QSSOP01 Research Governance Framework v1

Research Governance Framework

Standard Operating Procedure

Version: V1

Ratified by: Quality & Safety Committee

Date Ratified: 27/08/2020

Job Title of Author: Research and Audit Facilitator

Reviewed by Sub Group or Expert Group: Clinical Excellence Group

Related Procedural Documents: QSPOL13 Research Policy

Review Date: 27/08/2023

It is the responsibility of users to ensure that you are using the most up to date document template – i.e. obtained via the intranet.

In developing/reviewing this procedure Provide Community has had regard to the principles of the NHS Constitution.

Version Control Sheet

Version Date Author

V1 August2020 Research and AuditFacilitator

1. Purpose

The purpose of the Research Governance Framework (RGF) Standard Operating Procedure (SOP) is to ensure that all research undertaken at Provide is followed by Provide employees who are currently engaging in or plan to engage in clinical research across the East of England, and all research is undertaken within internationally accepted ethical and quality standards, referred to as Good Clinical Practice (GCP).

This SOP has been produced in accordance with The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) / GCP Guidelines, The Department of Health (DoH) Research Governance Framework (2005), the Medicines for Human Use (Clinical Trials) Regulations (2004) and Medicines for Human Use (Clinical Trials) Amendment Regulations (2006).

This SOP has been produced with permission from the Transform Research Alliance: RG SOP

2. Introduction

The Research Governance framework in Health and Social Care outlines principles of good governance that apply to all research. Research governance is a core standard for health care organisations. It sets out the principles, requirements and standards of research and defines the mechanisms to deliver them. It applies to those who design, participate, host, fund, manage and undertake research.

Healthcare research studies can be referred to as clinical trials. High quality clinical research involves investigations in human subjects intended to discover or verify the clinical, pharmacological and other pharmacodynamic effects of an investigational product with the aim of ascertaining safety and efficacy (National Institute of Health Research, 2011)

GCP is an international ethical and scientific quality standard for designing, conducting, recording and reporting trials that involve the participation of human subjects. Compliance with this standard provides public assurance that the rights, safety and well-being of trial participants are protected, consistent with the principles that have their origin in the Declaration of Helsinki (1964), and that the clinical trial data are credible.

3. Scope

This SOP applies to all research which is in any way connected with Provide, including clinical and non-clinical research, research undertaken on or by Provide staff using Provide resources and research undertaken by industry, charities, research councils, universities and other healthcare organisations. This SOP applies to all patients who provide consent to be recruited as research participants.

This SOP does not apply to the governance of clinical audit, service evaluation and quality improvement at Provide. Refer to My Compliance for CPOL12 Clinical Audit Effectiveness Policy.

This SOP has been devised to be read in association with the QSPOL13 Research Policy.

4. Definitions

The following definitions have been provided in relation to ‘Good Clinical Practice’ scientific and ethical principles and apply to patient safety in terms of clinical research:

Adverse Drug Reaction (ADR)

In the pre-approval stage, clinical experience with a new medicinal product or its new usages, particularly as the therapeutic dose(s), may not be established: all noxious and unintended responses to a medicinal product related to any dose should be considered adverse drug reactions. The phrase ‘responses to a medicinal product’ means that a causal relationship between a medicinal product and an adverse event is at least a reasonable possibility, i.e., the relationship cannot be ruled out. Regarding marketed medicinal products: a response to a drug which is noxious and unintended and which occurs at doses normally used in man for prophylaxis, diagnosis, or therapy of diseases or for modification of physiological function (see the ICH Guideline for Clinical Safety Data Management: Definitions and Standards for Expedited Reporting).

Amendment

A change made to the terms of a Research Ethics Committee (REC) application, the protocol or any other supporting documentation after the study has started. A research study is normally considered to start with the commencement of any protocol procedures.

Applicable Regulatory Requirement(s)

Any law(s) and regulation(s) addressing the conduct of research studies.

Approval (in relation to Research Ethics Committees)

The affirmative decision of a REC that the research study has been reviewed and may be conducted at the institution site within the constraints set forth by a REC, the institution, GCP, and the applicable regulatory requirements.

Audit

A systematic and independent examination of research study related activities and documents to determine whether the evaluated research study related activities were conducted, and the data were recorded, analysed and accurately reported according to the protocol, sponsor's SOPs, GCP, and the applicable regulatory requirement(s).

Audit Certificate

A declaration of confirmation by the auditor that an audit has taken place.

Audit Report

A written evaluation by the sponsor's auditor of the results of the audit.

Audit Trail

Documentation that allows reconstruction of the course of events.

Authorised Healthcare Professional

An Authorised healthcare professional is defined as: a) Doctor, b) Dentists, c) Nurse, d) Pharmacist. Authorised Healthcare Professionals can act as the Chief or Principle Investigator.

Blinding/Masking

A procedure in which one or more parties involved in a randomised controlled trial are kept unaware of the treatment assignment(s). Single-blinding usually refers to the research

participant(s) being unaware, and double-blinding usually refers to the research participant(s), principal investigator(s), monitor, and, in some cases, data analyst(s) being unaware of the treatment assignment(s).

Case Report Form (CRF)

A printed, optical, or electronic document designed to record all of the protocol required information to be reported to the sponsor on each research participant involved in a clinical trial.

Chief Investigator (CI)

An authorised healthcare professional who is responsible for the conduct of the whole project in the UK. The named CI should be a researcher who is professionally based in the UK, as they will be: able to supervise the research effectively; and be readily available to communicate with the Research Ethics Committee (REC) and other review bodies during the application process and where necessary during the conduct of the research. In a multi-site study, the chief investigator has co-ordinating responsibility for research at all sites.

Clinical Trial/Research Study

Any investigation in human research participants intended to derive generalisable new knowledge by addressing clearly defined questions with systematic and rigorous methods.

Clinical Trial/Research Study Report

A written description of a trial/research study, in which the clinical and statistical description, presentations, and analyses are fully integrated into a single report. The report usually consists of the following sections; Introduction, Background, Aims and Objectives, Methods, Results and Discussion/Implications for Practice (see the ICH Guideline for Structure and Content of Clinical Study Reports).

Comparator (Product)

An investigational or marketed product (i.e., active control), or placebo, used as a reference in a research study.

Compliance (in relation to trials)

Adherence to all the trial-related requirements, GCP requirements, and the applicable regulatory requirements.

Confidentiality

Prevention of disclosure, to other than authorised individuals, of a sponsor's proprietary information or of a research participant’s identity.

Contract

A written, dated, and signed agreement between two or more involved parties in a research study that sets out any arrangements on delegation and distribution of tasks and obligations and, if appropriate, on financial matters. The protocol may serve as the basis of a contract.

Coordinating Committee

A committee that a sponsor may organise to coordinate the conduct of a multicentre research study.

Coordinating Investigator

An investigator assigned the responsibility for the coordination of principal investigators at different centres participating in a multicentre research study. This is usually the chief investigator of the overall research study.

Contract Research Organisation (CRO)

A person or an organisation (commercial, academic, or other) contracted by the sponsor to perform one or more of a sponsor's research study-related duties and functions.

Data Collection Tool

Refers to the device/tool used to collect data, such as a paper questionnaire or computer assisted interviewing system.

Development Safety Update Report

The common format for annual safety reports on investigational drugs in the ICH regions under ICH guideline E2F.

Direct Access

Permission to examine, analyse, verify, and reproduce any records and reports that are important to evaluation of a research study. Any party (e.g. domestic and foreign regulatory authorities, sponsor's monitors and auditors) with direct access should take all reasonable precautions within the constraints of the applicable regulatory requirement(s) to maintain the confidentiality of research participants' identities and sponsor’s proprietary information.

Documentation

All records, in any form (including, but not limited to, written, electronic, magnetic, and optical records, scans, x-rays, and electrocardiograms) that describe or record the methods, conduct, and/or results of a research study, the factors affecting a research study, and the actions taken.

Essential Documents

Documents relating to a research study which enable both the conduct of the research study and the quality of the data produced to be evaluated; and show whether the research study is, or has been, conducted in accordance with the applicable regulatory requirements.

Good Clinical Practice (GCP)

A standard for the design, conduct, performance, monitoring, auditing, recording, analyses, and reporting of research studies that provides assurance that the data and reported results are credible and accurate, and that the rights, integrity, and confidentiality of research participants are protected.

Health Research Authority (HRA)

The Health Research Authority in England, established in the Care Act (2014) with functions relating to co-ordination and standardisation of practice relating to the regulation of research in health and social care, functions relating to ethics committees (appointing authority for English RECs), functions as a member of the United Kingdom Ethics Committee Authority (UKECA) and functions relating to approvals for processing confidential information relating to patients.

Independent Data-Monitoring Committee (IDMC) (Data and Safety Monitoring Board, Monitoring Committee, Data Monitoring Committee)

An independent data-monitoring committee that may be established by the sponsor to assess at intervals the progress of a research study, the safety data, and the critical efficacy endpoints, and to recommend to the sponsor whether to continue, modify, or stop a research study.

Impartial Witness

A person, who is independent of the research study, who cannot be unfairly influenced by people involved with the research study, who attends the informed consent process if the research participant or the research participant’s legally acceptable representative cannot read, and who reads the informed consent form and any other written information supplied to the research participant.

Informed Consent

A process by which a research participant voluntarily confirms his or her willingness to participate in a particular research study, after having been informed of all aspects of the research study that are relevant to the research participant’s decision to participate. Informed consent is documented by means of a written, signed and dated informed consent form.

Inspection

The act by a regulatory authority of conducting an official review of documents, facilities, records, and any other resources that are deemed by the authority to be related to the research study and that may be located at the site of the research study, at the sponsor's and/or contract research organisation’s (CRO’s) facilities, or at other establishments deemed appropriate by the regulatory authority.

Integrated Research Application System (IRAS)

The online application system used to apply for most permissions and approvals for research in health and social care. See http://www.myresearchproject.org.uk.

Interim Clinical Trial/Research Study Report

A report of intermediate results and their evaluation based on analyses performed during the course of a research study.

International Conference for Harmonisation (ICH)

A collaboration between regulators and the pharmaceutical industry in Europe, the United States and Japan to establish international standards for clinical trials. ICH GCP is a widely recognised standard for Good Clinical Practice in clinical trials.

Investigational Medicinal Product

A pharmaceutical form of an active ingredient or placebo being tested or used as a reference in a research study, including a product with a marketing authorisation when used or assembled (formulated or packaged) in a way different from the approved form, or when used for an unapproved indication, or when used to gain further information about an approved use.

Investigator's Brochure

A compilation of the clinical and non-clinical data on the investigational medicinal product(s) which is relevant to the study of the investigational medicinal product(s) in human research participants.

Legally Acceptable Representative

An individual or juridical or other body authorised under applicable law to consent, on behalf of a prospective research participant, to the research participant’s participation in the research study.

Monitoring

The act of overseeing the progress of aresearch study, and of ensuring that it is conducted, recorded, and reported in accordance with the protocol, SOPs, GCP, and the applicable regulatory requirement(s).

Monitoring Report

A written report from the monitor to the sponsor after each site visit and/or other research study-related communication according to the sponsor’s SOPs.

Multicentre Research Study

A research study conducted according to a single protocol but at more than one site, and therefore, carried out by more than one principal investigator.

Opinion (in relation to a Research Ethics Committee)

The judgement and/or the advice provided by aa REC relating to the research study. The ethical opinion given by a REC on a research study, with application to the whole of the UK. An ethical opinion may be either favourable or unfavourable.

Original Clinical Record

See Source data/documents.

Principal Investigator

The investigator responsible for the research site where the study involves specified procedures requiring site-specific assessment (SSA). There should be one principal investigator for each research site. In the case of a single-site study, the chief investigator and the principal investigator could be the same person.

Principal Investigator Site File

A file designed for use in organising and collating all essential documentation required to conduct a research study in accordance with the principles of GCP and the applicable regulatory requirements (e.g. REC approval letter/correspondence, MHRA approval, blank data collection tools, staff CVs, delegation of duties log, etc.). A site file must be held at each research study site and it is the responsibility of the principal investigator at the site to ensure that the file is kept up-to-date.

Protocol

A document that describes the objective(s), design, methodology, statistical considerations, and organisation of a research study. The protocol usually also gives the background and rationale for the research study, but these could be provided in other protocol referenced documents.

Protocol Amendment

A written description of a change(s) to or formal clarification of a protocol.

Quality Assurance (QA)

All those planned and systematic actions that are established to ensure that the research study is performed and the data are generated, documented (recorded), and reported in compliance with GCP and the applicable regulatory requirement(s).

Quality Control (QC)

The operational techniques and activities undertaken within the quality assurance system to verify that the requirements for quality of the research study-related activities have been fulfilled.

Randomisation

In randomised controlled clinical trials, the process of assigning research participants to treatment or control groups using an element of chance to determine the assignments in order to reduce bias.

Regulatory Authorities

Bodies having the power to regulate. In the ICH GCP Guidelines the expression “Regulatory Authorities”, includes the authorities that review submitted clinical data and those that conduct inspections. These bodies are sometimes referred to as competent authorities.

Research Ethics Committee (REC)

A REC established in any part of the UK. The Committee are an independent body constituted of clinical and non-clinical members, whose responsibility it is to ensure the protection of the rights, safety and well-being of human research participants involved in a research study (or other health-related activity) and to provide public assurance of that protection, by, among other things, reviewing and approving/providing favourable opinion on, the research study protocol, the suitability of the chief investigator and principal investigator(s), facilities, and the methods and material to be used in obtaining and documenting informed consent of the research study participants. All health research studies must have favourable opinion from aa REC before the study can commence.

Research Participant

An individual who participates in a research project.

Research Participant Identification Code

A unique identifier assigned by the principal investigator to each research participant to protect the research participant’s identity and used in lieu of the research participant’s name when the investigator reports serious adverse events and/or other research study related data.

Research Study Site

The organisation or unit responsible for conducting any of the research procedures in a study at a particular locality.

Serious Adverse Event (SAE) or Serious Adverse Drug Reaction (Serious ADR)

Any untoward occurrence that:

• results in death,

• is life-threatening,

• requires inpatient hospitalisation or prolongation of existing hospitalisation,

• results in persistent or significant disability/incapacity

• is a congenital anomaly/birth defect, or,

• is otherwise considered clinically significant by the chief/principal investigator

Source Data

All information in original records and certified copies of original records of clinical findings, observations, or other activities in a research study necessary for the reconstruction and evaluation of the research study. Source data are contained in source documents (original records or certified copies). Source data may be in hard copy or electronic format.

Source Documents

Original documents, data, and records (e.g. hospital records, clinical and office charts, laboratory notes, memoranda, research participants’ diaries or evaluation checklists, pharmacy dispensing records, recorded data from automated instruments, copies or transcriptions certified after verification as being accurate copies, microfiches, photographic negatives, microfilm or magnetic media, x-rays, research participant files, and records kept at the pharmacy, at the laboratories and at medico-technical departments involved in the research study).

Sponsor

An individual, company, institution, or organisation which takes responsibility for the initiation, management, and/or financing of a research study.

Sponsor-Investigator

An individual who both initiates and conducts, alone or with others, a research study, and under whose immediate direction the investigational medicinal product is administered to, dispensed to, or used by a research participant. The term does not include any person other than an individual (e.g., it does not include a corporation or an agency). The obligations of a sponsor-investigator include both those of a sponsor and those of a principal investigator.

Standard Operating Procedures (SOPs)

Detailed, written instructions to achieve uniformityof the performance of a specific function.

Sub-investigator

Any individual member of the research study team designated and supervised by the principal investigator at a research study site to perform critical research-related procedures and/or to make important research-related decisions (e.g. associates, research fellows).

Suspected

Unexpected Serious Adverse Reaction (SUSAR)

An adverse reaction is unexpected if its nature and severity are not consistent with the information about the medicinal product in question set out, either;

Vulnerable

Research Participants

Individuals whose willingness to volunteer in a research study may be unduly influenced by the expectation, whether justified or not, of benefits associated with participation, or of a retaliatory response from senior members of a hierarchy in case of refusal to participate.

Examples are members of a group with a hierarchical structure, such as medical, pharmacy, dental, and nursing students, subordinate hospital and laboratory personnel, employees of the pharmaceutical industry, members of the armed forces, and persons kept in detention.

Other vulnerable research participants include patients with incurable long-term conditions, patients in nursing homes, unemployed or patients from low socioeconomic backgrounds, patients in emergency situations, ethnic minority groups, homeless people, prisoners, refugees, minors, and those incapable of giving consent.

Well-being (of the research participants)

The physical and mental integrity of the research participants participating in a research study.

5. Responsibilities

Clinical research should be conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki, and that are consistent with GCP and the applicable regulatory requirement(s).

Before research is initiated, foreseeable risks and inconveniences should be weighed against the anticipated benefit for the individual research participant and society. A research study should be initiated and continued only if the anticipated benefits justify the risks.

The rights, safety, and well-being of the research participants are the most important considerations and should prevail over interests of science and society.

The available non-clinical and clinical information on an intervention should be adequate to support the proposed research study.

Research studies should be scientifically sound, and described in a clear, detailed protocol.

The clinical care given to, and clinical decisions made on behalf of, research participants should always be theresponsibility of aqualified physician or, when appropriate, aqualified dentist.

Each individual involved in conducting a research study should be qualified by education, training, and experience to perform his or her respective task(s).

Freely given informed consent should be obtained from every research participant prior to research study participation.

All clinical trial information should be recorded, handled, and stored in a way that allows its accurate reporting, interpretation and verification - irrespective of the type of media used.

The confidentiality of records that could identify research participants should be protected, respecting the privacy and confidentiality rules in accordance with the applicable regulatory requirement(s).

Investigational products should be manufactured, handled, and stored in accordance with applicable good manufacturing practice (GMP). They should be used in accordance with the approved protocol.

Systems with procedures that assure the quality of every aspect of the research study should be implemented. Aspects of the research study that are essential to ensure human participant protection and reliability of study results should be the focus of such systems.

6. Principle (Chief) Investigator Responsibilities

Note – This section assumes the chief and principal investigator are the same person (i.e. a single site research study led by one investigator). In multicentre research studies, the below is applicable to all principal investigators at each of the research study sites.

6.1 Principal Investigator's Qualifications and Agreements

6.1.1 The principal investigator(s) should be qualified by education, training, and experience to assume responsibility for the proper conduct of the research study; should meet all the qualifications specified by the applicable regulatory requirement(s), and should provide evidence of such qualifications through up-to-date curriculum vitae (CV) and/or other relevant documentation requested by the sponsor, a REC and Governance Approvals Body.

6.1.2 The principal investigator should be thoroughly familiar with the appropriate use of the investigational medicinal product(s)/intervention(s), as described in the protocol, in the current Investigator's Brochure, in the product information and in other information sources provided by the sponsor.

6.1.3 The principal investigator should be aware of, and should comply with, GCP and the applicable regulatory requirements.

6.1.4 The principal investigator should permit monitoring and auditing by the sponsor, and inspection by the appropriate regulatory authority.

6.1.5 The principal investigator should maintain a list of appropriately qualified persons to whom the principal investigator has delegated significant research-related duties (i.e. a delegation log).

6.2 Adequate Resources

6.2.1 The principal investigator should be able to demonstrate (e.g. based on retrospective data) potential for recruiting the required number of suitable research participants within the agreed recruitment period.

6.2.2 The principal investigator should have sufficient time to properly conduct and complete the research study within the agreed time period.

6.2.3 The principal investigator should have available an adequate number of qualified staff and adequate facilities for the foreseen duration of the research study to conduct the research study properly and safely.

6.2.4 The principal investigator should ensure that all persons assisting with the research project are adequately informed about the protocol, the investigational medicinal product(s)/intervention(s), and their research study-related duties and functions.

6.2.5 The principal investigator is responsible for supervising any individual or party to whom the principal investigator delegates research study-related duties and functions conducted at the research site.

6.2.6 If the principal investigator/institution retains the services of any individual or party to perform research study-related duties and functions, the principal investigator/institution should ensure this individual or party is qualified to perform those research study-related

duties and functions and should implement procedures to ensure the integrity of the research study-related duties and functions performed and any data generated.

6.3 Medical Care of Participants in Research Studies

6.3.1 A qualified primary care physician (or dentist, when appropriate), who is a principal investigator or a sub-investigator for the research study, should be responsible for all research-related medical (or dental) decisions.

6.3.2 During and following a research participant's participation in a research study, the principal investigator/institution should ensure that adequate medical and where appropriate, psychological, care is provided to a research participant for any adverse events, including clinically significant laboratory values, related to the research study. The principal investigator/institution should inform a research participant when medical care is needed for intercurrent illness(es) of which the principal investigator becomes aware.

6.3.3 It is recommended that the principal investigator inform the research participant's primary care physician about the research participant's participation in the research study if the participant has a primary care physician and if the research participant consents to the primary care physician being informed.

6.3.4 Although a research participant is not obliged to give his/her reason(s) for withdrawing prematurely from a research study, the principal investigator should make a reasonable effort to ascertain the reason(s), while fully respecting the research participant's rights.

6.4 Communication with a REC

6.4.1 Before initiating a research study, the principal investigator should have written and dated approval/favourable opinion from a REC for the research study protocol, written informed consent form, consent form updates, research participant recruitment procedures (e.g., advertisements), and any other written information to be provided to research participants.

6.4.2 As part of the principal investigator's written application to a REC, the principal investigator should provide a REC with a current copy of the Investigator's Brochure where applicable (i.e., in research studies exploring the use of investigational medicinal products). If the Investigator's Brochure is updated during the research study, the principal investigator should supply a copy of the updated Investigator’s Brochure to a REC.

6.4.3 During the research study, the principal investigator should provide to a REC all documents subject to review.

6.5 Compliance with Protocol

6.5.1 The principal investigator should conduct the research study in compliance with the protocol agreed to by the sponsor and, if required, by the regulatory authority(ies) and which was given approval/favourable opinion by aa REC. The principal investigator and the sponsor should sign the protocol, or an alternative contract, to confirm agreement.

6.5.2 The principal investigator should not implement any deviation from, or changes to the protocol without agreement by the sponsor and prior review and documented approval/favourable opinion from aa REC of an amendment, except where necessary to eliminate an immediate hazard(s) to research participants, or when the change(s) involves

only logistical or administrative aspects of the research study (e.g. change in monitor(s), change of telephone number(s)).

6.5.3 The principal investigator, or person designated by the principal investigator, should document and explain any deviation from the approved protocol.

6.5.4 The principal investigator may implement a deviation from, or a change of, the protocol to eliminate an immediate hazard(s) to research participants without prior REC approval/favourable opinion. As soon as possible, the implemented deviation or change, the reasons for it, and, if appropriate, the proposed protocol amendment(s) should be submitted:

(a) to a REC for review and approval/favourable opinion, (b) to the sponsor for agreement and, if required, (c) to the regulatory authority (for example the Medicines and Healthcare products Regulatory Agency [MHRA] for trials involving the regulation of medication/healthcare products).

6.6 Investigational Medicinal Product(s)

6.6.1 Responsibility for investigational medicinal product(s) accountability at the research study site(s) rests with the principal investigator.

6.6.2 Where allowed/required, the principal investigator may/should assign some or all of the principal investigator's duties for investigational medicinal product(s) accountability at the research study site(s) to an appropriate pharmacist or another appropriate individual who is under the supervision of the principal investigator.

6.6.3 The principal investigator and/or a pharmacist or other appropriate individual, who is designated by the principal investigator, should maintain records of the investigational medicinal product's delivery to the research study site, the inventory at the site, the use by each research participant, andthe return to the sponsor or alternative disposition of unused investigational medicinal product(s). These records should include dates, quantities, batch/serial numbers, expiration dates (if applicable), and the unique code numbers assigned to the investigational medicinal product(s) and research participants. Principal investigators should maintain records that document adequately that the research participants were provided the doses specified by the protocol and reconcile all investigational medicinal product(s) received from the sponsor.

6.6.4 The investigational medicinal product(s) should be stored as specified by the sponsor (see 6.27.2 and 6.28.3) and in accordance with applicable regulatory requirement(s).

6.6.5 The principal investigator should ensure that the investigational medicinal product(s) are used only in accordance with the approved protocol.

6.6.6The principal investigator, or a person designated bythe principal investigator, should explain the correct use of the investigational medicinal product(s) to each research participant and should check, at intervals appropriate for the research study, that each research participant is following the instructions properly.

6.7 Randomisation Procedures and Unblinding

The principal investigator should follow the research study’s randomisation procedures, if any, and should ensure that the code is broken only in accordance with the protocol. If the

research study is blinded, the principal investigator should promptly document and explain to the sponsor any premature unblinding (e.g., accidental unblinding, unblinding due to a serious adverse event) of the investigational medicinal product(s).

6.8 Informed Consent of Research Participants

6.8.1 In obtaining and documenting informed consent, the principal investigator should comply with the applicable regulatory requirement(s), and should adhere to GCP and to the ethical principles that have their origin in the Declaration of Helsinki. Prior to the beginning of the research study, the principal investigator should have a REC's written approval/favourable opinion of the written informed consent form and any other written information to be provided to research participants.

6.8.2 The written informed consent form and any other written information to be provided to research participants should be revised whenever important new information becomes available that may be relevant to the research participant’s consent. Any revised written informed consent form, and written information should receive a REC's approval/favourable opinion in advance of use. The research participant or the research participant’s legally acceptable representative should be informed in a timely manner if new information becomes available that may be relevant to the research participant’s willingness to continue participation in the research study. The communication of this information should be documented.

6.8.3 Neither the principal investigator, nor the research study staff, should coerce or unduly influence a potential research participant to participate or to continue to participate in a research study.

6.8.4 None of the oral and written information concerning the research study, including the written informed consent form, should contain any language that causes the research participant or the research participant’s legally acceptable representative to waive or to appear to waive any legal rights, or that releases or appears to release the principal investigator, the institution, the sponsor, or their agents from liability for negligence.

6.8.5The principal investigator, or a person designated bythe principal investigator, should fully inform the research participant or, if the research participant is unable to provide informed consent, the research participant’s legally acceptable representative, of all pertinent aspects of the research study including the written information and the approval/ favourable opinion by a REC.

6.8.6 The language used in the oral and written information about the research study, including the written informed consent form, should be as non-technical as practical and should be understandable to the research participant (or the research participant’s legally acceptable representative) and the impartial witness, where applicable. It is advised that any written information that will be reviewed by participants (or their legally acceptable representative) be checked by a patient and public involvement (PPI) representative(s) prior to submitting this to a REC for approval, to ensure that the language used is acceptable and understandable to the research participants (or their legally acceptable representative).

6.8.7 Before informed consent may be obtained, the principal investigator, or a person designated by the principal investigator, should provide the research participant or the research participant’s legally acceptable representative ample time and opportunity to inquire about details of the research study and to decide whether or not to participate in the research study. It is recommended to give research participants, or the research participant’s legally acceptable representative, at least twenty-four hours to reflect upon

the information provided in the participant information sheet before deciding whether or not to participate. All questions about the research study should be answered to the satisfaction of the research participant, or the research participant’s legally acceptable representative.

6.8.8 Prior to a research participant’s participation in the research study, the written informed consent form should be signed and personally dated by the research participant or by the research participant’s legally acceptable representative, and by the person who conducted the informed consent discussion.

6.8.9 If a research participant is unable to read or if a legally acceptable representative is unable to read, an impartial witness should be present during the entire informed consent discussion. After the written informed consent form and any other written information to be provided to research participants, is read and explained to the research participant or the research participant’s legally acceptable representative, and after the research participant or the research participant’s legally acceptable representative has orally consented to the research participant’s participation in the research study and, if capable of doing so, has signed and personally dated the informed consent form, the witness should sign and personally date the consent form. By signing the consent form, the witness attests that the information in the consent form and any other written information was accurately explained to, and apparently understood by, the research participant or the research participant’s legally acceptable representative, and that informed consent was freely given by the research participant or the research participant’s legally acceptable representative.

6.8.10 Both the informed consent discussion and the written informed consent form and any other written information to be provided to research participants should include explanations of the following:

(a) If the study is a trial, that the trial involves research.

(b) The purpose of the research study.

(c) The research study treatment(s) and the probability for random assignment to each treatment if applicable.

(d) The research study procedures to be followed, including all invasive procedures.

(e) The research participant’s responsibilities.

(f) Those aspects of the research study that are experimental.

(g) The reasonably foreseeable risks or inconveniences to the research participant and, when applicable, to an embryo, foetus, or nursing infant.

(h) The reasonably expected benefits. When there is no intended clinical benefit to the research participant, the research participant should be made aware of this.

(i) The alternative procedure(s) or course(s) of treatment that may be available to the research participant if applicable, and their important potential benefits and risks.

(j) The compensation and/or treatment available to the research participant in the event of injury resulting from participation in the research study.

(k) The anticipated prorated payment/incentive, if any, to the research participant for participating in the research study.

(l) The anticipated expenses, if any, to the research participant for participating in the research study.

(m) That the research participant’s participation in the research study is voluntary and that the research participant may refuse to participate or withdraw from the research study, at any time, without penalty or loss of benefits to which the research participant is otherwise entitled. If there is a certain date by which the participant must retrospectively withdraw (i.e. before data analysis), then this must be explicitly specified on the participant information sheet.

(n) That the monitor(s), the auditor(s), a REC, and the regulatory authority(ies) will be granted direct access to the research participant’s original clinical records for

verification of clinical research study procedures and/or data, without violating the confidentiality of the research participant, to the extent permitted by the applicable laws and regulations and that, by signing a written informed consent form, the research participant or the research participant’s legally acceptable representative is authorizing such access.

(o) That records identifying the research participant will be kept confidential and, to the extent permitted by the applicable laws and/or regulations, will not be made publicly available. If the results of the research study are published, the research participant’s identity will remain confidential.

(p) That the research participant or the research participant’s legally acceptable representative will be informed in a timely manner if new information becomes available that may be relevant to the research participant’s willingness to continue participation in the research study.

6.8.11 Prior to participation in the research study, the research participant or the research participant’s legally acceptable representative should receive a copy of the signed and dated written informed consent form and any other written information provided to the research participants. During a research participant’s participation in the research study, the research participant or the research participant’s legally acceptable representative should receive a copy of the signed and dated consent form updates and a copy of any amendments to the written information provided to research participants.

6.8.12 When a research study (therapeutic or non-therapeutic) includes research participants who can only be enrolled in the research study with the consent of the research participant’s legally acceptable representative (e.g., children under the age of 16, or patients with severe dementia), the research participant should be informed about the research study to the extent compatible with the research participant’s understanding and, if capable, the research participant should sign and personally date the written informed consent.

6.8.13 Except as described in 6.8.14, a non-therapeutic research study (i.e., a research study in which there is no anticipated direct clinical benefit to the research participant), should be conducted in research participants who personally give consent and who sign and date the written informed consent form.

6.8.14 Non-therapeutic research studies may be conducted in research participants with consent of a legally acceptable representative provided the following conditions are fulfilled:

(a) The objectives of the research study cannot be met by means of a research study in research participants who can give informed consent personally.

(b) The foreseeable risks to the research participants are low.

(c) The negative impact on the research participant’s well-being is minimised and low.

(d) The research study is not prohibited by law.

(e) The approval/favourable opinion of a REC is expressly sought on the inclusion of such research participants, and the written approval/ favourable opinion covers this aspect. Such research studies, unless an exception is justified, should be conducted in patients with a disease or condition for which the investigational medicinal product is intended. Research participants in these research studies should be particularly closely monitored and should be withdrawn if they appear to be unduly distressed.

6.8.15 In emergency situations, when prior consent of the research participant is not possible, the consent of the research participant’s legally acceptable representative, if

present, should be requested. When prior consent of the research participant is not possible, and the research participant’s legally acceptable representative is not available, enrolment of the research participant should require measures described in the protocol and/or elsewhere, with documented approval/favourable opinion by a REC, to protect the rights, safety and well-being of the research participant and to ensure compliance with applicable regulatory requirements. The research participant or the research participant’s legally acceptable representative should be informed about the research study as soon as possible and consent to continue and other consent as appropriate (see 6.8.10) should be requested.

6.9 Records and Reports

6.9.1 The principal investigator should maintain adequate and accurate source documents and research study records that include all pertinent observations on each of the site’s research participants. Source data should be attributable, legible, contemporaneous, original, accurate, and complete. Changes to source data should be traceable, should not obscure the original entry, and should be explained if necessary (i.e., via an audit trail).

6.9.2 The principal investigator should ensure the accuracy, completeness, legibility, and timeliness of the data reported to the sponsor in Case Report Forms (CRFs)/data collection tools and in all required reports.

6.9.3 Where applicable, data reported on the CRF, that are derived from source documents, should be consistent with the source documents or the discrepancies should be explained.

6.9.4 Any change or correction to a CRF/data collection tool should be dated, initialled, and explained (if necessary) and should not obscure the original entry (i.e., an audit trail should be maintained); this applies to both written and electronic changes or corrections (see 6.32.4 (n)). Sponsors should provide guidance to principal investigators and/or the principal investigators' designated representatives on making such corrections. Sponsors should have written procedures to assure that changes or corrections in CRFs/data collection tools made by sponsor's designated representatives are documented, are necessary, and are endorsed bythe principal investigator. The principal investigator should retain records of the changes and corrections.

6.9.5 The principal investigator should maintain the research study essential documents. The principal investigator should take measures to prevent accidental or premature destruction of these documents.

6.9.6 For clinical trials, essential documents should be retained until at least 2 years after the last approval of a marketing application in an ICH region and until there are no pending or contemplated marketing applications in an ICH region or at least 2 years have elapsed since the formal discontinuation of clinical development of the investigational medicinal product. These documents should be retained for a longer period however if required by the applicable regulatory requirements or by an agreement with the sponsor. It is the responsibility of the sponsor to inform the principal investigator as to when these documents no longer need to be retained (see 6.19.12).

6.9.7 For non-trial research studies, it is recommended to retain essential documents for 5 years after publication of the research study report. These documents should be retained for a longer period however if required by the applicable regulatory requirements or by an agreement with the sponsor. When seeking approval from a REC, the length of time that the research study data will be kept for must be stated in the application to conduct the research study.

6.9.8 The financial aspects of the research study should be documented in an agreement between the sponsor and the principal investigator.

6.9.9 Upon request of the monitor, auditor, REC, or regulatory authority, the principal investigator should make available for direct access all requested research study related records.

6.10 Progress Reports

6.10.1 The principal investigator should submit written summaries of the research study status to a REC annually, or more frequently, if requested by a REC.

6.10.2 The principal investigator should promptly provide written reports to the sponsor, a REC and, where applicable, the institution on any changes significantly affecting the conduct of the research study, and/or increasing the risk to research participants.

6.11 Safety Reporting

6.11.1 All serious adverse events (SAEs) and suspected unexpected serious adverse reactions (SUSARs) should be reported immediately to the sponsor, except for those serious adverse events that the protocol or other document (i.e. Investigator's Brochure) identifies as not needing immediate reporting. The immediate reports should be followed promptly by detailed, written reports. The immediate and follow-up reports should identify research participants by unique code numbers assigned to the research participants rather than by the research participants’ names, personal identification numbers, and/or addresses (for further information on safety reporting see 6.38).

6.11.2 For reported deaths, the principal investigator should supply the sponsor and a REC with any additional requested information (e.g., autopsy reports and terminal clinical reports).

6.12 Premature Termination or Suspension of a Research Study

If the research study is prematurely terminated or suspended for any reason, the principal investigator should promptly inform the research participants, should assure appropriate therapy and follow-up for the research participants, and, where required by the applicable regulatory requirement(s), should inform the regulatory authority(ies). In addition:

6.12.1 If the principal investigator terminates or suspends a research study without prior agreement of the sponsor, the principal investigator should inform the institution where applicable, and the principal investigator should promptly inform the sponsor and a REC, and should provide the sponsor and a REC a detailed written explanation of the termination or suspension.

6.12.2 If the sponsor terminates or suspends a research study (see 6.35), the principal investigator should promptly inform the institution where applicable and the principal investigator should promptly inform a REC and provide a REC a detailed written explanation of the termination or suspension.

6.12.3 If a REC terminates or suspends its approval/favourable opinion of a research study, the principal investigator should inform the institution where applicable and the principal investigator should promptly notify the sponsor and provide the sponsor with a detailed written explanation of the termination or suspension.

6.13 Final Report(s) by Principal Investigator

Upon completion of the research study, the principal investigator, where applicable, should inform the institution; the principal investigator should provide a REC with a summary of the research study’s outcome, and the regulatory authority(ies) with any reports required.

SPONSOR RESPONSIBILITIES

6.14 Quality Management

The sponsor should implement a system to manage quality throughout all stages of the research study process.

Sponsors should focus on research study activities essential to ensuring human research participant protection and the reliability of research study results. Quality management includes the design of efficient research study protocols and tools and procedures for data collection and processing, as well as the collection of information that is essential to decision making. The methods used to assure and control the quality of the research study should be proportionate to the risks inherent in the research study and the importance of the information collected.

The sponsor should ensure that all aspects of the research study are operationally feasible and should avoid unnecessary complexity, procedures, and data collection. Protocols, CRFs, and other operational documents should be clear, concise, and consistent. The quality management system should use a risk-based approach as described below.

6.14.1 Critical Process and Data Identification

During protocol development, the sponsor should identify those processes and data that are critical to ensure human research participant protection and the reliability of research study results.

6.14.2 Risk Identification.

The sponsor should identify risks to critical research study processes and data. Risks should be considered at both the system level (i.e., standard operating procedures, computerised systems, personnel) and research study level (i.e., research study design, data collection, informed consent process).

6.14.3 Risk Evaluation

The sponsor should assess and evaluate the identified risks, against existing risk controls by considering:

(a) The likelihood of errors occurring.

(b) The extent to which such errors would be detectable.

(c) The impact of such errors on human research participant protection and reliability of research study results.

6.14.4 Risk Control

The sponsor should decide which risks to reduce and/or which risks to accept, following robust risk assessment and evaluation. The approach used to reduce risk to an acceptable level should be proportionate to the significance of the risk.

Risk reduction activities may be incorporated in protocol design and implementation, monitoring plans, agreements between parties defining roles and responsibilities,

systematic safeguards to ensure adherence to standard operating procedures, and training in processes and procedures.

Predefined quality tolerance limits should be established, taking into consideration the clinical and statistical characteristics of the variables as well as the statistical design of the research study, to identify systematic issues that can impact research participant safety or reliability of research study results. Detection of deviations from the predefined quality tolerance limits should trigger an evaluation to determine if action is needed.

6.14.5 Risk Communication

The sponsor should document quality management activities. The sponsor should communicate quality management activities to those who are involved in or affected by such activities, to facilitate risk review and continual improvement during execution of the research study.

6.14.6 Risk Review

The sponsor should periodically review risk control measures to ascertain whether the implemented quality management activities remain effective and relevant, taking into account emerging knowledge and experience.

6.14.7 Risk Reporting

The sponsor should describe the quality management approach implemented in the research study and summarise important deviations from the predefined quality tolerance limits and remedial actions taken in the research study report.

6.15 Quality Assurance and Quality Control

6.15.1 The sponsor is responsible for implementing and maintaining quality assurance and quality control systems with written SOPs to ensure that research studies are conducted and data are generated, documented (recorded), and reported in compliance with the protocol, GCP, and the applicable regulatory requirement(s).

6.15.2 The sponsor is responsible for securing agreement from all involved parties to ensure direct access (see 4.23) to all research study related sites, source data/documents, and reports for the purpose of monitoring and auditing by the sponsor, and inspection by domestic and foreign regulatory authorities.

6.15.3 Quality control should be applied to each stage of data handling to ensure that all data are reliable and have been processed correctly.

6.15.4 Agreements, made by the sponsor with the principal investigator and any other parties involved with the research study, should be in writing, as part of the protocol or in a separate agreement.

6.16 Contract Research Organisation (CRO)

6.16.1 A sponsor may transfer any or all of the sponsor's research study-related duties and functions to a CRO (which could include another member organisation of the TRA which possesses the necessary skills, knowledge and expertise to fulfil such research duties and functions), but the ultimate responsibility for the quality and integrity of the research study data always resides with the sponsor. The CRO should implement quality assurance and quality control.

6.16.2 Any research study-related duty and function that is transferred to and assumed by a CRO should be specified in writing. The sponsor should ensure oversight of any research study-related duties and functions carried out on its behalf, including research studyrelated duties and functions that are subcontracted to another party by the sponsor’s contracted CRO(s).

6.16.3 Any research study-related duties and functions not specifically transferred to and assumed by a CRO are retained by the sponsor.

6.16.4 All references to a sponsor in this guideline also apply to a CRO to the extent that a CRO has assumed the research study related duties and functions of a sponsor.

6.17 Medical Expertise

For clinical trial research activity, the sponsor should designate appropriately qualified medical personnel who will be readily available to advise on trial related medical questions or problems. If necessary, outside consultant(s) may be appointed for this purpose.

6.18 Research Study Design

6.18.1 The sponsor should utilise qualified individuals (e.g., biostatisticians, clinical pharmacologists, and primary care physicians) as appropriate, throughout all stages of the research study process, from designing the protocol and data collection tools and planning the analyses to analysing and preparing interim and final research study reports.

6.19 Research Study Management, Data Handling, and Record Keeping

6.19.1 The sponsor should utilise appropriately qualified individuals to supervise the overall conduct of the research study, to handle the data, to verify the data, to conduct the statistical analyses, and to prepare the research study reports.

6.19.2 The sponsor may consider establishing an Independent Data-Monitoring Committee (IDMC) to assess the progress of a research study, particularly if the study is a clinical trial, including the safety data and the critical efficacy endpoints at intervals, and to recommend to the sponsor whether to continue, modify, or stop a research study/trial. The IDMC should have written operating procedures and maintain written records of all its meetings.

6.19.3 When using electronic research study data handling and/or remote electronic research study data systems, the sponsor should:

(a) Ensure and document that the electronic data processing system(s) conforms to the sponsor’s established requirements for completeness, accuracy, reliability, and consistent intended performance (i.e., validation). The sponsor should base their approach to validation of such systems on a risk assessment that takes into consideration the intended use of the system and the potential of the system to affect human research participant protection and reliability of research study results.

(b) Maintain SOPs for using these systems. The SOPs should cover system setup, installation, and use. The SOPs should describe system validation and functionality testing, data collection and handling, system maintenance, system security measures, change control, data backup, recovery, contingency planning, and decommissioning. The responsibilities of the sponsor, principal investigator, and other parties with

respect to the use of these computerised systems should be clear, and the users should be provided with training in their use.

(c) Ensure that the systems are designed to permit data changes in such a way that the data changes are documented and that there is no deletion of entered data (i.e., maintain an audit trail, data trail, edit trail).

(d) Maintain a security system that prevents unauthorised access to the data.

(e) Maintain a list of the individuals who are authorised to make data changes

(f) Maintain adequate backup of the data.

(g) Safeguard the blinding, if any (e.g., maintain the blinding during data entry and processing), when conducting clinical randomised controlled research trials.

(h) Ensure the integrity of the data including any data that describe the context, content, and structure. This is particularly important when making changes to the computerised systems, such as software upgrades or migration of data.

6.19.4 If data are transformed during processing, it should always be possible to compare the original data and observations with the processed data.

6.19.5 The sponsor should use an unambiguous research participant identification code that allows identification of all the data reported for each research participant.

6.19.6 The sponsor, or other owners of the data, should retain all of the sponsor specific essential documents pertaining to the research study.

6.19.7 The sponsor should retain all sponsor-specific essential documents in conformance with the applicable regulatory requirement(s) of the country(ies) where the product is approved, and/or where the sponsor intends to apply for approval(s).

6.19.8 If the sponsor discontinues the clinical development of an investigational medicinal product (i.e., for any or all indications, routes of administration, or dosage forms), the sponsor should maintain all sponsor-specific essential documents for at least 2 years after formal discontinuation or in conformance with the applicable regulatory requirement(s).

6.19.9 If the sponsor discontinues the clinical development of an investigational medicinal product, the sponsor should notify all the research study principal investigators and all the regulatory authorities.

6.19.10 Any transfer of ownership of the data should be reported to the appropriate authority(ies), as required by the applicable regulatory requirement(s).

6.19.11 The sponsor specific essential documents should be retained until at least 2 years after the last approval of a marketing application in an ICH region and until there are no pending or contemplated marketing applications in an ICH region or at least 2-years have elapsed since the formal discontinuation of clinical development of the investigational medicinal product. These documents should be retained for a longer period, however, if required by the applicable regulatory requirement(s) or if needed by the sponsor.

6.19.12 The sponsor should inform the principal investigator(s) in writing of the need for record retention and should notify the principal investigator(s) in writing when the research study related records are no longer needed.

6.20 Investigator Selection

6.20.1 The sponsor is responsible for selecting the principal investigator(s). Each principal investigator should be qualified by training and experience and should have adequate resources (see 6.1 and 6.2) to properly conduct the research study for which the principal investigator is selected. If organisation of a coordinating committee and/or selection of coordinating investigator(s) are to be utilised in multicentre research studies, their organisation and/or selection are the sponsor's responsibility.

6.20.2 Before entering an agreement with a principal investigator to conduct a research study, the sponsor should provide the principal investigator(s) with the protocol and an upto-date Investigator's Brochure, and should provide sufficient time for the principal investigator to review the protocol and the information provided.

6.20.3 The sponsor should obtain the principal investigator's agreement:

(a) to conduct the research study in compliance with GCP, with the applicable regulatory requirement(s), and with the protocol agreed to by the sponsor and given approval/favourable opinion by a REC

(b) to comply with procedures for data recording/reporting

(c) to permit monitoring, auditing and inspection and

(d) to retain the research study related essential documents until the sponsor informs the principal investigator these documents are no longer needed. The sponsor and the principal investigator should sign the protocol, or an alternative document, to confirm this agreement.

6.21 Allocation of Responsibilities

Prior to initiating a research study, the sponsor should define, establish, and allocate all research study-related duties and functions.

6.22 Compensation to Research Participants and Principal Investigators

6.22.1 If required by the applicable regulatory requirement(s), the sponsor should provide insurance or should indemnify (legal and financial coverage) the principal investigator against claims arising from the research study, except for claims that arise from malpractice and/or negligence.

6.22.2 The sponsor's policies and procedures should address the costs of treatment of research participants in the event of research study-related injuries in accordance with the applicable regulatory requirement(s).

6.22.3 When research participants receive compensation, the method and manner of compensation should comply with applicable regulatory requirement(s).

6.23 Financing

The financial aspects of the research study should be documented in an agreement between the sponsor and the principal investigator. 6.24 Notification/Submission to Regulatory Authority(ies)

Before initiating the research study, the sponsor (or the sponsor and the principal investigator, if required by the applicable regulatory requirement(s)) should submit any required application(s) to the appropriate authority(ies) for review, acceptance, and/or permission (as required by the applicable regulatory requirement(s)) to begin the research study. Any notification/submission should be dated and contain sufficient information to identify the protocol.

6.25 Confirmation of Review by a REC

6.25.1 The sponsor should obtain from the principal investigator:

(a) The name and address of the principal investigator's REC.

(b) A statement obtained from a REC that it is organised and operates according to GCP and the applicable laws and regulations.

(c) Documented REC approval/favourable opinion and, if requested by the sponsor, a current copy of protocol, written informed consent form(s) and any other written information to be provided to research participants, research participant recruiting procedures, and documents related to payments and compensation available to the research participants, and any other documents that a REC may have requested.

6.25.2 If a REC conditions its approval/favourable opinion upon change(s) in any aspect of the research study, such as modification(s) of the protocol, written informed consent form and any other written information to be provided to research participants, and/or other procedures, the sponsor should obtain from the principal investigator a copy of the modification(s) made and the date approval/favourable opinion was given by a REC.

6.25.3 The sponsor should obtain from the principal investigator documentation and dates of any REC re-approvals/re-evaluations with favourable opinion, and of any withdrawals or suspensions of approval/favourable opinion.

6.26 Information on Investigational Medicinal Product(s)

6.26.1 When planning research studies involving investigational medicinal products, the sponsor should ensure that sufficient safety and efficacy data from nonclinical studies and/or clinical trials are available to support human exposure by the route, at the dosages, for the duration, and in the research population to be studied.

6.26.2 The sponsor should update the Investigator's Brochure as significant new information becomes available.

6.27 Manufacturing, Packaging, Labelling, and Coding Investigational Medicinal Product(s)

6.27.1 The sponsor should ensure that the investigational medicinal product(s) (including active comparator(s) and placebo, if applicable) is characterised as appropriate to the stage of development of the product(s), is manufactured in accordance with any applicable GMP, and is coded and labelled in a manner that protects the blinding, if applicable. In addition, the labelling should comply with applicable regulatory requirement(s).

6.27.2 The sponsor should determine, for the investigational medicinal product(s), acceptable storage temperatures, storage conditions (e.g., protection from light), storage

times, reconstitution fluids and procedures, and devices for product infusion, if any. The sponsor should inform all involved parties (e.g., monitors, investigators, pharmacists, storage managers) of these determinations.

6.27.3 The investigational medicinal product(s) should be packaged to prevent contamination and unacceptable deterioration during transport and storage.

6.27.4 In blinded trials, the coding system for the investigational medicinal product(s) should include a mechanism that permits rapid identification of the product(s) in case of a medical emergency, but does not permit undetectable breaks of the blinding.

6.27.5 If significant formulation changes are made in the investigational medicinal or comparator product(s) during the course of clinical development, the results of any additional studies of the formulated product(s) (e.g., stability, dissolution rate, bioavailability) needed to assess whether these changes would significantly alter the pharmacokinetic profile of the product should be available prior to the use of the new formulation in research studies.

6.28 Supplying and Handling Investigational Medicinal Product(s)

6.28.1 The sponsor is responsible for supplying the principal investigator(s) with the investigational medicinal product(s).

6.28.2 The sponsor should not supply a principal investigator with the investigational medicinal product(s) until the sponsor obtains all required documentation (e.g., approval/favourable opinion from a REC and regulatory authority(ies)).

6.28.3 The sponsor should ensure that written procedures include instructions that the principal investigator should followfor the handling and storage of investigational medicinal product(s) for the research study and documentation thereof. The procedures should address adequate and safe receipt, handling, storage, dispensing, retrieval of unused product from research participants, and return of unused investigational medicinal product(s) to the sponsor (or alternative disposition if authorised by the sponsor and in compliance with the applicable regulatory requirement(s)).

6.28.4 The sponsor should:

(a) Ensure timely delivery of investigational medicinal product(s) to the principal investigator(s).

(b) Maintain records that document shipment, receipt, disposition, return, and destruction of the investigational medicinal product(s).

(c) Maintain a system for retrieving investigational medicinal products and documenting this retrieval (e.g., for deficient product recall, reclaim after research study completion, expired product reclaim).

(d) Maintain a system for the disposition of unused investigational medicinal product(s) and for the documentation of this disposition.

6.28.5 The sponsor should:

(a) Take steps to ensure that the investigational medicinal product(s) are stable over the period of use.

(b) Maintain sufficient quantities of the investigational medicinal product(s) used in the research studies to reconfirm specifications, should this become necessary, and maintain records of batch sample analyses and characteristics. To the extent stability permits, samples should be retained either until the analyses of the

research study data are complete or as required by the applicable regulatory requirement(s), whichever represents the longer retention period.

6.29 Record Access

6.29.1 The sponsor should ensure that it is specified in the protocol or other written agreement that the principal investigator(s) provide direct access to source data/documents for research study-related monitoring, audits, REC review, and regulatory inspection.

6.29.2 The sponsor should verify that each research participant has consented, in writing, to direct access to his/her original clinical records for research study-related monitoring, audit, REC review, and regulatory inspection.

6.30 Safety Information

6.30.1 The sponsor is responsible for the ongoing safety evaluation of the investigational medicinal product(s)/interventions.

6.30.2 The sponsor should promptly notify all concerned principal investigator(s) and the regulatory authority(ies) of findings that could affect adversely the safety of research participants, impact the conduct of the research study, or alter a REC's approval/favourable opinion to continue the research study.

6.31 Safety Reporting

The primary responsibility for monitoring the safety of research participants lies with the sponsor. The sponsor has a duty to take action, which may include urgent safety measures, protocol amendments or even the suspension or termination of a research study, where the safety profile or the risk/benefit analysis changes significantly (for further information on safety reporting see section 6.38).

6.32 Monitoring

6.32.1 Purpose

The purposes of research study monitoring are to verify that:

a) The rights and well-being of human research participants are protected

b) The reported research study data are accurate, complete, and verifiable from source documents

c) The conduct of the research study is in compliance with the currently approved protocol/ amendment(s), with GCP, and with the applicable regulatory requirement(s).

6.32.2 Selection and Qualifications of Monitors

(a) Monitors should be appointed by the sponsor.

(b) Monitors should be appropriately trained, and should have the scientific and/or clinical knowledge needed to monitor the research study adequately. A monitor’s qualifications should be documented.

(c) Monitors should be thoroughly familiar with the investigational medicinal product(s)/interventions where applicable, the protocol, written informed consent form and any other written information to be provided to research participants, the sponsor’s SOPs, GCP, and the applicable regulatory requirement(s).

6.32.3 Extent and Nature of Monitoring

The sponsor should ensure that the research studies are adequately monitored.

The sponsor should determine the appropriate extent and nature of monitoring.

The determination of the extent and nature of monitoring should be based on considerations such as the; objective, purpose, design, complexity, size, and outcomes of the research study. In general, there is a need for on-site monitoring, before, during, and after the research study; however, in exceptional circumstances the sponsor may determine that central monitoring in conjunction with procedures such as principal investigators’ training and meetings, and extensive written guidance can assure appropriate conduct of the research study in accordance with GCP.

Statistically controlled sampling may be an acceptable method for selecting the data to be verified.

The sponsor should develop a systematic, prioritised, risk-based approach to monitoring research studies. The flexibility in the extent and nature of monitoring described in this section is intended to permit varied approaches that improve the effectiveness and efficiency of monitoring.

The sponsor may choose onsite monitoring, a combination of on-site and centralised monitoring, or, where justified, centralised monitoring.

The sponsor should document the rationale for the chosen monitoring strategy (i.e. in the monitoring plan). On-site monitoring is performed at the sites at which the research study is being conducted.

Centralised monitoring is a remote evaluation of accumulating data, performed in a timely manner, supported by appropriately qualified and trained persons (e.g., data managers, biostatisticians). Centralised monitoring processes provide additional monitoring capabilities that can complement and reduce the extent and/or frequency of on-site monitoring and help distinguish between reliable data and potentially unreliable data.

Review, which may include statistical analyses, of accumulating data from centralised monitoring can be used to:

(a) identify missing data, inconsistent data, data outliers, unexpected lack of variability and protocol deviations.

(b) examine data trends such as the range, consistency, and variability of data within and across sites.

(c) evaluate for systematic or significant errors in data collection and reporting at a site or across sites; or potential data manipulation or data integrity problems.

(d) analyse site characteristics and performance metrics.

(e) select sites and/or processes for targeted on-site monitoring.

6.32.4

Monitor's Responsibilities

The monitor(s), in accordance with the sponsor’s requirements, should ensure that the research study is conducted and documented properly by carrying out the following activities when relevant and necessary to the research study and the research study site:

(a) Acting as the main line of communication between the sponsor and the principal investigator.

(b) Verifying that the principal investigator has adequate qualifications and resources and that these remain adequate throughout the research study period, that facilities, including laboratories, equipment, and staff, are adequate to safely and properly conduct the research study and remain adequate throughout the research study period.

(c) Verifying, for the investigational medicinal product(s):

(i) That storage times and conditions are acceptable, and that supplies are sufficient throughout the research study.

(ii) That the investigational medicinal product(s) are supplied only to research participants who are eligible to receive it and at the protocol specified dose(s).

(iii) That research participants are provided with necessary instruction on properly using, handling, storing, and returning the investigational medicinal product(s).

(iv) That the receipt, use, and return of the investigational medicinal product(s) at the research study sites are controlled and documented adequately.

(v) That the disposition of unused investigational medicinal product(s) at the research study sites complies with applicable regulatory requirement(s) and is in accordance with the sponsor.

(c) Verifying that the principal investigator follows the approved protocol and all approved amendment(s), if any.

(d) Verifying that written informed consent was obtained before each research participant’s participation in the research study.

(e) Ensuring that the principal investigator receives the current Investigator's Brochure, all documents, and all research study supplies needed to conduct the research study properly and to comply with the applicable regulatory requirement(s).

(f) Ensuring that the principal investigator and the principal investigator's research study staff are adequately informed about the research study.

(g) Verifying that the principal investigator and the principal investigator's research study staff are performing the specified research study functions, in accordance with the protocol and any other written agreement between the sponsor and the principal investigator, and have not delegated these functions to unauthorised individuals.

(h) Verifying that the principal investigator is enrolling only eligible research participants.

(i) Reporting the research participant recruitment rate.

(j) Verifying that source documents and other research study records are accurate, complete, kept up-to-date and maintained.

(l) Verifying that the principal investigator provides all the required reports, notifications, applications, and submissions, and that these documents are accurate, complete, timely, legible, dated, and identify the research study.

(m) Checking the accuracy and completeness of the data collation paperwork (i.e. CRF entries and/or data collection tools), source documents and other research study-related records against each other. The monitor specifically should verify that:

(i) The data required by the protocol are reported accurately on the CRFs/data collection tools and are consistent with the source documents.

(ii) Any dose and/or therapy modifications are well documented for each of the research study research participants.

(iii) Adverse events, concomitant medications and intercurrent illnesses are reported in accordance with the protocol.

(iv) Visits that the research participants fail to make, tests that are not conducted, and examinations that are not performed are clearly reported as such on the CRFs/data collection tools.

(v) All withdrawals and dropouts of enrolled research participants from the research study are reported and explained.

(n) Informing the principal investigator of any CRF/data collection tool entry error, omission, or illegibility. In the case of clinical trials, the monitor should ensure that appropriate corrections, additions, or deletions are made, dated, explained (if necessary), and initialled by the principal investigator or by a member of the principal investigator's research study staff who is authorised to initial CRF changes for the principal investigator. This authorisation should be documented.

(o) Determining whether all Adverse Events (AEs) are appropriately reported within the time periods required by GCP, the protocol, a REC, the sponsor, and the applicable regulatory requirement(s).

(p) Determining whether the principal investigator is maintaining the essential documents.

(q) Communicating deviations from the protocol, SOPs, GCP, and the applicable regulatory requirements to the principal investigator and taking appropriate action designed to prevent recurrence of the detected deviations.

6.32.5

Monitoring Procedures

The monitor(s) should follow the sponsor’s established written SOPs as well as those procedures that are specified by the sponsor for monitoring a specific research study.

6.32.6

Monitoring Report

(a) The monitor should submit a written report to the sponsor after each research study-site visit or research study-related communication.

(b) Reports should include the date, research study site, name of the monitor, and name of the principal investigator or other individual(s) contacted.

(c) Reports should include asummary of what the monitor reviewed and themonitor's statements concerning the significant findings/facts, deviations and deficiencies, conclusions, actions taken or to be taken and/or actions recommended to secure compliance.

(d) The review and follow-up of the monitoring report with the sponsor should be documented by the sponsor’s designated representative (i.e. research governance manager).

(e) Reports of on-site and/or centralised monitoring should be provided to the sponsor (including appropriate management and staff responsible for research study and site oversight) in a timely manner for review and follow up. Results of monitoring activities should be documented in sufficient detail to allow verification of compliance with the monitoring plan. Reporting of centralised monitoring activities should be regular and may be independent from site visits.

6.32.7 Monitoring Plan

The sponsor should develop a monitoring plan that is tailored to the specific human research participant protection and data integrity risks of the research study in question. The plan should describe the monitoring strategy, the monitoring responsibilities of all the parties involved, the various monitoring methods to be used, and the rationale for their use. The plan should also emphasise the monitoring of critical data and processes. Particular attention should be given to those aspects that are not routine clinical practice and that require additional training. The monitoring plan should reference the applicable policies and procedures.

6.33 Audit

If or when sponsors perform audits, as part of implementing quality assurance, they should consider:

6.33.1 Purpose

The purpose of a sponsor's audit, which is independent of and separate from routine monitoring or quality control functions, should be to evaluate research study conduct and compliance with the protocol, SOPs, GCP, and the applicable regulatory requirements.

6.33.2 Selection and Qualification of Auditors

(a) The sponsor should appoint individuals, who are independent of the research study/systems, to conduct audits.

(b) The sponsor should ensure that the auditors are qualified, by training and experience, to conduct audits properly. An auditor’s qualifications should be documented (i.e. via a current copy of the auditor’s CV).

6.33.3 Auditing Procedures

(a) The sponsor should ensure that the auditing of research studies/systems is conducted in accordance with the sponsor's written procedures on what to audit, how to audit, the frequency of audits, and the form and content of audit reports.

(b) The sponsor's audit plan and procedures for a research study audit should be guided by the importance of the research study to submissions to regulatory authorities, the number of research participants in the research study, the type and complexity of the research study, the level of risks to the research study participants, and any identified problem(s).

(c) The observations and findings of the auditor(s) should be documented.

(d) To preserve the independence and value of the audit function, the regulatory authority(ies) should not routinely request the audit reports. Regulatory authority(ies) may seek access to an audit report on a case by case basis when evidence of serious GCP non-compliance exists, or in the course of legal proceedings.

(e) When required by applicable law or regulation, the sponsor should provide an audit certificate.

6.34 Noncompliance

6.34.1 Noncompliance with the protocol, SOPs, GCP, and/or applicable regulatory requirement(s) by a principal investigator, or by member(s) of the sponsor's staff should lead to prompt action by the sponsor to secure compliance.

If noncompliance that significantly affects or has the potential to significantly affect human research participant protection or reliability of research study results is discovered, the sponsor should perform a root cause analysis and implement appropriate corrective and preventive actions.

6.34.2 If the monitoring and/or auditing identifies serious and/or persistent noncompliance on the part of a principal investigator, the sponsor should terminate the principal investigator's participation in the research study. When a principal investigator's participation is terminated because of noncompliance, the sponsor should notify promptly the regulatory authority(ies) and a REC.

6.35 Premature Termination or Suspension of a Research Study

If a research study is prematurely terminated or suspended, the sponsor should promptly inform the principal investigators, and the regulatory authority(ies) of the termination or suspension and the reason(s) for the termination or suspension. A REC should also be informed promptly and provided the reason(s) for the termination or suspension by the sponsor or by the principal investigator, as specified by the applicable regulatory requirement(s).

6.36 Research Study Reports

Whether the research study is completed or prematurely terminated, the sponsor should ensure that the research study reports are prepared and provided to a REC and the regulatory agency(ies) as required by the applicable regulatory requirement(s).

The sponsor should also ensure that the research study reports in marketing applications meet the standards of the ICH Guideline for Structure and Content of Clinical Study Reports.

A report should be complete, free from ambiguity, well organised and easy to review. The report should provide a clear explanation of how the critical design features of the study were chosen and enough information on the plan, methods and conduct of the study so that there is no ambiguity in how the study was carried out.

The report, with its appendices, should also provide enough individual research participant data, including the demographic and baseline data, and details of analytical methods, to allow replication of the critical analyses when or if required. It is also particularly important that all analyses, tables, and figures carry, in text or as part of the table, clear identification of the set of research participants from which they were generated.

Depending on the regulatory authority's review policy, abbreviated reports using summarised data or with some sections deleted, may be acceptable for uncontrolled studies or other studies not designed to establish efficacy (but a controlled safety study should be reported in full), for seriously flawed or aborted studies, or for controlled studies that examine conditions clearly unrelated to those for which a claim is made. However, a full description of safety aspects should be included in these cases.

If an abbreviated report is submitted, there should be enough detail of design and results to allow the regulatory authority to determine whether a full report is needed. If there is any question regarding whether the reports are needed, it may be useful to consult the regulatory authority.

6.37 Multicentre Research Studies

For multicentre research studies, the sponsor should ensure that:

6.37.1 All principal investigators conduct the research study in strict compliance with the protocol agreed to by the sponsor and, if required, by the regulatory authority(ies), and given approval/favourable opinion by a REC.

6.37.2 The CRFs/data collection tools are designed to capture the required data at all multicentre research study sites. For those principal investigators who are collecting additional data at certain sites, supplemental CRFs/data collection tools should also be provided that are designed to capture the additional data. Prior approval/favourable opinion for the collection of this additional data at the site must be sought from a REC.

6.37.3 The responsibilities of coordinating investigator(s) and the other participating principal investigators are documented prior to the start of the research study.

6.37.4 All principal investigators are given instructions on following the protocol, on complying with a uniform set of standards for the assessment of research findings, and on completing the CRFs/data collection tools.

6.37.5 Communication between principal investigators at the different research study sites is facilitated by the co-ordinating investigator(s)

6.38 Safety Reporting

6.38.1 Safety Reporting in Research Involving Investigational Medicinal Products

6.38.1.1 Annual safety reports should be submitted to a REC by the sponsor, but may also be submitted by the sponsor’s legal representative or the chief/principal investigator for the study. Reports should normally be sent to a REC by email (see Appendix B for standard safety report form to be submitted to a REC).

6.38.1.2 If any SUSARs occur during the conduct of a research study exploring an investigational medicinal product, the sponsor must complete a safety report form and submit this within the specified time-frame (i.e. within 7 days of the sponsor becoming aware of the event in the case of death or life-threatening illness, or within 15 days of the sponsor becoming aware of the event in the case of hospitalisation or prolonged hospitalisation, significant disability or congenital abnormality or birth defect; see Appendix B for further guidance).`

6.38.1.3 Sponsors are required to submit complete data on all SUSARs occurring in EU member states to EudraVigilance Clinical Trial Module (EVCTM). This enables the relevant competent authorities, in collaboration where necessary, to maintain an effective overview of the safety issues in clinical trials. In the UK regulatory context, the MHRA will actively monitor the safety of clinical trials through its access to the European databases. Where the MHRA raises safety concerns with the sponsor, it will directly inform a REC so that any implications for the ethics of the research study can be considered in parallel.

6.38.2 Safety Reporting in Research Not Involving Investigational Medicinal Products (i.e. Non CTIMP studies)

6.38.2.1 In annual progress reports submitted to a REC, the chief/principal investigator should include a report on the safety of research participants.

6.38.2.2 A serious adverse event occurring to a research participant should be reported to a REC where in the opinion of the chief/principal 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.

6.38.2.3 Reports of related and unexpected serious adverse events should be submitted within 15 days of the chief/principal investigator becoming aware of the event, using the serious adverse event report form for non CTIMPs published on the Health Research Authority website (see Appendix C).

6.39 Research Study Protocol and Protocol Amendment(s)

The contents of a research study protocol should generally include the following topics. However, site specific information may be provided on separate protocol page(s), or addressed in a separate agreement, and some of the information listed below may be contained in other protocol referenced documents, such as an Investigator’s Brochure.

6.40

General Information

6.40.1 Protocol title, protocol identifying number, and date. Any amendment(s) should also bear the amendment number(s) and date(s).

6.40.2 Name and address of the sponsor and monitor (if other than the sponsor).

6.40.3 Name and title of the person(s) authorised to sign the protocol and the protocol amendment(s) for the sponsor.

6.40.4 Name, title, address, and telephone number(s) of the sponsor's clinical expert (or dentist when appropriate) for the research study.

6.40.5 Name and title of the principal investigator(s) who is (are) responsible for conducting the research study, and the address and telephone number(s) of the research study site(s).

6.40.6 Name, title, address, and telephone number(s) of the qualified primary care physician (or dentist, if applicable), who is responsible for all research study-site related medical (or dental) decisions (if other than the principal investigator).

6.40.7 Name(s) and address(es) of the clinical laboratory(ies) and other medical and/or technical department(s) and/or institutions involved in the research study where applicable.

6.41 Background Information

6.41.1 In studies exploring the use of investigational medicinal product(s), the name and description of the investigational medicinal product(s) should be provided.

6.41.2 In studies exploring the use of a particular non-medicinal intervention, a description of the intervention should be provided.

6.41.3 A summary of findings from nonclinical studies that potentially have clinical significance and from other research studies that are relevant to the research study.

6.41.4 Summary of the known and potential risks and benefits, if any, to research participants.

6.41.5 Description of and justification for the route of administration, dosage, dosage regimen, and treatment period(s) for research studies exploring investigational product(s)/interventions.

6.41.6 A statement that the research study will be conducted in compliance with the protocol, GCP and the applicable regulatory requirement(s).

6.41.7 Description of the population to be studied.

6.41.8 References to literature and data that are relevant to the research study, and that provide background for the research study.

6.42 Research Study Objectives and Purpose

A detailed description of the objectives and the purpose of the research study.

6.43

Research Study Design

The scientific integrity of the research study and the credibility of the datafrom the research study depend substantially on the design of the research study. A description of the research study design, should include:

6.43.1 A specific statement of the primary outcomes and the secondary outcomes, if any, to be measured during the research study.

6.43.2 A description of the type/design of research study to be conducted (e.g., randomised controlled trial, cross-sectional study, qualitative interview study).

6.43.3 A description of the measures taken to minimise/avoid bias, including:

(a) Randomisation.

(b) Blinding.

(c) Triangulation.

(d) Random selection of research participants from the population under study.

(e) Coding of qualitative data by more than one person.

6.43.4 A description of the research study treatment(s) and the dosage and dosage regimen of the investigational medicinal product(s)/intervention(s). Also include a description of the dosage form, packaging, and labelling of the investigational medicinal product(s).

6.43.5 The expected duration of research participant involvement in the research study, and a description of the sequence and duration of all research study periods, including follow-up, if any.

6.43.6 A description of the "stopping rules" or "discontinuation criteria" for individual research participants, parts of the research study and the entire research study.

6.43.7 Accountability procedures for the investigational medicinal product(s), including the placebo(s) and comparator(s), if any.

6.43.8 In the case of randomised controlled trials, maintenance of trial treatment randomisation codes and procedures for breaking codes.

6.43.9 The identification of any data to be recorded directly on the CRFs/data collection tools (i.e., no prior written or electronic record of data), and to be considered to be source data.

6.44 Selection and Withdrawal of Research Participants

6.44.1 Research participant inclusion criteria.

6.44.2 Research participant exclusion criteria.

6.44.3 Research participant withdrawal criteria (i.e. withdrawal from the entire research study, terminating investigational medicinal product/intervention treatment) and procedures specifying:

(a) When and how to withdraw research participants from the research study and/or investigational medicinal product treatment/intervention.

(b) The type and timing of the data to be collected for withdrawn research participants.

(c) Whether and how research participants are to be replaced.

(d) The follow-up for research participants withdrawn from investigational product treatment/intervention.

6.45 Treatment of Research Participants

6.45.1 The treatment(s) to be administered, including the name(s) of all the product(s), the dose(s), the dosing schedule(s), the route/mode(s) of administration, and the treatment period(s), including thefollow-up period(s) for research participantsfor each investigational medicinal product treatment/intervention/trial treatment group/arm of the research study.

6.45.2 Medication(s)/treatment(s) permitted (including rescue medication) and not permitted before and/or during the research study.

6.45.3 Procedures for monitoring research participant compliance.

6.46 Assessment of Efficacy

6.46.1 Specification of the efficacy parameters.

6.46.2 Methods and timing for assessing, recording, and analysing of efficacy parameters.

6.47

Assessment of Safety

6.47.1 Specification of safety parameters.

6.47.2 The methods and timing for assessing, recording, and analysing safety parameters.

6.47.3 Procedures for eliciting reports of and for recording and reporting adverse event and intercurrent illnesses

6.47.4 The type and duration of the follow-up of research participants after adverse events.

6.48 Statistics

6.48.1 A description of the statistical methods to be employed, including timing of any planned interim analysis(ses).

6.48.2 The number of research participants planned to be enrolled. In multicentre research studies, the numbers of enrolled research participants projected for each research study site should be specified. Reason for choice of sample size, including reflections on (or calculations of) the power of the research study and clinical justification.

6.48.3 The level of significance to be used (i.e. p value of 0.05).

6.48.4 Criteria for the termination of the research study.

6.48.5 Procedure for accounting for missing, unused, and spurious data.

6.48.6 Procedures for reporting any deviation(s) from the original statistical plan (any deviation(s) from the original statistical plan should be described and justified in the protocol and/or in the final report, as appropriate).

6.48.7 The selection of research participants to be included in the analyses (e.g., all randomised research participants, all dosed research participants, all eligible research participants, evaluable research participants).

6.49

Direct Access to Source Data/Documents

The sponsor should ensure that it is specified in the protocol or other written agreement that the principal investigator(s) will permit research study-related monitoring, audits, REC review, and regulatory inspection(s), providing direct access to source data/documents.

6.50

Quality Control and Quality Assurance

Description of measures that will be taken to ensure quality control and assurance (see section 4.48 and 4.49).

6.51 Ethics

Description of ethical considerations relating to the research study. This includes a statement of a REC approval/favourable opinion that will be sought before the research study commences.

6.52

Data Handling and Record Keeping

Description of how the data will be handled (including storage) and by whom, and how long research records will be kept for.

6.53

Financing and Insurance

Financing and insurance if not addressed in a separate agreement.

6.54 Publication Policy

Publication policy, if not addressed in a separate agreement.

INVESTIGATOR’S BROCHURE (IB) FOR INVESTIGATIONAL MEDICINAL PRODUCT(S)

6.55 Introduction

The Investigator's Brochure (IB) is a compilation of the clinical and non-clinical data on the investigational medicinal product(s) that are relevant to the study of the product(s) in human research participants. Its purpose is to provide the principal investigators and others involved in the research study with the information to facilitate their understanding of the rationale for, and their compliance with, many key features of the protocol, such as the dose, dose frequency/interval, methods of administration: and safety monitoring procedures. The IB also provides insight to support the clinical management of the study research participants during the course of the research study. The information should be presented in a concise, simple, objective, balanced, and non-promotional form that enables a clinician, or potential principal investigator, to understand it and make his/her own unbiased risk-benefit assessment of the appropriateness of the proposed research study.

For this reason, a clinically qualified person should generally participate in the editing of an IB, but the contents of the IB should be approved by the disciplines that generated the described data. This guideline delineates the minimum information that should be included in an IB and provides suggestions for its layout. It is expected that the type and extent of information available will vary with the stage of development of the investigational medicinal product. In the case of investigational medicinal products, if the investigational medicinal product is marketed and its pharmacology is widely understood by medical practitioners, an extensive IB may not be necessary. Where permitted by regulatory authorities, a basic product information brochure, package leaflet, or labelling may be an appropriate alternative, provided that it includes current, comprehensive, and detailed information on all aspects of the investigational medicinal product that might be of importance to the principal investigator.

If a marketed product is being studied for a new use (i.e., a new indication), an IB specific to that new use should be prepared. The IB should be reviewed at least annually and revised as necessary in compliance with a sponsor's written procedures. More frequent revision may be appropriate depending on the stage of development and the generation of relevant new information. However, in accordance with GCP, relevant new information may be so important that it should be communicated to the principal investigators, and possibly to a REC and/or regulatory authorities before it is included in a revised IB.

Generally, the sponsor is responsible for ensuring that an up-to-date IB is made available to the principal investigator(s) and the principal investigators are responsible for providing the up-to-date IB to the responsible REC. In the case of a principal investigator sponsored research study, the sponsor investigator should determine whether a brochure is available from the commercial manufacturer. If the investigational medicinal product is provided by the sponsor-investigator, then he or she should provide the necessary information to the research study personnel. In cases where preparation of a formal IB is impractical, the sponsor-investigator should provide, as a substitute, an expanded background information section in the research study protocol that contains the minimum current information described in this guideline.

6.56 General Considerations

The IB should include:

6.56.1 Title Page

This should provide the sponsor's name, the identity of each investigational medicinal product (i.e., research number, chemical or approved generic name, and trade name(s) where legally permissible and desired by the sponsor), and the release date. It is also suggested that an edition number, and a reference to the number and date of the edition it supersedes, be provided.

6.56.2 Confidentiality Statement

The sponsor may wish to include a statement instructing the principal investigator/recipients to treat the IB as a confidential document for the sole information and for the use of the principal investigator's team and a REC.

6.57 Contents of the Investigator’s Brochure

The IB should contain the following sections, each with literature references where appropriate:

6.57.1 Table of Contents 6.57.2 Summary

A brief summary (preferably not exceeding two pages) should be given, highlighting the significant physical, chemical, pharmaceutical, pharmacological, toxicological, pharmacokinetic, metabolic, and clinical information available that is relevant to the stage of clinical development of the investigational medicinal product.

6.57.3 Introduction

A brief introductory statement should be provided that contains the chemical name (and generic and trade name(s) when approved) of the investigational medicinal product(s), all active ingredients, the investigational medicinal product(s) pharmacological class and its expected position within this class (e.g., advantages), the rationale for performing research with the investigational medicinal product(s), and the anticipated prophylactic, therapeutic, or diagnostic indication(s). Finally, the introductory statement should provide the general approach to be followed in evaluating the investigational medicinal product.

6.57.4 Physical, Chemical, and Pharmaceutical Properties and Formulation

A description should be provided of the investigational medicinal product substance(s) (including the chemical and/or structural formula(e)), and a brief summary should be given of the relevant physical, chemical, and pharmaceutical properties. To permit appropriate safety measures to be taken in the course of the research study, a description of the formulation(s) to be used, including excipients, should be provided and justified if clinically relevant. Instructions for the storage and handling of the dosage form(s) should also be given.

Any structural similarities to other known compounds should be mentioned.

7. References

The International Conference on Harmonisation (ICH) GCP Guidelines. Available online at: https://www.ich.org/ (accessed 06/04/2020)

The Department of Health (DoH). Research Governance Framework for Health and Social Care 2005. Available online at: https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/139565/dh _4122427.pdf (accessed (06/04/2020)

The Medicines for Human Use (Clinical Trials) Regulations 2004. Available online at: http://www.legislation.gov.uk/uksi/2004/1031/contents/made (accessed 06/04/2020)

Medicines for Human Use (Clinical Trials) Amendment Regulations 2006. Available online at: http://www.legislation.gov.uk/uksi/2006/1928/contents/made (Accessed 06/04/2020)

NHS Health Research Authority Available online: https://www.hra.nhs.uk/ (accessed 07/04/2020)

8. Acknowledgments

The author would like to acknowledge the Transform Research Alliance Research Governance Framework Standard Operating Procedure for sharing good practice.

Appendix B: Clinical Trials of Investigational Medicinal Products

SAFETY REPORT TO RESEARCH ETHICS COMMITTEE

Please indicate which type(s) of safety report you wish to notify with this cover sheet (tick all that apply). Use a separate sheet for notifications relating to different trials. Please send by email to the main REC for the trial concerned together with enclosures. For further guidance see: http://www.hra.nhs.uk/research-community/during-your-researchproject/safetyreporting/

1. Expedited report(s) of SUSAR in the UK

Notify only Suspected Unexpected Serious Adverse Reactions occurring in the concerned trial at a UK site. SUSAR reports must follow the ICH E2B format.

2. Annual safety report / DSUR

ASRs must follow the ICH E2F format for Development Safety Update Reports (DSUR). Include a global list of all SSARs (Suspected Serious Adverse Reactions) related to the IMP and occurring in the reporting period.

3. Other For example, report of Data Monitoring Committee or other safety review.

Full title of study:

EudraCT number:

Research sponsor:

Name of Chief Investigator:

Name of main REC:

Main REC reference number:

Contact details for person making this notification

Name:

Address:

Telephone:

Fax:

Email:

Date of this notification:

9.1.1 List of enclosed documents

Please list each report submitted with this notification (insert extra rows in table as required).

1. Expedited SUSARs (UK only)

10. SPONSOR’S REPORT NO. / REFERENCE 11. TRIAL SITE 12. DATE SUSAR FIRST REPORTED TO SPONSOR

12.1 Is this a7- or 15-day report?

2. Other reports

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 only to the sponsor (or other person submitting the report).

Copy to be kept for information by main REC.

Appendix C: 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 REC 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:

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 hospitalisation

Persistent or significant disability or incapacity

4. Circumstances of event

Date of SAE:

Location:

Describe the circumstances of the event:

(Attach copy of detailed report if necessary)

Congenital anomaly or birth defect

Other

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

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.