Document Title: Adverse Event Reporting Document Number…s3-eu-west-1.amazonaws.com/files.royalfree.nhs.uk/Research/SOPs/S… · Document Title: Adverse Event Reporting Document

SOP 031: Adverse Event Reporting


Version 1, 01/07/2014

Page 1 of 28

Document Title: Adverse Event Reporting

Document Number: 031

Version: 1

Ratified by: RFL R&D Committee

Date ratified: 24.06.2014

Name of originator/author: Vashist Deelchand / Hameedah Bogle-Dawoud

Directorate: Medical Directorate

Department: Research and Development

Name of responsible individual: Liba Stones

Date issued: 1 July 2014

Review date: 30 June 2017

Target audience: All Trust staff

Intranet:

Key related documents: SOP006 Roles and Responsibilities for the Conduct of Research Studies

SOP012 Ethical Approval

SOP018 Trust Research Governance Approval

SOP 019 Investigator File

This document supports:

Standards and legislation

ICH Harmonised Tripartite Guideline for Good Clinical Practice E6(R1)

Medicines for Human Use (Clinical Trials) Regulations 2004 and all associated amendments.

Research Governance Framework for Health and Social care (2005).

Date equality analysis completed. 18/06/2014

This is a controlled document Whilst this document may be printed, the electronic version maintained on the RFL website is the controlled copy. Any printed copies of this document are not controlled.



Version 1, 01/07/2014

Page 2 of 28

Version Control

Version Date Author Status Comment



Version 1, 01/07/2014

Page 3 of 28

Contents

Section Page

1 Introduction 4

2 Objective 4

3 Definitions 4

4 Equality statement 6

5 Duties 6

6 Details of procedure 8

7 Policy 13

8 Risk management/liability/monitoring & audit 13

9 Forms/templates to be used 14

10 References 17

Appendices

Appendix 1 MHRA Address 18

Appendix 2 Recording AEs - Grades 19

Appendix 3 Safety Reporting Assessment Flowchart with glossary 20

Appendix 4 Safety Reporting Flowchart Adverse Event Reporting 22

Appendix 5 SOP reading log 24

Appendix 6 Equality analysis guide and tool 26



Version 1, 01/07/2014

Page 4 of 28

1. INTRODUCTION

This document sets out the procedures for recording, managing and reporting Adverse Events to be followed by all Royal Free London NHS Foundation Trust Staff, who are involved in, or undertaking, research.

It aims to provide clear guidance on the Adverse Event Reporting requirements for sponsored studies of both Investigational Medicinal Products and non- Investigational Medicinal Products, so as to ensure that all staff involved in Research Studies and Clinical Trials including Clinical Trials of Investigational Medicinal Products (CTIMP) at RFL are aware of, and have an understanding of the process.

2. OBJECTIVE

This document defines the Trust’s requirements with regards to Adverse Event Reporting specifically this includes Investigators and Researchers involved in any part of the research process that lies outside of the normal pathway of care.

It is essential that all Adverse Events (AE) which occur during the participants’ involvement in a research project are appropriately recorded and reported in order to ensure their continuing safety. The document aims to provide clear guidance on who takes overall responsibility for each process.

3. DEFINITIONS

Adverse Event: (AE)

Any untoward medical occurrence in a patient or clinical trial subject administered a medicinal product and which does not necessarily have a causal relationship with this treatment.

Adverse Reaction (AR)

Any untoward and unintended response to an investigational medicinal product related to any dose administered.

CI - Chief Investigator (CI) is the authorised health care professional who takes primary responsibility for the conduct of the trial. There is only one Chief Investigator per Member State.

CTIMP (Clinical Trial of Investigational Medicinal Product) - Any investigation in human subjects intended to discover or verify the clinical, pharmacological and/or other pharmacodynamics effects of one or more investigational medicinal product(s), and/or to identify any adverse reactions to one or more investigational medicinal products(s) and/or Study absorption, distribution, metabolism and excretion of one or more investigational product(s) with the object of ascertaining its (their) safety and/or efficacy.



Version 1, 01/07/2014

Page 5 of 28

GCP - Good Clinical Practice (GCP) is an international ethical and scientific quality standard for the design, conduct, performance, monitoring, auditing, recording, analyses, and reporting of clinical trials that provides assurance that the data and equality statement

IMPs Investigational Medicinal Products

MHRA - Medicines and Healthcare Products Regulatory Agency

Non-IMPS Investigational Medicinal Products

PI - Principal Investigator (PI) is the person who takes responsibility for the initiation and conduct of the study at site. There is one Principal Investigator at each site participating in a research study. For a single site study the Chief investigator may also take on the role of Principal investigator

R&D - Research & Development

REC – Research Ethics Committee

RFL - Royal Free London Hospital NHS Foundation Trust

RM&G - Research Management & Governance

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

Any adverse event or adverse reaction that:

1. Results in death

2. Is life –threatening*

3. Requires inpatient hospitalisation or prolongation of existing hospitalisation

4. Results in persistent or significant disability/incapacity

5. Is a congenital anomaly/birth defect

* Life-threatening in the definition of a serious adverse event or serious adverse

reaction refers to an event in which the subject was at risk of death at the time of the event. It does not refer to an event which hypothetically might have caused death if it were more severe.

Severity: The term “severe” is often used to describe the intensity (severity) of a specific event. This is not the same as “serious”, which is based on patient/event outcome or action criteria. Sponsor - Individual, organisation or group taking on responsibility for securing the arrangements to initiate, manage and finance a study. A group of individuals and/or organisations may take on sponsorship responsibilities and distribute them by agreement among the members of the group, provided that, collectively, they make arrangements to allocate all the responsibilities in this research governance framework that are relevant to the study.

Suspected Serious Adverse Reaction (SSAR) Any adverse reaction that is classed as serious and which is consistent with the information about the IMP listed in the Summary of Product Characteristics (SmPC)



Version 1, 01/07/2014

Page 6 of 28

or Investigator Brochure (IB). Information on known adverse reactions can be found at http://emc.medicines.org.uk. Sudden Unexpected Serious Adverse Reaction (SUSAR):

An adverse reaction that is both unexpected (not consistent with the applicable product information) and also meets the definition of a Serious Adverse Event/Reaction.

A SUSAR may occur during clinical trials or clinical care

4. EQUALITY STATEMENT

The Royal Free London NHS Foundation Trust is committed to creating a positive culture of respect for all individuals, including job applicants, employees, patients, their families and carers as well as community partners. The intention is, as required by the Equality Act 2010, to identify, remove or minimise discriminatory practice in the nine named protected characteristics of age, disability (including HIV status), gender reassignment, marriage and civil partnership, pregnancy and maternity, race, religion or belief, sex or sexual orientation. It is also intended to use the Human Rights Act 1998 to treat fairly and value equality of opportunity regardless of socio-economic status, domestic circumstances, employment status, political affiliation or trade union membership, and to promote positive practice and value the diversity of all individuals and communities.

This document forms part of the trust’s commitment. You are responsible for ensuring that the trust’s policies, procedures and obligation in respect of promoting equality and diversity are adhered to in relation to both staff and service delivery.

The equality analysis for this SOP is attached at Appendix 4.

5. DUTIES

The Trust is committed to the delivery of world class care and expertise to both staff and patients, and our values of positively welcoming, actively respectful, visibly reassuring and clearly communicating are fundamental to the delivery of this. This policy has been developed with our values in mind, and is intended to be implemented within the spirit of these values.

There are a number of responsibilities when managing adverse events. Below is a list of responsibilities for both the Investigator and the Sponsor (for RFL Sponsored studies, the RFL R&D) will act on behalf of the Sponsor). The Chief Investigator (CI) has overall responsibility for the conduct of the study. In a multi-site study, the CI has co-ordinating responsibility for reporting adverse events to the Medicines and Healthcare products Regulatory Agency (MHRA) and to the relevant Research Ethics Committee (REC). The Principal Investigator (PI) has responsibility for the research at a local site where the study involves specified procedures requiring site-specific assessment. There should be one PI for each research site. In the case of a single-site study, the CI and the PI will normally be the same person. The PI is responsible for informing the CI, or

http://emc.medicines.org.uk/



Version 1, 01/07/2014

Page 7 of 28

the organising research team, of all adverse events that occur at their site following the guidelines below. Any CI/PI who has agreed to undertake duties for pharmacovigilance delegated by the Sponsor must undertake both Investigator’s and Sponsor’s responsibilities as described throughout this document. 5.5.1 Investigator’s Responsibilities

1. PI to report all SAEs and SUSARs within agreed timelines to the CI (see

section 6). The initial report may be discussed and reported. 2. RFL Trust related SUSARs are reporting via Trust Intranet DATIX Reporting.

Ensuring that the RFL R&D has been notified about SUSARs that have occurred in any RFL trial patients.

3. Completing the trial specific SAE reporting form and submitting to the Sponsor following the initial SAE report. Ensuring that as much detail as possible is included in the report. Providing the Sponsor with details of all AEs identified in the protocol as critical to the evaluation of safety within the agreed timeframes specified in the protocol.

4. Assessing each event for causality and expectedness 5. Sign and date the SAE form (if required) 6. CI to report all SAEs within agreed timelines to Sponsor 7. CI to report SUSARs within agreed timelines to Sponsor, MHRA, REC and

relevant NHS Trust Research and Development Office (R&D) (see section 6 8. Provide the Sponsor with details of all AEs identified in the protocol as critical to

the evaluation of safety within the agreed timeframes specified in the protocol. 9. Assess each event for causality and seriousness between the IMP and/or

concomitant therapy and the adverse event. 10. Supply the Sponsor, MHRA, REC and relevant NHS Trust R&D with any

supplementary information they request. It is acknowledged that all these activities (except (4 and 5) are often undertaken by the Research Nurse, Clinical Trials Practitioner (CTP) or Data Manager (DM) where appropriate, and where this has been delegated by the PI in the site delegation/participants log that the person is suitably qualified. As important as it is to report SAE’s in urgent situations, every effort must be made by the RN/CTP/DM to discuss the SAE with the PI. 5.5.2 Responsibilities of other members of the research team e.g. Registrars,

Junior Doctors (FY2/3/4/5) Ward Sister etc.

1. To report details of an SAE as defined in the study protocol as soon as possible to the PI or research support staff.

5.5.3 Responsibilities of Research Nurse /Clinical Trials Practitioner

1 As soon as they are made aware of an SAE in a subject who has consented to

a trial being conducted at RFL they must inform the PI and Sponsor of the trial immediately within 24 hours (see procedures section 5.5.4 for further details).

2 If the RN or CTP is unsure whether an event should be defined as serious they should ask the CI/PI or a sub investigator for clarification.



Version 1, 01/07/2014

Page 8 of 28

5.5.4 Sponsor’s Responsibilities

1. Ongoing safety evaluation of any IMP(s), including trend analyses. 2. Promptly notify all Investigators, REC(s) and MHRA, of any findings that may

affect the health of subjects. This may include informing investigators using the same IMP in different studies.

3. Keep detailed written reports of all AEs reported by PIs and performing an evaluation with respect to seriousness, causality and expectedness.

4. Report all relevant safety information to the relevant REC and MHRA. 5. Report all SUSARs to the MHRA, REC and relevant NHS Trust R&D in concerned

Member States associated with comparator product(s) and Marketing Authorisation (MA) holder(s), within given timelines.

6. Break treatment codes before submitting expedited reports to MHRA and REC for specific subjects, even if the Investigator has not broken the code. (Note: A system for maintaining blinding for the CI/PI and trial staff may need to be agreed in advance).

7. Submit the annual safety report to Sponsor, MHRA and REC. 8. Encourage the set-up of Independent Data Monitoring Committees (IDMC) for

phase III clinical trials that have high morbidity/mortality and describe their function in the protocol.

9. Ensure written SOPs and systems are in place to ensure quality standards are met.

10. Register users for pharmacovigilance data entry with the European Medicines Evaluation Agency (EMEA) if required.

6. DETAILS OF THE PROCEDURE

6.1 Study Planning

All Protocols should list known side effects and adverse reactions contained within the manufacturer’s product information. This should be written in agreement with the relevant drug/device company where applicable. Rare/very rare events may or may not be included depending on individual study requirements.

A detailed explanation of SAE reporting procedures should also be included in the Protocol. A generic SAE reporting form is available from http://www.hra.nhs.uk/resources/during-and-after-your-study/nhs-research-ethics-committee-rec-ctimp-safety-report-form. . This form can be amended to create a study specific form.

6.1.1 Which AE to Record? The CI can decide how to record and report adverse events, whether expected or not. Adverse events are usually described on case report forms (CRFs), unless they are classified as serious, in which case, these should be reported on a specific SAE form (see http://www.hra.nhs.uk/resources/during-and-after-your-study/nhs-research-ethics-committee-rec-ctimp-safety-report-form for an example). It should be clearly stated in the study protocol and the local SOP what will be recorded and how the reporting is to be managed.

http://www.hra.nhs.uk/resources/during-and-after-your-study/nhs-research-ethics-committee-rec-ctimp-safety-report-form






Version 1, 01/07/2014

Page 9 of 28

It may be decided that all, or only some, non-serious AEs are to be recorded. Whatever option is chosen, it must be consistent with the purpose of the trial and any toxicity and efficacy end points.

6.1.2 Which SAE to Report?

The management and reporting arrangements for SAEs should be in place for all trials. Agreements at the beginning of the trial should be made for such SAEs that can be defined as disease-related and therefore not subject to expedited reporting. The procedures for managing and reporting SAEs must be clearly defined in the Protocol. It is recommended that an Independent Data Monitoring Committee (IDMC) is appointed in order to review safety data regularly throughout the trial and when necessary, recommend to the Sponsor whether to continue, modify or terminate the trial. Again, this procedure must be defined in the protocol. As with all recording and reporting, subject confidentiality and adherence to the Data Protection Act (1998) must be maintained on all reports.

6.2 During the Trial

Each AE must be evaluated for seriousness (see 3 definitions), causality, and expectedness. The responsibility for this evaluation can be shared between the CI and PIs. It may be most appropriate for the treating PI at each local site to evaluate each event, before reporting it to the CI. It must be stated in the clinical trial protocol and the local SOP who will take responsibility for the assessment and reporting of such events to the Sponsor and CI simultaneously. As expedited reporting may be required, this SOP assumes that responsibility of initial assessment and reporting to the CI lies with the PI.

6.2.1 Causality Adverse reactions should be assessed for causality. The definitions below can be used:

Relationship Description

Unrelated There is no evidence of any causal relationship

Unlikely There is little evidence to suggest there is a causal relationship (e.g. the event did not occur within a reasonable time after administration of the trial medication). There is another reasonable explanation for the event (e.g. the patient’s clinical condition, other concomitant treatment).

Possible* There is some evidence to suggest a causal relationship (e.g. because the event occurs within a reasonable time after administration of the trial medication). However, the influence of other factors may have contributed to the event (e.g. the patient’s clinical condition, other concomitant treatments).

Probable* There is evidence to suggest a causal relationship and the influence of other factors is unlikely

Definitely* There is clear evidence to suggest a causal relationship



Version 1, 01/07/2014

Page 10 of 28

and other possible contributing factors can be ruled out Not assessable There is insufficient or incomplete evidence to make a

clinical judgement of the causal relationship.

* If the AE is serious and unexpected, the possible, probable and definitely

related should be notified to the MHRA, the relevant REC and the Sponsor as SUSARS. Where different causality definitions are specified in the Protocol, it must be clear which definitions constitute a ‘related’ event.

6.3 Reporting Guidelines –Clinical Trials of Investigational Medicinal Products (CTIMPS) Once the CI/PI has evaluated and determined the AE in terms of seriousness, causality and expectedness, the following guidelines should be followed.

6.3.1 AEs

AEs that are not considered serious should be included in the patient notes and on the relevant case report forms (CRFs). The completed form should be filed along with the other CRFs for the study and a copy provided to the Sponsor as agreed.

6.3.2 SAEs

If the AE is assessed as serious, the PI must report the event to the CI immediately or within 24 hours of being made aware of the event (other than those SAEs identified in the protocol as not requiring immediate reporting). The initial report can be made verbally but must be promptly followed with a detailed, written report. The PI must record the event with their assessment of seriousness, (along with causality, expectedness and severity) on a trial SAE form provided by the CI (see http://www.hra.nhs.uk/resources/during-and-after-your-study/nhs-research-ethics-committee-rec-ctimp-safety-report-form). The PI should ensure that follow-up information is provided when available. The CI should include all SSAR’s and SUSAR’s in the annual safety report (see section 6.4). Local research governance procedures at each site should also be followed.

6.3.3 SUSARs

Any AE that the PI evaluate as serious, is suspected of having a causal relationship to the trial medication and is unexpected, will require expedited reporting to the RFL R&D, DATIX, MHRA, REC and to other organisations as required under the terms of the individual contracts (e.g.: relevant Pharmaceutical Companies, NHS Trusts). If the CI, or Trial Management Group if appropriate, is not in agreement with the “expectedness” decision of the PI, the CI cannot overrule the PI’s decision. Both opinions should be recorded on the relevant SAE form. SUSARs should be reported following the timelines in section 6.3.3.1. http://www.hra.nhs.uk/resources/during-and-






Version 1, 01/07/2014

Page 11 of 28

after-your-study/nhs-research-ethics-committee-rec-ctimp-safety-report-formcontains the covering document required for the main REC. The minimum data required for reporting SUSARs to the MHRA and REC are: i) The suspected Investigational Medicinal Product (IMP) ii) Subject trial Identification iii) An adverse event assessed as serious and unexpected, and for which there is a reasonable suspected causal relationship iv) An identifiable reporting source The CI must send all RFL Trust related SUSARs reports to the RFL R&D soon as possible after becoming aware of the event and complete the DATIX Reporting on the Trust’s Freenet. 6.3.3.1 Timeframes for expedited reporting Fatal/life threatening SUSARs The CI must inform the RFL R&D, DATIX, MHRA, REC, and relevant Pharmaceutical Companies (if required under the terms of the contract) of fatal or life threatening SUSARs as soon as possible, but no later than 7 calendar days after the CI has first knowledge of the minimum criteria for expedited reporting. In each case, relevant follow-up information should be sought and a report completed as soon as possible. This should be sent within an additional 8 calendar days. Non- fatal and non-life threatening SUSARs The CI must report all other SUSARs and safety issues to the RFL R&D, DATIX, MHRA, REC, and relevant pharmaceutical companies (if required under the terms of the contract) as soon as possible, but no later than 15 calendar days after the CI has first knowledge of the minimum criteria for expedited reporting. Further relevant information should be given as soon as possible. 6.3.4 Urgent Safety Measures

The Chief and Principal Investigators have the authority to deviate from the protocol if doing so relates to the immediate safety of a participant, where continuing to follow protocol would put that participant at risk. This is classed as an urgent safety measure and must be reported to the RFL R&D, MHRA and REC within 3 calendar days of the occurrence. This may be reported verbally in the first instance but must be supported by a written report as soon as information is available. 6.3.5 Unblinding Systems for SUSAR and SAR reporting should, as far as possible, maintain blinding of individual clinicians and of trials staff involved in the day-to-day running of the trial. It is important that the details of the unblinding process are included in the trial protocol. For blinded trials involving a placebo and an active drug, seriousness, causality and expectedness should be evaluated as though the patient was on active drug. Cases that are considered serious, unexpected and possibly, probably or definitely related (i.e. possible SUSARs) would have to be unblinded. Only those events occurring



Version 1, 01/07/2014

Page 12 of 28

among patients on the active drug (unless thought to be due to the excipient in the placebo) should be considered to be SUSARs requiring reporting to the MHRA, RECs and RFL R&D, DATIX. It may be that individuals who are not directly involved in the management of the trial could perform unblinding. For blinded trials involving two active drugs, the person responsible for the evaluation for causality and expectedness might be able to state that if the patient were on drug A the event would be causal and/or unexpected, but if on drug B it would be expected. If the event were unexpected for either of the active drugs, the case should be unblended by the individual charged with unblinding, who would then classify the event accordingly. An IDMC has access to semi-blinded or unblended data and can oversee the assessment of emerging risks, such as an increase in frequency or severity of adverse events. The committee’s assessments are carried out without disclosure to the trial team. They may recommend protocol amendments, or termination of the study, if they detect serious safety issues. In addition, the chairman of an IDMC might be able to play a role in unblinding individual reports of SUSARs for expedited reporting (if this could be managed within the requisite timeframes) and SSARs for annual reports. 6.3.6 Reporting to PIs involved in Study All PIs within the trial concerned must also be informed of the SUSAR, although this does not have to be within the 7/15-day deadline. All PIs should be sent a summary of SUSARs approximately every 3 months. This timeframe may vary between trial depending on the rates of recruitment and/or SUSARs. If the CI is informed of SUSARs from other trials using the IMP by a Pharmaceutical Company, the CI should inform PIs as above.

6.4 Reporting Guidelines – Non-IMP Studies

If a research participant experiences a SAE you should report this to the relevant Research Ethics Committee and the RFL R&D, where in the opinion of the Chief Investigator the event was:

‘related’: that is, it resulted from administration of any of the research procedures; and

‘unexpected’: that is, the type of event is not listed in the protocol as an expected occurrence.

Reports of related and unexpected SAEs should be submitted within 15 days of the CI becoming aware of the event, using the form http://www.hra.nhs.uk/documents/2013/12/safety-report-form-non-ctimps-2.doc. The form should be completed in typescript and signed by the Chief Investigator. Reports of double-blind studies should be unblinded.

6.5 Adverse Event Reporting for International Trials

Clinical trials that involve sites outside of the UK must follow the requirements of the countries in which the trial is taking place.

http://www.hra.nhs.uk/documents/2013/12/safety-report-form-non-ctimps-2.doc



Version 1, 01/07/2014

Page 13 of 28

The procedures for reporting relevant events onwards to regulatory and ethics committees should be included in any agreements between international groups performing the trial. The protocol and/ or study specific SOP should specify procedures for both the timing and format of reports of SUSARs in sites outside the EU. 6.5.1 Reporting SUSARs to the Ethics committee

The reporting requirements of the main Ethics Committee responsible for the trial in each country should be established prior to the start of the study. These requirements will vary, therefore it should be detailed in the protocol/study specific SOP which SUSARs will need to be reported and where they should be sent e.g. the UK RECs evaluate UK SUSARs only. 6.5.2 Reporting SUSARs to the Competent Authorities

For trials taking place within the EU, the CI must ensure that all SUSARs are reported to the competent authority for each country in which the trial is taking place.

6.5.3 Annual Safety Reports/Developmental Safety Update Reports An annual safety report should be submitted to the main REC and competent authority in each EU country that has a site participating in the trial. This should include all SSARs and SUSARs occurring in all countries participating in the trial. The requirements for countries outside the EU should be included in the protocol/study specific SOP. Annual reporting should take place as required.

7 POLICY

This SOP is mandatory and non-compliance with it may result in disciplinary procedures.

8 RISK MANAGEMENT/ LIABILITY/MONITORING & AUDIT

The SOP Working Group will ensure that this SOP and any future changes to this document are adequately disseminated.

The R&D Department will monitor adherence to this SOP via the routine audit and monitoring of individual clinical trials and the Trust’s auditors will monitor this SOP as part of their audit of Research Governance. From time to time, the SOP may also be inspected by external regulatory agencies (e.g. Care Quality Commission, Medicines and Healthcare Regulatory Agency).

In exceptional circumstances it might be necessary to deviate from this SOP for which written approval of the RM&G Manager/Deputy R&D Director should be gained before any action is taken.

SOP deviations should be recorded including details of alternative procedures followed and filed in the Investigator and Sponsor Master File.

The Research and Development Directorate is responsible for the ratification of this procedure.



Version 1, 01/07/2014

Page 14 of 28

9 Forms/Templates to be used

SAE Reporting Form for non-IMP studies This form can also be found on:

http://www.hra.nhs.uk/documents/2013/10/overview-of-safety-and-progress-reporting-requirements-non-ctimps.pdf http://www.hra.nhs.uk/documents/2013/12/safety-report-form-non-ctimps-2.doc

REPORT OF SERIOUS ADVERSE EVENT (SAE) (For all studies except clinical trials of investigational medicinal products)

The Chief Investigator should report any SAE that is both related to the research procedures and is unexpected. Send the report to the Research Ethics Committee that gave a favourable opinion of the research within 15 days of the CI becoming aware of the event.

1. Details of Chief Investigator

Name:

Address:

Telephone:

Email:

Fax:

2. Details of study

Full title of study:

http://www.hra.nhs.uk/documents/2013/10/overview-of-safety-and-progress-reporting-requirements-non-ctimps.pdf

http://www.hra.nhs.uk/documents/2013/10/overview-of-safety-and-progress-reporting-requirements-non-ctimps.pdf

http://www.hra.nhs.uk/documents/2013/12/safety-report-form-non-ctimps-2.doc



Version 1, 01/07/2014

Page 15 of 28

Name of main REC:

Main REC reference number:

Research sponsor:

Sponsor’s reference for this report:

(if applicable)

3. Type of event

Please categorise this event, ticking all appropriate options:

Death Life threatening Hospitalisation or

prolongation of existing hospitalization

Persistent or significant

disability or incapacity

Congenital anomaly

or birth defect

Other

4. Circumstances of event

Date of SAE:

Location:

Describe the circumstances of the event:

(Attach copy of detailed report if necessary)

What is your assessment of the implications, if any, for the safety of study participants and how will these be addressed?



Version 1, 01/07/2014

Page 16 of 28

5. Declaration

Signature of Chief Investigator:

Print name:

Date of submission:

6. Acknowledgement of receipt by main REC (please insert name): The [ ] Research Ethics Committee acknowledges receipt of the above.

Signed:

Name:

Position on REC:

Date:

Signed original to be sent back to Chief Investigator (or other person submitting report) Copy to be kept for information by main REC.

Safety Reporting CTIMPs

http://www.hra.nhs.uk/documents/2013/08/safety-reporting-ctimps-procedural-table.pdf

http://www.hra.nhs.uk/documents/2013/08/safety-reporting-ctimps-procedural-table.pdf



Version 1, 01/07/2014

Page 17 of 28

10 REFERENCES

DATA PROTECTION ACT (1998)

http://www.opsi.gov.uk/acts/acts1998/ukpga_19980029_en_1 Detailed guidance on the collection, verification and presentation of adverse reaction reports arising from clinical trials on medicinal products for human use http://ec.europa.eu/enterprise/pharmaceuticals/eudralex/vol10/21_susar_rev2_2006_04_11.pdf

Detailed guidance on the European database of Suspected Unexpected Serious Adverse Reactions (Eudravigilance – Clinical Trial Module) http://ec.europa.eu/enterprise/pharmaceuticals/eudralex/vol10/22_cp_and_guidance_database_susars16_april_2004.pdf

The Medicines for Human Use (Clinical Trials) Regulations 2004 Part 5 http://www.opsi.gov.uk/si/si2004/20041031.htm#32 National Research Ethics Service guidance on safety reporting http://www.hra.nhs.uk/resources/during-and-after-your-study/progress-and-safety-reporting/ MRC/DH joint project, Workstream 6: Pharmacovigilance http://www.cttoolkit.ac.uk/route_maps/stations.cfm?current_station_id=317&view_type=map

http://www.opsi.gov.uk/acts/acts1998/ukpga_19980029_en_

http://ec.europa.eu/enterprise/pharmaceuticals/eudralex/vol10/21_susar_rev2_2006_04_11.pdf

http://ec.europa.eu/enterprise/pharmaceuticals/eudralex/vol10/21_susar_rev2_2006_04_11.pdf

http://ec.europa.eu/enterprise/pharmaceuticals/eudralex/vol10/22_cp_and_guidance_database_susars16_april_2004.pdf

http://ec.europa.eu/enterprise/pharmaceuticals/eudralex/vol10/22_cp_and_guidance_database_susars16_april_2004.pdf

http://www.opsi.gov.uk/si/si2004/20041031.htm#32

http://www.hra.nhs.uk/resources/during-and-after-your-study/progress-and-safety-reporting/

http://www.hra.nhs.uk/resources/during-and-after-your-study/progress-and-safety-reporting/

http://www.cttoolkit.ac.uk/route_maps/stations.cfm?current_station_id=317&view_type=map

http://www.cttoolkit.ac.uk/route_maps/stations.cfm?current_station_id=317&view_type=map



Version 1, 01/07/2014

Page 18 of 28

Appendix 1: MHRA Address Developmental Safety Update Reports should be provided to the MHRA as electronic documents on disk and sent to: Information Processing Unit Medicines and Healthcare products Regulatory Agency 151 Buckingham Palace Road Victoria London SW1W 9SZ



Version 1, 01/07/2014

Page 19 of 28

APPENDIX 2



Version 1, 01/07/2014

Page 20 of 28

Appendix 3 Safety Reporting Assessment Flowchart Safety Reporting Assessment Flowchart

Related?

Yes

Adverse Event

Serious

Adverse

Reaction [SAR]

Seri

ou

sne

ss*

Serious Not Serious

Serious Adverse Event

[SAE]

Adverse Event

[AE]

Not

Related to

IMP

Related

to IMP

Related

to IMP

Not

Related to

IMP

Cau

salit

y

Adverse

Reaction

[AR]

Adverse

Event

[AE]

Serious

Adverse

Event [SAE]

Expected

Exp

ect

ed

ne

ss**

Unexpected

Serious Adverse Reaction [SAR]

Suspected Unexpected Serious

Adverse Reaction [SUSAR]

Unexpected?

Yes

Related?

Yes *See definition of SAE in glossary

*Assessed in line with the current

approved IB [or SmPC]



Version 1, 01/07/2014

Page 21 of 28

Glossary Adverse Event [AE] Any untoward medical occurrence in a patient or clinical trial subject administered a medicinal

product and which does not necessarily have a causal relationship with this treatment.

Adverse Reaction [AR] Any untoward and unintended response to an investigational medicinal product related to any

dose administered. Comment: All adverse events judged by either the reporting investigator or the Sponsor as

having a reasonable causal relationship to a medicinal product would qualify as adverse

reactions. The expression ‘reasonable causal relationship’ means to convey, in general, that there

is evidence or argument to suggest a causal relationship. Investigator’s Brochure [IB] A document containing a summary of the clinical and non-clinical data relating

to an investigational medicinal product which are relevant to the study of the product in human

subjects. Investigational Medicinal

Product [IMP]

A pharmaceutical form of an active substance or placebo being tested, or to be

tested, or used, or to be used, as a reference in a Clinical Trial, and includes a

medicinal product which has a marketing authorisation but is, for the purposes

of the trial—(a) used or assembled (formulated or packaged) in a way different

from the form of the product authorised under the authorisation,(b) used for an

indication not included in the summary of product characteristics under the authorisation for

that product, or (c) used to gain further information about the form of that product as

authorised under the authorisation.

Serious Adverse Event

[SAE] or Serious Adverse

Reaction [SAR]

Any adverse event or adverse reaction that results in death, is life-threatening*, requires

hospitalisation or prolongation of existing hospitalisation, results in persistent or significant

disability or incapacity, or is a congenital anomaly or birth defect.

Comment: Medical judgement should be exercised in deciding whether an adverse

event/reaction should be classified as serious in other situations.

Important adverse events/reactions that are not immediately life-threatening or

do not result in death or hospitalisation, but may jeopardise the subject or may require

intervention to prevent one of the other outcomes listed in the definition above, should also be

considered serious.

*Life-threatening in the definition of a serious adverse event or serious adverse reaction refers to

an event in which the subject was at risk of death at the time of the event. It does not refer to an

event which hypothetically might have caused death if it were more severe.

Summary of Product

Characteristics [SmPC]

The SmPC is the basis of information for health professionals on how to use the medicinal

product safely and effectively. SmPCs are written and updated by pharmaceutical companies and

are based on their research and product knowledge. The SmPC is then checked and approved by

the UK or European medicines licensing agency.

The leaflet that is included in the pack with a medicine is a patient-friendly

version of the SmPC.

Suspected Unexpected

Serious Adverse Reactions

[SUSAR]

An adverse reaction that is both unexpected (not consistent with the applicable

product information) and also meets the definition of a Serious Adverse

Event/Reaction.



Version 1, 01/07/2014

Page 22 of 28

Appendix 4 Safety Reporting Flowchart Adverse Event Reporting

Safety Reporting Flowchart Adverse Event Reporting

CI/PI assesses causality1

CI/PI assesses seriousness

Related Not related

Adverse Reaction [AR] Adverse Event [AE]

Serious SAE/R

Not

serious 2

Adverse Event/Reaction {AE/R]

CI/PI records & notifies Sponsor as per protocol

CI/PI checks Protocol to confirm whether SAE/R requires expedited reporting

No

‘Non-Expeditable’ [SAE/R]

CI/PI records & notifies Sponsor as per Protocol

Yes

CI/PI notifies Sponsor of SAE/R within 24 hours

Sponsor’s assessment of causality3 Unrelated

to IMP

Serious Adverse Event [SAE]

Sponsor keeps records & follows up until resolution

Related to IMP

Serious Adverse Reaction [SAR]

Sponsor’s assessment of expectedness

using the RSI4

Unexpected

Expected

Suspected Unexpected Serious Adverse

Reaction [SUSAR]

Sponsor to report to MHRA and Ethics Committee: -Fatal or life threatening

SUSARs within 7 days -All other SUSARs within days

SUSARs reported to PIs as per Protocol

Trust related SUSARs to be reported to R&D + DATIX

Expected Serious Adverse Reaction [SAR] Sponsor keeps records & follows up until resolution



Version 1, 01/07/2014

Page 23 of 28

Adverse Event [AE]:

Any untoward medical occurrence in a clinical trial subject administered a medicinal product and which does not necessarily have a causal relationship with this treatment.

- Results in persistent or

significant disability or

incapacity

- is a congenital anomaly or birth

defect

- any other safety issues

considered medically important

Adverse Reaction[AR]:

Any untoward and unintended response to an IMP which Is related [a reasonable causal relationship] to any dose administered

PI should actively seek follow –up

information on reported SAE/Rs

Serious Adverse Event / Reaction [SAE/R]:

- Results in death

- Is life-threatening

- Requires hospitalisation or

prolongation of existing

hospitalisation

Footnotes

1PI or delegate

2Notable or safety critical events must be reported as per Protocol

3Sponsor cannot downgrade the PI’s causality assessment, but can updgrade it

4Reference Safety Information [RSI] in IB or SmPC



Version 1, 01/07/2014

Page 24 of 28

Appendix 5

SOP Reading Log

READ BY

NAME TITLE SIGNATURE DATE



Version 1, 01/07/2014

Page 25 of 28



Version 1, 01/07/2014

Page 26 of 28

APPENDIX 6

Royal Free London NHS Foundation Trust Equality Analysis guide and Tool

An equality analysis is a review of a policy, practice, function, business case, project or service change which establishes whether there is a negative effect or impact on particular social groups. This In turn enables the organisation to demonstrate it does not discriminate and, where possible, it promotes equality to meet the needs of the diverse patients and communities we serve.

This check list is a way to help you think carefully about the likely impact on equality groups and take action to improve services. This is also an opportunity to evidence positive practices in our services and demonstrate strategic integrity to ensure that our services and employment practices are fair, accessible and appropriate for all patients, visitors and carers, as well as our talented and diverse workforce.

Name of the policy / function / service development being assessed SOP 031: Adverse Event Reporting

Briefly describe its aims and objectives: This document defines the Trust’s procedures for identifying and reporting adverse events in research studies taking place at Royal Free London Hospital. This SOP applies to all studies sponsored or hosted by Royal Free London NHS Foundation Trust.

Directorate and Lead: Medical Directorate

Evidence sources: DH, legislation. JSNA, audits, patient and staff feedback

Medicines for Human Use (Clinical Trials) Regulations 2004 and all associated amendments. Research Governance Framework for Health and Social care (2005)

Is the Trust Equality Statement present?

Yes if no do not proceed with Equality Analysis (EA)

If you are conducting an EA on a procedural document please identify evidence sources and references, who has been involved in the development of the document, process or strategy, and identify positive or negative impacts. It is the discussion regarding the equality impact of the document that is important.



Version 1, 01/07/2014

Page 27 of 28

Equality Analysis Checklist

Go through each protected characteristic below and consider whether the policy, practice, function, business case, project or service change could have any impact on groups from the identified protected characteristic, involve service users where possible and get their opinion, use demographic / census data (available from public health and other sources), surveys (past or maybe carry one out), talk to staff in PALS and Complaints and Patient Experience.

Please ensure any remedial actions are Specific, Measureable, Achievable, Realistic, and Timely ( SMART).

Equality Group Identify negative impacts

What evidence, engagement or audit has been used?

How will you address the issues identified?

Identifies who will lead the work for the changes required and when?

Please list positive impacts and existing support structures

Age

None identified R&D administrative document

N/A

N/A This SOP includes the Trust Equality Statement, as well as the results from the Equality Assessment for this SOP. These actions are designed to embed the equality agenda and promote equality compliance within the Trust.

Disability


N/A

N/A

Gender Reassignment


N/A

N/A

Marriage and Civil Partnership


N/A

N/A

Pregnancy and maternity


N/A

N/A

Race


N/A

N/A



Version 1, 01/07/2014

Page 28 of 28

Equality Group Identify negative impacts

What evidence, engagement or audit has been used?

How will you address the issues identified?

Identifies who will lead the work for the changes required and when?

Please list positive impacts and existing support structures

Religion or Belief


N/A

N/A

Sex


N/A

N/A

Sexual Orientation


N/A

N/A

Carers


N/A

N/A

It is important to record the names of everyone who has contributed to the policy, practice, function, business case, and project or service change.

Equality Analysis completed by: (please include every person who has read or commented and approval committee(s). Add more lines if necessary)

Organisation Date

SOP Development Group Royal Free London NHS Foundation Trust 17.06.2014

R&D Committee Royal Free London NHS Foundation Trust 24.06.2014

Documents

Document Title: Adverse Event Reporting Document Number…s3-eu-west-1.amazonaws.com/files.royalfree.nhs.uk/Research/SOPs/S… · Document Title: Adverse Event Reporting Document