information about the medicinal product listed in the relevant reference documentation:

(a) Summary of Product Characteristics (SPC) in the case of a licensed product being used within its licensed dosage and indication.

(b) An Investigator’s Brochure (IB) or a simplified IMPD in the case of any other IMP or a licensed product being used outside its licensed dosage and indication.



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Unexpected Adverse Reaction

An adverse reaction, the nature or severity of which is not consistent with the applicable product information (SPC or IB).

Suspected Unexpected Serious Adverse Reaction (SUSAR)

An adverse reaction that is classified in nature as both serious and unexpected.

3.2 OTHER SAFETY ISSUES CONSIDERED TO BE SERIOUS IN CLINICAL TRIALS Events which may materially alter the current benefit-risk assessment of an IMP or which could be sufficient to consider changes in the IMP administration or in the overall conduct of the trial may fall into the category of ‘Other Safety Issues’ and be considered as serious events which will require reporting to the sponsor in a letter headed Safety Report: a. An increase in the rate of occurrence or a qualitative change of an expected serious adverse

reaction, which is judged to be clinically important, b. Post-study SUSARs that occur after the patient has completed a clinical trial and are

reported by the investigator to the Sponsor, c. New events related to the conduct of the trial or the development of the IMPs and likely to

affect the safety of the subjects, such as:

an SAE which could be associated with the trial procedures and which could modify the conduct of the trial,

a significant hazard to the subject population such as lack of efficacy of an IMP used for the treatment of a life-threatening disease,

a major safety finding from a newly completed animal study (such as carcinogenicity),

any anticipated end or temporally halt of a trial for safety reasons and conducted with the same investigational medicinal products in another country by the same Sponsor,

d. Recommendations of the Data Monitoring Committee (DMC), if any, where relevant to the safety of the subjects.

An ‘Other Safety Issue’ can also fall into the category of Urgent Safety Measures. Please refer to Standard Operating Procedure for the Recording and Reporting of Deviations, Violations, Potential Serious breaches, Serious breaches and Urgent Safety Measures. Details pertaining to an ‘Other Safety Issue’ will be documented in the DSUR.

3.3 SEVERE ADVERSE EVENT OR REACTION The term “severe” is often used to describe the intensity of an event or reaction (e.g. mild, moderate or severe) and should not be confused or interchanged with the term “serious”.

3.4 KEY RESPONSIBILITIES FOR THE INVESTIGATOR This section describes the key pharmacovigilance responsibilities of the investigator, further delegation of these responsibilities to other team members must be documented on the trial delegation log.

1

Safety Reference Documents: The CI must ensure that the trial team are using the most up to date version of safety reference document described in the CTA application and protocol. The CI must also ensure that the team have all reviewed and are familiar with the updated information.



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The CI must request the updated IB/IMPD from the manufacturer annually for IMP sourced from a manufacturer directly. Please refer to SOP JRO/SPON/S03/ Standard Operating Procedure for creating and maintaining an Investigator’s Brochure (IB) for UCL Developed Products for procedures relating to UCL developed products.

For trials using SPCs, the CI must ensure they perform a check for updates regularly either by contacting the manufacturer or searching on the following website: http://www.medicines.org.uk/emc. The CI must ensure a copy is filed in the TMF/ ISF/ PSF and a copy is forwarded to all sites. The investigator must further ensure that the team are all familiar with the appropriate use of the IMP(s), as described in the protocol, safety reference document and/or IMPD.

2

Protocol: The protocol must be written using the JRO UCL protocol template in order for the appropriate pharmacovigilance information to be included. Please refer to JRO/SPON/S07 SOP for granting UCL sponsorship for Clinical Trials of Investigational Medicinal Products (CTIMPs)

3 AE Recording: All AEs must be recorded in the medical records (if source data) and/or the CRF, SAE forms and AE logs as described in the protocol.

4 AE Assessment: The investigator must assess each event for seriousness, severity, expectedness and causality using the appropriate documentation (protocol and safety reference document).

5

Trend/signal analysis: The CI must ensure the AE log is reviewed regularly. This can be performed by the CI alone or reviewed collectively at trial meetings. For some Phase I and high risk trials (and if deemed necessary by the sponsor for Phase I/II trials), an Independent Data Monitoring Committee may be requested to perform this duty.

6 SAE Reports: The CI must ensure that initial and follow-up SAE reports are sent to the JRO, according to the protocol.

7 AEs of interest: The CI must provide the JRO with details of all AEs identified in the protocol as critical to the evaluation of safety within the agreed timeframes specified in the protocol.

8 Follow-up reports: The CI must supply the JRO with any supplementary information requested as soon as possible in order for the JRO to meet its regulatory timelines.

9

IDMC: For some phase I and high risk trials, an Independent Data Monitoring Committee or Data Safety Committee must be established. In cases of phase I/II trials, advice from the sponsor may be sought to establish the need of the committee. Members of the IDMC must have signed the UCL IDMC charter.

10 Data Safety Monitoring Committee: Provide the DSMC (if there is one for the trial) with all relevant information required for an independent assessment.

11 Pregnancies: The CI must submit all initial and follow-up pregnancy forms to the JRO.

12 Confidentiality: The CI must maintain subject confidentiality at all times. No patient identifiable data is to be sent to the JRO or other external organisations by the PIs.

13

Urgent Safety Measure: The investigator may take appropriate urgent safety measures to protect clinical trial subjects from any immediate hazard to their health and safety. This may be taken immediately. However, following the measure the investigator must follow the SOP on “Deviations, serious breaches and urgent safety measures” JRO/SPON/S15

14 DSUR: In conjunction with the JRO, the CI must aid in the production of the DSUR JRO/SPON/S31



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4. SCOPE OF THIS SOP

What this SOP covers

This SOP covers the procedures for the recording, management and reporting of all AEs, ARs, SAEs, SSARs and SUSARs that occur in subjects participating in CTIMPs sponsored by UCL. This document further details pregnancy and overdose reports, safety alerts, safety reference document updates, DSURs and highlights the key PVG responsibilities of the CI.

What this SOP doesn’t cover

In circumstances where the JRO (in its role as a representative or a legal representative of the Sponsor) has delegated the responsibilities to a third party such as a Clinical Research Organization (CRO) or an external Clinical Trials Unit (CTU), the pharmacovigilance procedures will be outlined in a trial specific agreement between the Sponsor, the CRO and the Chief Investigator. Therefore description of this procedure falls outside the scope of this SOP.

5. RESPONSIBLE PERSONNEL

The CI and the individual investigators within a trial team are responsible for keeping records of all adverse events that occur in trial subjects as per protocol. The CI may further delegate who within the trial team is responsible for reporting to the Sponsor. This delegation must be performed on whether trial members are qualified to perform the delegated task. This must be authorised in the delegation log. For international trials: responsibilities will be outlined in the contract between sites, CTU (if appropriate) and Sponsor.

6. PROCEDURE

6.1 Duration of AE Recording

The protocol must clearly define the duration of AE recording.

All S/AEs should be recorded and reported within the established off therapy follow-up period for safety described in the protocol. This time period will be defined in the protocol as per the UCL protocol template.

6.2 Which AE to record and which Forms to use?

The table below provides guidelines for where to record AE information:

Type of Adverse Events Format of Recording Information

All Adverse events Medical Records

All AEs and SAEs (as per protocol) AE section of CRF

All SAEs (as per protocol) AE log

All SAEs (as per protocol) SAE report form

6.3 Which AE to report to the JRO? All AE/Rs that fulfil the criteria for the definition of serious, whether expected or not, need to be reported to the JRO, unless specified in the protocol. The protocol will list all the expected SAE/Rs that do not need to be reported to the JRO. 6.4 When and how to report Serious AE/Rs to the Sponsor?



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6.4.1 What needs to be reported within 24 hours?

1. SUSARs 2. Serious adverse events/reactions as defined in section 3.1 3. Other Safety Issues.

6.5 When to report other SAE/Rs to the JRO which do not require expedited reporting?

Some expected SAE/Rs should be reported to the JRO on the AE log only as per protocol. The timeline for submission will vary depending on the purpose of the trial, toxicity and efficacy endpoints. 6.6 Where to report AEs and SAEs?

The SAE Reporting Form, line listings and the Pregnancy Reporting Form must be either emailed to [email protected] or to a relevant member of the JRO. The report can alternatively be faxed to the JRO on 020 3108 2312.

The trial team must request an acknowledgment of receipt of the report which should be kept with the original form in the TMF.

In the event that the form is not acknowledged by the Sponsor’s office within 3 working days, site must contact relevant members of the sponsor’s office to confirm receipt of the report.

Subject confidentiality and adherence to the Data Protection Act (1998) must be maintained on all reports in relation to recording and reporting of AEs. No personal identifiable data must be forwarded to the JRO or other external organisations.

6.7 Other reporting arrangements for Multi-Centre Trials

For multi-centre trial sponsored by UCL, PIs may report directly to a trial management team at a lead site and the trial Pharmacovigilance responsible person will be responsible for forwarding the report to the JRO within 24 hours of receipt (if applicable). Trial specific arrangements for SAE management must be documented in the protocol and contractual agreements.

6.8 Evaluation of AE/Rs during the trial

The following documents need to be referred to when assessing any AE in the trial:

Protocol

Safety Reference Document (SPC, IB)

Trial specific procedure for unblinding (if applicable)

Each AE must be evaluated for seriousness, causality, severity and expectedness. The treating physician should make these assessments which are documented on the SAE Reporting Form. For multi-sites trials a CI cannot downgrade a PI’s assessment of an event but the CI may upgrade an event. 6.8.1. Evaluation of seriousness The PI must assess the AE as serious as per the definition of an SAE in section 3. 6.8.2. Evaluation of causality The Council for Internal Organisations of Medical Sciences (CIOMS) VI group agree that the Investigator's causality assessment is vital information since the Investigator is best placed to review how the subject has changed since baseline (before treatment is administered). Every



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effort must be made by the PI to obtain all the required information to determine whether the AE is related to the trial intervention. It is important to note that if the investigator indicates an unknown causality assessment the adverse experience will be considered as related by the JRO (taking the most conservative option) and could warrant expedited reporting. To help Investigators with the decision, the CIOMS VI group recommends that PI be asked to consider the following before reaching a decision:

Medical History

Lack of efficacy/worsening of existing condition

Study treatment(s)

Other treatments-concomitant or previous

Withdrawal of study treatment-especially following study discontinuation/end of study

Erroneous treatment with study medication (or concomitant)

Protocol related process

The CI/PIs evaluation of severity It is common practice for events to be assessed for clinical severity (intensity defined as: mild, moderate or severe) of the specific event. As already explained in the definitions, severity must not be confused with “serious” which is a regulatory definition based on subject/event outcome or action criteria. 6.8.3. Evaluation of expectedness

The PI must evaluate whether the event is expected or unexpected against the protocol and the safety reference documents for the trial (i.e. IB for non-licensed product or SPC for a licensed product in the EU assuming that the product is being used in the trial exactly as stated in the SPC). An event can be considered as “unexpected” if it adds significant information on the specificity or severity of an expected event. 6.9 How to manage reports in blinded trials

The blind for the investigator and if applicable, for those persons responsible for data-analysis and interpretation of results should be maintained until the trial data is locked.

However a patient’s allocation may need to be unblinded under the following conditions:

1. Emergency unblinding: Patient experiencing an adverse event and requiring treatment which cannot be given without knowledge of the trial arm the patient was randomised to.

2. SUSAR Unblinding: The JRO requires unblinding for the submission of a SUSAR report to the MHRA and REC.

The unblinding procedure is protocol specific and each trial must clearly document their procedure and the location of the unblinding information. The Investigator must forward the Trial specific unblinding SOP to the JRO. This SOP must be written using the JRO “Standard Operating Procedure for the Preparation of a Study Specific Randomisation, Blinding and Code Break Standard Operating Procedure”.



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6.10 Follow-up information

On receipt of relevant or missing information, site staff must complete a new SAE report form and tick the follow-up box. The form must be forwarded to the JRO as per section 6.9.

All SAEs must be followed up until a resolution is reached (i.e. recovered, recovering, recovered with sequelae, fatal, not recovered or unknown).

6.11 Recording and Reporting a Pregnancy Pregnancy data provides vital information to the overall knowledge concerning the IMP and is therefore reportable to the sponsor but not reportable to the regulatory agencies as expedited reports and will be incorporated into the DSUR report. On the notification of a pregnancy in a trial participant or their partner, a member of the trial team must inform the PI. The pregnancy needs to be recorded in the medical notes, AE log and CRF. The JRO Pregnancy Reporting Form must also be completed and forwarded to the sponsor within 24 hours of being made aware of the event by email to [email protected] or to a relevant member of the JRO. The report can alternatively be faxed to the JRO on 020 3108 2312.The completed pregnancy report form should be kept in the TMF/ISF with any relevant correspondence. The Sponsor must be kept informed of any new developments involving the pregnancy. Any pregnancy that occurs in a female trial subject during a clinical trial should be followed to termination or to term. Under special circumstances, it may be necessary to monitor the development of the new-born for an appropriate period post-delivery. There may also be special situations when it will be necessary to monitor the pregnancy of a woman whose male partner is the trial subject. In the event that the pregnancy report form is not acknowledged by the Sponsor’s office within 3 working days, site must contact relevant members of the sponsor’s office to confirm receipt. 6.11.1 Escalation of report to the Safety Committee The JRO will forward the pregnancy report form, safety reference document and protocol to a JRO clinician for review and comment on recommended follow-up (as appropriate) and tests/procedures to be performed above the protocol to protect the patient and the foetus. 6.11.2 Update to PIS/Consent Form Recommendations will be forwarded to the CI by the JRO. A new PIS and consent form will be supplied to the trial team to re-consent the patient or partner for follow-up of pregnancy until term or termination. These must be kept in the TMF. 6.11.3 Follow-up of pregnancy Once site are made aware of the pregnancy outcome, (birth or termination) the outcome section must be completed and forwarded to the JRO within 24 hours. If the event that the pregnancy meets the following definition; a SAE report form must also be completed and forwarded to the JRO with the pregnancy follow-up form within 24 hours:

Congenital anomaly(ies) in the foetus/child

Foetal death or spontaneous abortion



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Any SAE occurring in the neonate or mother

6.12 Overdose Reports In the event of an accidental or intentional overdose by a trial participant, the site staff must immediately inform the PI and the Sponsor’s office. The deviation log must be completed and the medical notes, CRF, AE log updated to reflect this information. In the event that the overdose is associated with an S/AE, the two events should be linked. In the event of an AE associated with an overdose, a SAE report form must be completed detailing the AE and the overdose details. 6.13 Review of new safety reference document It is the CI’s responsibility to check which document (IB or SPC) is referred to in the CTA application and request the relevant updated document as explained below. 6.13.1 IBs The RSI must clearly be identifiable in the IB. IBs are required to be updated annually. For trials where the IB is supplied by a drug supplier, the update will normally be requested by the site team from the supplier directly. Please refer to SOP JRO/SPON/S03/ for procedures relating to UCL developed products. The CI must provide the JRO with a copy of the updated IB and confirm if the new information impacts on the trial and patient safety and if any amendments are required to the protocol, PIS and consent forms. An updated IB must be submitted to the regulatory authorities as a substantial amendment if there is a change to the RSI or other changes likely to have an impact on the safety of the trial subjects or to change the interpretation of the scientific documents in support of the conduct of the trial, or if they are otherwise significant,. The new version cannot be used until it is approved. The previous version must be superseded in the TMF and a copy of the updated document placed in the file. 6.13.2 SPCs The RSI is located in section 4.8 of the SPC. The investigator must regularly check for SPC updates. When the Investigator is made aware of an update to a SPC, the CI must review the document and assess if the updated information affects the study protocol, RSI, safety of the study patients or the Patient Information Sheets and consent forms. The trial team must be forwarded a copy of the updated SPC as well as a copy sent to the relevant members of the sponsor’s office. The CI must confirm they have read the document and detail any actions required (if appropriate). The previous version must be superseded in the TMF and a copy of the updated document placed in the file. If there is a change to the RSI or other changes likely to have an impact on the safety of the trial subjects or to change the interpretation of the scientific documents in support of the conduct of the trial, or if they are otherwise significant, then this is considered a substantial amendment. The new version of the RSI cannot be used until it is approved. 6.13.3 Safety warning and drug alerts Safety Alerts (from the MHRA and drug suppliers) may be forwarded by the JRO or be sent directly by another organisation to the CI. The received information must be reviewed immediately by the CI or delegated member of the trial team to assess whether action is required to protect patient safety. The information must be forwarded to the JRO with any recommendations and an acknowledgement receipt requested. The CI(s) must confirm what actions (if any) are required.



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6.13.4 Provisions in Multicentre trials The CI or delegated member of the trial must ensure all updates are forwarded to PIs in an appropriate timeframe and confirm that any relevant training on the new document is performed. This must be documented in the TMF/ISF. 6.14 What to expect from the JRO once a report has been submitted A member of the JRO will confirm receipt of all reports within 3 working days. In the event that the report is not acknowledged by the Sponsor’s office within 3 working days, site must contact the JRO. 6.15 Development Safety Update Report The Investigator and relevant trial staff will be made aware when the data lock point for the DSUR has been reached. The trial staff will work in conjunction with the JRO to facilitate in the production of the report JRO/SPON/S31 SOP for the preparation and submission of Development Safety Update Reports

Flowchart 1: Decision framework for assessment of adverse events by Investigators and research personnel

Summary of procedures Flowchart 1 Flowchart 1 illustrates the decision framework which Investigators and research personnel should follow to assess S/AEs and to determine if the event requires further expedited reporting. Please note: The CI cannot downgrade the PI’s assessment.

Expectedness

Causality

Seriousness

Adverse events noted

Adverse Events (AE)

Related to IMP

Serious Adverse Event (SAE)

Unexpected AE

Adverse Event (AE)

Unrelated to IMP

Unrelated to IMP

Related to IMP

Adverse Reaction

(AR)

Serious Adverse Event (SAE)

Serious Adverse

Expected AE

Expected

Unexpected SAE

Unexpected AR

Expected AR

Unexpected SAR

Expected

SUSAR



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7. REFERENCES www.ucl.ac.uk/jro Directive 2001/20/EC of the European Parliament and of the Council of 4th April 2001 on the approximation of the laws, regulations and the administrative provisions of the Member States relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use. The Medicines for Human Use (Clinical Trials) Regulations 2004 (SI 2004/1031) and amended regulations. European Commission Document “Detailed guidance on the collection, verification and presentation of adverse reaction reports arising from clinical trials on medicinal products for human use” April 2006 (Revision 2) Brussels, ENTR/CT 3. MRC/DH joint project Work stream 6: Pharmacovigilance (PV Document-final version for clinical trials tool kit (12th Jan 2007). Sponsor’s SOP for the Preparation of a Study Specific Randomisation, Blinding and Code Break Standard Operating Procedure Sponsor’s SOP for the Recording and Reporting of Deviations, Serious Breaches and Urgent Safety Measures 8. APPENDICES NA 9. TEMPLATES/LOGS ASSOCIATED TO THIS SOP

1 Adverse Event Recording & Reporting log

2 Serious Adverse Event Reporting Form

3 Pregnancy Reporting Form in clinical trial subjects

10. SOP DISSEMINATION & TRAINING This SOP will be provided to the PIs prior to, or at initiation at the latest. All staff trial team concerned by this SOP will sign the SOP training log (12. SOP TRAINING LOG) part of this SOP. In addition each PI trial team member should have an “Individual staff SOP and courses log” which will need to be updated once trained on this SOP. These documents should be filed in the ISF. Existing trials “in progress”: This SOP will be emailed to the PIs and their teams having existing trials “in progress”. These investigators will be requested to read the new SOP and email back to acknowledge receipt and understanding of this new SOP. These PIs should ensure that relevant team members have read and understood this SOP. They should ensure that section 12 has been signed by all the trial team members. The email sent to the PIs and their email acknowledging receipt and understanding of the SOP should be printed out and filed in the JRO SOP folder.



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11. SIGNATURE PAGE

Author and Job Title: Farhat Gilani, Pharmacovigilance Manager

Signature:

Date: 17/10/16

Authorised by: Name and Job Title

Helen Cadiou, Head of Quality Assurance

Signature:

Date: 17/10/16


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12. SOP TRAINING LOG:

Name of Staff (Capital letters):

Job Title:

Department:

Training

Date

I confirm that I understand & agree to work to this SOP

SIGNATURE Name of Trainer

(if applicable) Signature Date

1

2

3

4

5

6

7


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Name of Staff (Capital letters):

Job Title:

Department:

Training

Date

I confirm that I understand & agree to work to this SOP

SIGNATURE Name of Trainer

(if applicable) Signature Date

8

9

10

11

12

13