Clinical Research Regulation For Australia and United Kingdom

Last content review/update: May 2, 2024

Overview

In accordance with the G-CTHandbook, the G-TrialsSOP, and AUS-47, the Therapeutic Goods Administration (TGA) allows for the supply of unapproved therapeutic goods to be used in clinical trials under two (2) regulatory schemes—the Clinical Trial Notification (CTN) scheme and the Clinical Trial Approval (CTA) scheme. The G-CTHandbook specifies that the scope of the TGA’s assessment includes all clinical trials (Phases I-IV).

Under either regulatory scheme, per the TGR, the G-CTHandbook, the G-TrialsSOP, and AUS-47, an ethics committee (EC) (Human Research Ethics Committee (HREC) in Australia) must approve the research protocol. The G-NatlStmt further specifies that any research that involves greater than low risk must be reviewed by an EC.

According to AUS-40, all public and private health organizations must also undertake a site-specific assessment (SSA) of each research project. This allows the institution to consider whether the project is suitable for the site and whether it has the capacity to conduct the research at that site. Per the G-TrialsSOP, the SSA and ethics review may occur in parallel. However, EC approval must be obtained and submitted to the research governance officer (RGO) of each participating institution before institutional authorization is granted.

For summaries of the clinical trials regulatory environment, legislation, and guidance, see AUS-40.

Clinical Trial Review Process

Per the G-CTHandbook, the sponsor is responsible for the overall decision as to whether the CTN or CTA scheme should be used. Consulting the EC responsible for protocol approval may assist the sponsor in making the decision. The main difference between the CTN and CTA schemes is the TGA’s level of involvement in reviewing data about the therapeutic goods before the clinical trial commences.

See AUS-27 for more information on choosing a clinical trial scheme.

CTN Scheme

As per the G-CTHandbook, the G-TrialsSOP, and AUS-47, under the CTN scheme, the sponsor must notify the TGA of its intention to sponsor a clinical trial involving an unapproved therapeutic good. The TGA does not assess any data relating to the proposed trial at the time of submission. As further indicated in AUS-47, sponsors may submit the CTN to the TGA concurrently with the EC’s and institution’s review and approval/authorization. However, it is the sponsor’s responsibility to ensure that all relevant approvals and authorizations are in place before commencement of the trial.

The G-CTHandbook indicates that a clinical trial is deemed to be notified as soon as the online CTN form (via the TGA Business Services (TBS) webpage (AUS-36)) has been submitted and the relevant fee has been paid. If there are any changes to the trial details notified to the TGA (such as a change in the details of the principal investigator (PI), the address of the site, or the therapeutic good), the sponsor must update the relevant fields on the online CTN form.

The G-CTHandbook further states that the TGA may request additional information if the trial raises any concern, or ask specific questions to address any deficiencies. Specifically, the TGA can request certain information or documents from the sponsor relating to the supply and handling of the goods, as well as the monitoring and results of the supply of the goods. If the TGA directs a trial notified under the CTN scheme not to be conducted or becomes aware that conducting or continuing the trial would be contrary to the public interest, then the goods used in the trial would no longer be exempt from inclusion in the Australian Register of Therapeutic Goods (ARTG) (AUS-22) and cannot be lawfully supplied. This may occur if the TGA becomes aware that allowing the trial to proceed or continue carries an unacceptable risk of death, serious illness, or serious injury.

CTA Scheme

According to AUS-47, parties that are considering submitting a CTA application are strongly encouraged to contact the TGA at clinical.trials@health.gov.au for advice regarding the application process (some class IV biologicals must be submitted under the CTA scheme). Pre-submission meetings with the TGA may be requested through the forms found on AUS-17.

AUS-47 indicates that the CTA scheme consists of a two (2)-part process. Part 1 constitutes the formal CTA application, which the sponsor completes and submits directly to the TGA. Part 2 requires the sponsor to notify the TGA when a trial commences and alert the TGA to new sites in ongoing CTA trials.

As per the G-CTHandbook, the TGA reviews relevant, but limited, scientific data, and its primary responsibility is to review the safety of the product. In addition, the TGA can request certain information or documents from the sponsor about therapeutic goods approved under the CTA scheme relating to the supply and handling of the goods, as well as the monitoring and results of the supply of the goods.

AUS-47 further specifies that the evaluation of a CTA application includes consideration of the manufacturing and quality and safety data in conjunction with the trial's usage guidelines, to inform a risk-benefit decision by the TGA on whether or not to approve the clinical trial. Any significant changes to the information provided in support of the trial are considered a variation and need to be approved, since they have the potential to affect the initial decision to approve a trial. The TGA advises clinical trial sponsors to contact them via clinical.trials@health.gov.au if they intend to change a previously approved CTA application.

The G-CTHandbook further states that the TGA can revoke an approval of a clinical trial under the CTA scheme where the conditions of approval are not met.

Inspection

According to the G-GCP-Inspect, clinical trials of medicines and biologicals regulated under the CTN or CTA schemes are subject to the TGA’s Good Clinical Practice (GCP) Inspection Program. See the G-GCP-Inspect for more details on how the TGA prioritizes and schedules GCP inspections, the kinds of inspections the TGA might conduct, the inspection process, and how the TGA reports and follows up on inspections. Additionally, see AUS-59 for frequently asked questions about the GCP Inspection Program.

CTN Scheme, CTA Scheme, and FAQs

About this handbook, Is the product a therapeutic good?, Determine if the product is ‘unapproved’, Choosing between the CTN and CTA schemes, The CTN scheme, The CTA scheme, and Responsibilities under the CTN and CTA schemes

Introduction, Terms, and SOP 05

Purpose, Scope and Limits of this Document

Part 3 (12 and 12AA-12AD) and Schedule 5A

Last content review/update: May 16, 2024

Overview

In accordance with the MHCTR and the MHCTR2006, the Medicines and Healthcare Products Regulatory Agency (MHRA) is responsible for reviewing, evaluating, and approving applications for clinical trials using registered or unregistered investigational products (IPs). (Note: IPs are known as investigational medicinal products (IMPs) in the United Kingdom (UK)). The G-CTApp specifies that the scope of the MHRA’s assessment includes all clinical trials (Phases 1-4). Per G-CTApp and G-IRASCombRev, all new clinical trial applications must be prepared, submitted, and reviewed via the combined review process, which offers a single application route and parallel/coordinated review from MHRA and the ethics committee (EC) leading to a single UK decision for clinical trials.

Regarding licensing of biosimilars (i.e., generic biotech medicines), see the G-Biosimilars for details on the UK’s recent regulatory changes to ease or remove clinical trial requirements for the MHRA’s review and approval of biosimilars.

Clinical Trial Review Process

Per GBR-72, under combined review, research teams make a single application using a new part (GBR-125) of the Integrated Research Application System (IRAS) (GBR-78), which goes to both the MHRA and an EC at the same time. The regulatory and ethics reviews are done in parallel and any requests for further information are raised jointly. A single response to these requests leads to a single decision from both reviews. The G-CTApp states that the initial combined review assessment will be completed within 30 days of application submission. Applications for healthy volunteer trials and sponsor-determined phase 1 trials in non-oncology participants may qualify for a shortened assessment time and the MHRA will work with the EC to expedite these applications. When applications need expert advice, the MHRA will seek advice from the Clinical Trials, Biologicals and Vaccines Expert Advisory Group (CTBV EAG) of the Commission on Human Medicines (CHM). In addition, the CHM will then discuss the trial at their meeting, which will take place later in the same week as the CTBV EAG meeting. See the G-CTApp for examples of which trials require expert advice and for detailed requirements. The MHRA also supports the conduct of trials with complex innovative designs such as umbrella, basket, platform, and master protocol plus submodules. These trial designs are characterized by the presence of prospective major adaptations, such as the addition of new IPs or introducing new trial populations. Before submitting a clinical trial application with a complex innovative design and/or an amendment requesting approval of major adaptations, sponsors are recommended to establish a dialogue with the MHRA and seek advice.

The G-CTApp states that under the combined review process, the MHRA will inform applicants of the outcome of the submission along with the EC’s review and decision. The outcomes could be one (1) of the following:

Acceptance of the request for a clinical trial authorization
Acceptance of the request for a clinical trial authorization subject to conditions
Grounds for non-acceptance of the request for a clinical trial authorization

As indicated in the G-CTApp, with respect to grounds for non-acceptance, applicants will have the opportunity to respond, usually within 14 days; however, this may be extended on request. A communication informing the applicant of the combined MHRA and EC decision will usually be sent within 60 days of receiving the original valid application. If an extension to the response date has been agreed to, then this will impact the final decision timeline. Notification of a decision relating to a gene therapy product, somatic cell therapy (including xenogenic cell therapy) product, tissue engineered product, or products containing genetically modified organisms will be sent within 90 days of receiving the original application, unless otherwise advised. Communications will be sent electronically via email from MHRA_CT_Ecomms@mhra.gov.uk. The MHRA will only send official correspondence to the named applicant email address. According to the MHCTR, if the sponsor or the designated representative does not receive a request for additional information from the MHRA within 30 days, the application is considered authorized. (See the Timeline of Review section for additional details.)

Per GBR-9, the EC’s ethical opinion applies for the duration of the study, which was stated in the clinical trial application and protocol. An extension of the study period is not in itself a substantial amendment, except where it is related to other amendments that would be substantial, such as an increase in target recruitment, addition of new procedures or sub-studies, or extension of follow-up. Where the duration of the study is to be extended beyond the period specified in the application form, the EC should be notified.

IRAS (GBR-78) is a single system for applying for the permissions and approvals for health and social care/community care research in the UK. It generates the IRAS ID and uses filters to ensure that the data collected and collated is appropriate to the type of study, and consequently the permissions and approvals required. The system helps applicants meet the regulatory and governance requirements. As described in GBR-67, approval from the Health Research Authority (HRA) is required for all National Health Service (NHS) project-based research led from England or Wales. HRA and Health and Care Research Wales (HCRW) approval brings together the assessment of governance and legal compliance. For any new studies led from Scotland or Northern Ireland but have English and/or Welsh NHS sites, the national research and development coordinating function of the lead nation will share information with the HRA and HCRW assessment teams, who can issue HRA and HCRW approval for English and Welsh sites and thereby retain existing compatibility arrangements. Studies led from England or Wales with sites in Northern Ireland or Scotland will be supported through existing UK-wide compatibility systems, by which each country accepts the centralized assurances, as far as they apply, from national coordinating functions without unnecessary duplication. For details on HRA’s assessment criteria and standards for approval, see GBR-29.

Notification Scheme

Per the G-CTApp, MHRA’s notification scheme enables a more streamlined and risk-proportionate approach to processing clinical trial authorization for “initial” applications. The scheme only applies to clinical trial applications for Phase 4 and certain Phase 3 clinical trials deemed to be of lower risk. Interest in the notification scheme should be registered via the combined review process described above (GBR-125). MHRA acceptance of an application under the notification scheme will be confirmed within 14 calendar days from the application received effective date and authorization by the MHRA will be granted unless any criterion is not suitably met. If the MHRA determines the application does not meet the notification scheme criteria, an objection decision will be communicated within 14 calendar days from the application received effective date, and the application will continue under full clinical trial assessment with a decision communicated within the 30-day statutory timeframe.

As indicated in the G-CTApp, the notification scheme acceptance criteria are as follows:

Phase 4 trials must meet both of the following criteria:

All IPs are licensed and used according to the relevant UK, United States of America (USA), or European Union (EU) marketing authorization (except for placebo)
There are no ongoing safety concerns with the IP(s) that the sponsor is aware of, for example other trials on temporary halt/clinical hold, other trials with unresolved urgent safety measures or post-marketing regulatory restrictions

Phase 3 trials must meet at least one (1) of the following criteria:

The trial is already approved in the USA or EU based on the same protocol and Investigator’s Brochure (IB) versions submitted to MHRA, and for EU approvals, the same version of the IP dossier. For trials approved in the USA only, the IP dossier submitted to the MHRA must document the same IP manufacturing process
The MHRA has approved in the last two (2) years a previous Phase 3 clinical trial of the IP(s) at the same dose (or a higher dose), dosing frequency (or a higher frequency) and route of administration, and for the same indication (even if the trial was with a different sponsor) and utilizing the same manufacturing process
IPs are licensed and used according to the relevant UK, USA, or EU marketing authorization (except for placebo)

In addition, the G-CTApp states that to be eligible for the scheme, a Phase 3 trial must not include any of the following:

Complex, innovative trial design (e.g., basket, umbrella, and platform) that allows for prospective major adaptations such as the addition of indications or IPs via future amendments
Includes pediatric participants
Includes pregnant or breastfeeding participants
IP is first in class
IP is an advanced therapy medicinal product (ATMP)

Brexit Background

Per the G-MHRASubmiss, Brexit, the EUCouncil-Brexit, the WithdrlAgrmt, and the G-AfterTransition, the UK withdrew from the EU on January 31, 2020. The MHRA updated and published clinical trials guidance that became effective on January 1, 2021. G-AfterTransition summarizes the guidance to sponsors and researchers. Furthermore, the G-MHRASubmiss describes how to make certain regulatory submissions to the MHRA (substantial amendments, end-of-trial notifications, and developmental safety update reports (DSURs)). Per the MHCTR-EUExit and as explained in GBR-115, the new guidance went into force via the MHCTR-EUExit (also known as the “Exit Regulations”). The Exit Regulations also update existing UK legislation by, for example, replacing references to EU databases with newly established UK databases. The G-IPsNIreland delineates that the supply and use of IPs in Northern Ireland must follow EU laws as per the Northern Ireland Protocol. For policy papers and details on the Northern Ireland Protocol, see GBR-119. For broader information and a comprehensive Brexit “checker” of new rules in the UK, see GBR-60.

To help ensure the continuity of supply of IPs for clinical trials the BrexitLtr-IPs indicates that the UK will unilaterally recognize certain EU regulatory processes for a time-limited period. This recognition is known as “standstill.”

GBR-115 indicates that the UK is committed to being as aligned as possible with the EU Clinical Trials Regulation (GBR-21). The MMDAct grants authority for regulations to be made that correspond or are similar to GBR-21. For more information about GBR-21, see GBR-54.

6

10.9

Help (Preparing and Submitting Applications)

When a clinical trial authorization (CTA) is needed, Trial Sponsor and legal Representative, Registration of your clinical trial, Combined review of clinical trials of investigational medicinal products, Documents to send with your application, Assessment of your submission, New notification scheme, Requesting approval of trials with complex innovative designs, and Applications that need expert advice

Part 4 (Article 126)

Part 2 (Chapter 1)

Introduction and Article 1

Amendment of Regulation 12 of the Principal Regulations; and Part 2 (Conditions Based on Article 3 of the Directive)

Part 1 (2), Part 2 (5, 6, and 7), Part 3 (12, 14, 15, 17, and 18), and Schedule 2

Regulatory Fees

Last content review/update: July 3, 2024

Therapeutic Goods Administration

As per the TGR, the sponsor is responsible for paying a fee to the Therapeutic Goods Administration (TGA) to submit an application under the clinical trial notification (CTN) or clinical trial approval (CTA) scheme for evaluation. Per the G-FeesCharges, the fees are as follows:

$429 Australian dollars for unapproved medicines CTN, and for each notification of one (1) or more additional trial sites
$2,046 Australia dollars for unapproved medicines CTA (30-day evaluation)
$562 Australian dollars for unapproved medicines CTA – variation (30-day evaluation)
$25,426 Australian dollars for unapproved medicines CTA (50-day evaluation)
$6,940 Australian dollars for unapproved medicines CTA – variation (50-day evaluation)
$429 Australian dollars for unapproved biologicals CTN, and for each notification of one (1) or more additional trial sites
$30,964 Australian dollars for unapproved biologicals CTA
$8,448 Australian dollars for unapproved biologicals CTA – variation

According to AUS-47, a higher fee is applicable to clinical trial applications under the CTA scheme due to the more complex nature of the evaluation process. Certain variations to an existing CTN may incur a fee, such as the addition of a new site, change to a previously notified therapeutic good that creates separate and distinct goods, or the addition of a new therapeutic good to a previously notified trial. For additional fee information, refer to Schedules 9 and 9A of the TGR and the G-FeesCharges.

Payment Instructions

AUS-66 indicates that regulatory fees and charges may be paid online or by bank transfer (electronic funds transfer (EFT)). Online payment by credit card is the preferred payment option, and all payments must be in Australian dollars.

As stated in AUS-25, online payment is made via the TGA Online Payment Portal (AUS-16). Once the payment has been finalized, the Portal will confirm that the payment has been successful. The user may request an email confirmation. Certain payments, including a CTN fee and a variation to a medicine (e.g., a therapeutic good), may be made online without an invoice. See AUS-25 for more information.

AUS-66 further indicates that to ensure all payments made by EFT are correctly allocated, the organization’s Identification Number (e.g., TGA00xxxxx) should be included in the payment ‘Reference’ field. Bank transfer fees are the payer’s responsibility. Additionally, bank transfers must be accompanied by a remittance advice, which must be issued within 24 hours for all bank transfers. Remittance advices must be emailed to TGARemittanceAdvices@health.gov.au and contain the organization’s Identification Number in the subject field. The TGA’s bank account details are as follows:

Bank: Commonwealth Bank of Australia
BSB: 062-909
Account Number: 10215498

Per AUS-66, payments from overseas can only be accepted in Australian denominations. Payers must ensure that their payment covers any international banking fees. The TGA’s international banking details are as follows:

IBAN: 06290910215498
Swift Code: CTBAAU2S

Clinical Trials

Schedules 5A, 9 (Part 2), and 9A (Part 2)

FAQs

Last content review/update: May 16, 2024

Medicines and Healthcare Products Regulatory Agency

As per the MHCTR, the MHCTR2006, and the G-CTApp, the sponsor or the designated representative is responsible for paying a fee to the Medicines and Healthcare Products Regulatory Agency (MHRA) to submit a clinical trial application for authorization. According to the G-MHRAPaymt, applicants will receive an invoice to make a payment for the outstanding amount after validation of the application. Applicants must pay invoices upon receipt or they will incur penalty fees. Non-payment may also result in suspension of any license or authorization, followed by legal proceedings for any unpaid amounts.

As delineated in the G-MHRAFees, the MHRA levies the following clinical trial processing fees:

3,366 British Pounds – Applications with an Investigational Medicinal Product (IMP) dossier (higher fee for phase 1, full and simplified IMP dossier)
248 British Pounds – Applications without an IMP dossier (lower fee for phase IV, cross referral, additional protocol)
248 British Pounds – Clinical trial variation/amendment
No cost – Phase 4 notification
248 British Pounds – Assessment of annual safety reports

Note per the G-MHRAFees, there is no annual clinical trials fee and no fee for Phase IV notifications. For a cross-referral or additional protocol submission, no new IMP dossier or investigators brochure data should be provided; however, copies of the relevant manufacturer’s authorization(s) and qualified person declaration (if applicable) should be provided since these are study specific.

Per the G-CTAuth-GBR, the fees for the annual safety reports are applicable to annual progress reports and Development Safety Update Reports (DSURs). From June 1, 2024, MHRA will only accept online payment of this fee via MHRA’s payments service (GBR-26) prior to submission of an annual safety report. Receipts generated will be sent by email and must be included in the report submission as proof of payment. Failure to provide evidence of payment will result in the submission being made invalid.

The G-CTApp further indicates that no fees are required for applications submitted and authorized under the Notification Scheme.

Payment Instructions

According to the G-MHRAPaymt, the MHRA does not accept checks. Payments can be made electronically by bank transfer, credit card, or debit card. The relevant invoice and customer number should be quoted when making payments. Bank transfers should be sent to:

Account Name: MHRA
Account Number: 10004386
Sort code: 60-70-80
Swift code: NWBKGB2L
IBAN: GB68NWBK60708010004386
Bank: National Westminster Bank

Bank address:
National Westminster Bank RBS
London Corporate Service Centre, 2^nd Floor
280 Bishopsgate
London
EC2M 4RB
UK

As per G-MHRAPaymt, credit or debit card payments may be made securely online using GBR-26. Remittance advice notices can be sent to sales.invoices@mhra.gov.uk and should include the relevant invoice number on the remittance advice. MHRA cannot accept any documentation sent by postal mail service. Further information can be obtained by emailing sales.invoices@mhra.gov.uk. G-MHRAPaymt further provides that clinical trial application invoice disputes/queries should be emailed to ctdhelpline@mhra.gov.uk and cc: sales.invoices@mhra.gov.uk.

The G-CTApp indicates that invoices for clinical trial authorization applications and substantial amendment applications are sent directly to the applicant shortly after a valid submission has been established. The applicant’s cover letter should clearly highlight the purchase order (PO) number where available. It is the responsibility of the applicant to ensure timely payment of invoices for their submissions. Invoices must be settled on receipt of invoice. For additional information, applicants may contact the MHRA Finance Department at 020 3080 6533 or sales.invoices@mhra.gov.uk.

Fees

Development Safety Update Reports (DSURs)

8. Clinical trials - application fees

11, 13, and Explanatory Note

Part 3 (17)

Ethics Committee

Last content review/update: May 2, 2024

Overview

As indicated in the TGAct, the TGR, the G-CTHandbook, the G-NatlStmt, and AUS-47, Australia has a decentralized process for the ethics review and approval of clinical trial research. According to the TGR, the G-CTHandbook, the G-TrialsSOP, and AUS-47, Australia requires human research protocols to be reviewed by an institutional-level ethics committee (EC). The G-NatlStmt further specifies that any research that involves greater than low risk must be reviewed by an EC. (Note: Institutional ECs are referred to as Human Research Ethics Committees (HRECs) in Australia.)

The G-NatlStmt indicates that one (1) or more institutions can individually or jointly establish an EC or any other ethics review body. Institutions that establish an EC are responsible for adequately resourcing and maintaining it, including providing sufficient administrative support. Per the TGAct and AUS-20, ECs are required to be constituted and operate in accordance with the guidelines issued by the National Health and Medical Research Council (NHMRC), and to have notified the NHMRC of their existence. According to the TGR, the G-NatlStmt, the G-TrialsSOP, and AUS-20, institutional ECs ensure that clinical trial research complies with the NHMRC’s ethical standards published in the G-NatlStmt. See the Oversight of Ethics Committees section for more information on notification.

For summaries of the clinical trials regulatory environment, legislation, and guidance, see AUS-40.

Ethics Committee Composition

As stated in the G-NatlStmt, an EC must be composed of at least eight (8) members in the following categories:

A chairperson with suitable experience
Two (2) people who bring a broader community or consumer perspective and have no paid affiliation with the institution
One (1) person with knowledge of and current experience in the professional care, counseling, and/or treatment of people
One (1) person who performs a pastoral care role in the community
One (1) qualified lawyer, who may or may not be currently practicing and, where possible, is not engaged to advise the institution on research-related or any other matters
Two (2) people with current research experience relevant to the research proposals to be considered at the meetings they attend

The G-NatlStmt further states that wherever possible, one (1) or more of the members listed above should be experienced in reflecting on and analyzing ethical decision-making. As far as is practicable, institutions should ensure that their EC’s membership at each meeting has diversity, including gender diversity, and at least one third of those participating in each meeting are from outside of the institution. ECs that review research about Aboriginal and Torres Strait Islander people or communities should appoint one (1) or more members who have knowledge of research with Aboriginal and Torres Strait Islander peoples or are familiar with relevant cultural knowledge, if such a person has not already been appointed.

Per the G-NatlStmt, ECs may also include other members with the above areas of expertise or with additional areas of expertise. Institutions are encouraged to establish a pool of appointed EC members to draw on as needed to help meet minimum membership requirements and/or provide additional experience or expertise. The institution should ensure that its EC has access to the expertise necessary to properly review research, which may necessitate going outside of the EC’s membership.

Terms of Reference, Review Procedures, and Meeting Schedule

As delineated in the G-NatlStmt, institutional ECs must ensure that it documents, implements, and publicizes standard operating procedures (SOPs) that promote good ethics review, including:

Meeting frequency, attendance, and conduct
Minutes and agenda preparation
Timely distribution of materials to members before meetings
Timely consideration of applications
Methods of deliberation and decision-making
Processes, if any, for reviewing applications from unaffiliated or international researchers
Disclosure of interests and management of conflicts of interest
Appropriate confidentiality of the content of applications and the deliberations of review bodies
Prompt notification of decisions to researchers
Communicating with researchers, including face to face, by telephone and in writing, (including available forms of electronic communication)
Record keeping
Monitoring of approved research
Reporting and handling of adverse events
Receiving and handling of complaints
Advising the institution(s) of decisions to suspend or withdraw ethics approval of research projects
Attendance of people other than members at meetings

Pursuant to the G-NatlStmt, EC members should be familiar with the G-NatlStmt and other relevant guidelines; prepare for and attend EC meetings or, if unavailable, provide opinions before the meetings; and attend research ethics training programs or continuing education at least every three (3) years. Members should be appointed to an EC using open and transparent processes, and institutions should consider reviewing appointments to the EC at least every three (3) years.

The G-NatlStmt states that as far as possible, each EC meeting should be arranged to enable attendance of all members of the minimum membership categories listed above and other relevant appointed members, either in person or via available technology. Meeting papers should be provided enough in advance to enable members to be fully informed. An EC’s decision about whether a research proposal meets the requirements of the G-NatlStmt must be informed by an exchange of opinions from all members of the EC participating in the meeting. The exchange should, ideally, take place at a meeting with all those members present. Where there is less than full attendance of the minimum membership categories at a meeting, the chairperson must be satisfied, before a decision is reached, that the views of those absent who belong to the minimum membership have been received and considered. The EC should attempt to reach decisions by general agreement or consensus. Voting is neither required nor prohibited. Some decisions may not be unanimous, and a dissent should be recorded in the minutes of the meeting. Where requested by a dissenting member, the reasons for the dissent should also be recorded in the minutes of the meeting.

According to the G-NatlStmt, ECs may invite researchers, and researchers may request, to be present for discussion of their proposed research. In addition, ECs may seek advice from external experts to help in considering a research proposal. Communication between the sponsor and the EC is not prohibited but should be restricted so that it does not inappropriately influence the review of any relevant research proposals.

As delineated in the G-NatlStmt, ECs must maintain a complete record of all research proposals received and reviewed. Approved project documentation and any relevant correspondence must also be retained. Records must be maintained in accordance with the requirements of relevant Commonwealth and state or territory legislation and guidelines. See G-NatlStmt for detailed records requirements.

For more details on the governance and responsibilities of Australian institutional ECs, see the G-NatlStmt.

CTN Scheme and CTA Scheme

The CTN and CTA schemes and Responsibilities under the CTN and CTA schemes

Terms

Purpose, Scope and Limits of this Document, and Section 5 (Chapters 5.1 and 5.2)

Chapter 1 (3) and Chapter 3 (Part 3-2 (18 and 19))

Part 3 (12AA and 12AD) and Schedule 5A

Last content review/update: May 16, 2024

Overview

As set forth in GAfREC, the United Kingdom (UK) has a centralized recognition process for ethics committees (ECs), known as research ethics committees (RECs) in the UK. ECs are part of an accountable and independent Research Ethics Service (RES) (GBR-62).

As described in GBR-51 and GBR-62, the RES has a dual mission to protect the rights, safety, dignity, and well-being of research participants and to facilitate and promote ethical research that is of potential benefit to participants, science, and society. To achieve this, GBR-62 states that the RES works with the devolved administrations to conduct the following activities:

Provide robust, proportionate, and responsive ethical review of research through ECs
Provide ethical guidance to ECs
Provide and deliver a managed structure to support ECs
Deliver a quality assurance (QA) framework
Deliver a training program
Work with colleagues across the UK to maintain a UK-wide framework for ethical review
Work with colleagues in the wider regulatory environment to streamline the processes for approving research
Promote and support transparency in research

As stated in GAfREC, the RES encompasses England’s Department of Health and Social Care (DHSC), Northern Ireland’s Department of Health, the Scottish Government Health and Social Care, Finance, Digital and Governance Directorates, the Welsh Government’s Department of Health and Social Care as well as the ECs that are collectively recognized or established by these authorizing bodies. The UK Health Departments have authorized the head office of the RES in England, within the Health Research Authority (HRA), to perform some UK-wide functions on behalf of the other head offices, including performing some of the functions of the UK Ethics Committee Authority (UKECA), which is the statutory body that recognizes ECs for the review of clinical trials of investigational medicinal products (CTIMPs). (See Oversight of Ethics Committees section for more details on RES and UKECA functions.) In accordance with the MHCTR and the MHCTR2006, ECs recognized to conduct reviews of clinical trials for CTIMPs are authorized by the UKECA.

All recognized RES ECs are required to comply with the provisions delineated in GAfREC, the International Council for Harmonisation’s Guideline for Good Clinical Practice E6(R2) (GBR-113), and GBR-9. However, specific ECs within the RES are recognized, or otherwise designated, to review certain types of research proposals. A list of recognized ECs within the RES is available through GBR-111. Also see GBR-64 for EC definitions.

Ethics Committee Composition

As delineated in the MHCTR and GAfREC, a RES-recognized EC, which includes those recognized by UKECA, may consist of up to 18 members. Collectively, members must encompass the qualifications and experience required to review and evaluate the scientific, medical, and ethical aspects of a proposed clinical trial. The ECs should include a diverse mixture of members in terms of age, disability, gender, race, religion, and sexual orientation. One third of the committee must also be lay members, and half of the lay members must be persons who are not and never have been health care professionals, clinical researchers, or managers of clinical research (also known as lay members). Additionally, GAfREC states that a quorate meeting must be attended by at least seven (7) members and include the chair, at least one (1) expert member, and one (1) lay member. GBR-9 mirrors this requirement, but adds that when investigational products are reviewed, a lay member must be present. See GBR-113 for additional recommendations for composition.

Per GBR-9, in order to accommodate the United States’ (US) quorum definition pursuant to regulations for the protection of human subjects in research (45 CFR 46) and the Common Rule (45 CFR 46 Subpart A), the RES also makes special arrangements to review UK-based research funded by US Federal Government departments and their agencies. In such cases, the quorum is a majority of the EC. See the ClinRegs United States page, Ethics Committee topic for more information on ethics review requirements in the US.

As indicated in GAfREC, committee member appointments are valid for up to five (5) years. Appointments may be renewed; however, members should not normally serve more than two (2) consecutive terms of five (5) years on the same EC, and members may resign at any time. Members must maintain confidentiality regarding all ethical review related matters and refuse any projects in which they have a conflict of interest. See the MHCTR and GAfREC for additional EC composition requirements.

Terms of Reference, Review Procedures, and Meeting Schedule

In addition to complying with composition requirements, GAfREC, GBR-113, and GBR-9 state that an EC must also adopt written standard operating procedures (SOPs). The SOPs should cover the entire review process from application submission to opinion and notification, amendments, and annual reporting.

Per GBR-9, applications that have been submitted via the CTIMP combined review service will be validated by the MHRA, and EC staff do not need to undertake a formal validation check. ECs should check the application against the validation checklist and request any missing information or clarifications from the applicant if required. All validated clinical trial applications for an ethical opinion should be reviewed at a full meeting of an EC. An EC should normally hold at least 10 scheduled full meetings in each year for the purpose of ethical review of applications. Additional meetings may be held where necessary to ensure that an ethical opinion on an application is given within the relevant time limit (or to discuss matters relating to the establishment or operating procedures of the EC or for training purposes). Meetings to review applications should normally be held at intervals of one (1) month unless there are holidays. The schedule of EC meetings for the financial year commencing on April 1^st should be agreed to by December 1^st in the previous financial year. The schedule should set out the dates, times, and venues of meetings, and the closing date for applications for each meeting. All members and deputy members of the EC should receive details of the schedule. The closing dates for full applications should normally be 14 calendar days prior to each EC meeting. In the case of applications for Phase 1 clinical trials in healthy volunteers, Type 1 ECs may adopt a later closing date for applications not less than seven (7) calendar days prior to the meeting and may accept applications booked in advance of the closing date which are submitted up to seven (7) days before the date of the meeting.

According to GBR-9, the EC Chair is responsible for ensuring that the EC reaches clearly agreed to decisions on all matters. If the Chair is unavailable, then the meeting should normally be chaired by the vice-Chair or, if the vice Chair is also unavailable, by the alternate vice-Chair. The EC meeting should reach unanimous decisions by consensus wherever possible. Where a consensus is not achievable, a formal vote should be taken by a counting of hands. The decision of the EC should be determined by a simple majority of those members present and entitled to vote. A record should be kept of the number of votes, including abstentions, in the minutes. Where the vote is tied, the Chair may give a casting vote, but should first consider any other options to arrive at a more consensual decision. Where any member wishes to record a formal dissent from the decision of the committee, this should be recorded in the minutes but should not be included in the opinion letter. An agenda should be prepared for an EC meeting and EC staff must prepare minutes of the EC meetings. See GBR-9 for additional requirements on the agenda, meeting conduct/decisions, and minutes during full EC meetings.

As per GBR-9, documents for EC meetings should be distributed as soon as possible after the agenda is finalized and applications have been validated, and in any case no later than 10 calendar days prior to the meeting (with the exception of expedited, proportionate review, and Phase 1 applications where there has been prior agreement). Under no circumstances should full applications be tabled at the meeting. Applications should be made available to members via the HRA Assessment and Review Portal (HARP) as soon as the application is validated, and an email sent to the EC members to inform them the application is now viewable.

GBR-9 requires ECs to retain all the documentation relating to a CTIMP on which it gives an opinion:

Where the trial proceeds, for at least three (3) years from the conclusion or early termination of the trial
Where the trial does not proceed (e.g., it is given an unfavorable opinion, or does not start following a favorable opinion), for at least three (3) years from the date of the opinion

In accordance with GBR-9, documentation should be retained on all invalid applications for at least one (1) year from the date of invalidation; and for three (3) years where the application is withdrawn by the EC, the chief investigator, or the sponsor after the EC review but before a final opinion is given. Signed final copies of the minutes of full EC meetings and sub-committee business should be retained electronically for at least 20 years. Where paper records are destroyed in accordance with this policy, they should be shredded and disposed of as confidential waste. Electronic records of studies will be retained indefinitely.

For detailed EC procedures and information on other administrative processes, see GAfREC, GBR-113, and GBR-9.

Introduction (Purpose and Scope, and Implementation), Terminology (Glossary), and Sections 1, 2, 3, and 15

Foreword, Introduction, 1.24, 1.27, 2.6, 3, and 5.11

Search Research Ethics Committee

Definitions of Authorised REC and Recognized REC

1-6, Glossary, Annex C, Annex E, and Annex F

Amendment of Regulation 12 of the Principal Regulations; and Part 2 (Conditions Based on Article 3 of the Directive)

Part 2, Part 3 (11, 12, 14, 15, 17, and 18), and Schedule 2

Scope of Review

Last content review/update: May 2, 2024

Overview

According to the G-NatlStmt, the institutional ethics committee (EC) (Human Research Ethics Committee (HREC) in Australia) is responsible for protecting the interests of research participants and for promoting good research by ensuring adherence to the values of research merit and integrity, beneficence, justice, and respect for persons throughout the conduct of the research project. The EC must review the recruitment and consent processes, weigh the benefits and risks of the research, and consider the impact of the research on certain groups of participants deemed to merit special consideration. Additionally, ECs may conduct both scientific and ethics review or may delegate scientific review to a sub-committee.

Pursuant to the G-NatlStmt, the establishment and maintenance of ethics review processes and processes for assessing the risk level of the research are part of an institution’s overall governance responsibility. In addition to ethics approval, research must also be authorized by each institution with responsibility for oversight of the research before it can proceed. See the Oversight of Ethics Committees, Submission Process, Submission Content, Timeline of Review, and Initiation, Agreements & Registration sections for more information on research governance requirements.

Role in Clinical Trial Approval Process

According to the G-CTHandbook, the G-TrialsSOP, and AUS-47, ECs are responsible for reviewing and approving protocols involving unapproved therapeutic goods under one (1) of two (2) regulatory schemes—the Clinical Trial Notification (CTN) scheme or the Clinical Trial Approval (CTA) scheme—prior to the sponsor initiating a trial. According to AUS-40, all public and private health organizations must also undertake a site-specific assessment (SSA) of each research project. This allows the institution to consider whether the project is suitable for the site, and whether it has the capacity to conduct the research at that site. Per the G-TrialsSOP, the SSA and ethics review may occur in parallel. However, EC approval must be obtained and submitted to the research governance officer (RGO) of each participating institution before institutional authorization is granted.

The G-CTHandbook states that a CTN scheme is a notification scheme under which the Therapeutic Goods Administration (TGA) does not review or evaluate any data relating to the clinical trial. The EC is responsible for assessing the scientific validity of the trial design, the balance of risk versus harm of the therapeutic good(s), and the overall ethical acceptability of the trial. Per AUS-47, EC and institutional review and approval/authorization may be conducted in parallel to the CTN form submission to the TGA; however, it is the sponsor’s responsibility to ensure that all relevant approvals and authorizations are in place before commencement of the trial.

Under the CTA scheme, as delineated in the G-CTHandbook, the TGA reviews relevant, but limited, scientific data, while the EC is responsible for considering the scientific and ethical issues of the proposed trial protocol.

Per the G-CTHandbook, the sponsor determines whether to conduct a clinical trial under the CTN or CTA scheme. Consulting the EC responsible for protocol approval may assist the sponsor in making the decision. One of the determining factors for an EC is whether the committee has access to appropriate scientific and technical expertise in order to assess the safety of the product. If an EC feels that it requires additional expertise to review a CTN, it may seek advice from external authorities or it may seek to collaborate with another EC that has the required expertise. An EC may also determine that it does not have access to the appropriate scientific and technical expertise to review the proposed trial under the CTN scheme and recommend review under the CTA scheme.

AUS-14 states that prior to approving a clinical trial, the EC must be satisfied that the trial protocol complies with the following requirements:

G-NatlStmt
Declaration of Helsinki (AUS-52)
AU-ICH-GCPs
TGA requirements, including the G-CTHandbook and the G-SafetyDataMgt
Any relevant Australian Government and/or state/territory laws

The G-CTHandbook and the TGR state that during its review, the EC also needs to be aware of relevant state and territory laws pertaining to the supply of therapeutic goods or other clinical trial-related matters. The G-CTHandbook further indicates that ECs have a high level of independence and are responsible for establishing their own processes for reviewing research proposals. According to the G-CTHandbook and the AU-ICH-GCPs, if requirements specified in the G-NatlStmt appear to differ from those specified in the AU-ICH-GCPs, the TGA recommends compliance with the G-NatlStmt.

As stated in AUS-20, ECs also consider the protection of privacy for humans participating in research and their data. ECs do this by considering whether the research proposal conforms to relevant legislation, principles, and guidelines, including federal and/or state/territory legislation as well as the G-PrivacyAct95 and G-PrivacyAct95A guidelines. See the Personal Data Protection section for more information.

Per the G-NatlStmt, an EC may approve, request modification of, reject, or withdraw approval of a research proposal. The EC must clearly communicate its decision to the researcher(s):

Where a proposal is approved or rejected, or where approval is withdrawn, communication must be in writing (which may include electronic formats) and should include an explicit statement that the proposal meets or did not meet the requirements of the G-NatlStmt. If rejecting or withdrawing approval of a research proposal, the EC should provide the rationale for its decision, including citing the provisions of the G-NatlStmt or relevant institutional policy that underpins its decision, if relevant.
Where modifications are requested, communication may be written or, where appropriate, informal; however, a record should be kept of any informal communication, and guidance should be clearly communicated regarding to whom the researcher’s response should be directed .

According to the G-NatlStmt, varying processes may be used for the review and approval of project extensions, amendments to an approved project, progress reports, and renewal of project approval. Appropriate processes depend on the nature of the original project and any proposed changes, but any process authorized by an institution for these purposes must prioritize the safety and well-being of participants, researchers, and/or the community.

Pursuant to the G-CTHandbook and the TGR, when the EC approves a trial protocol, it takes responsibility for monitoring the progress and conduct of the trial. However, the G-NatlStmt indicates that each institution has ultimate responsibility for ensuring, via its research governance arrangements, that all its authorized research is monitored. Monitoring arrangements should be commensurate with the risk, size, and complexity of the research. Monitoring responsibilities that are performed by the institution’s EC should be based on the EC’s review of the project. However, where research that will take place at multiple sites has been reviewed by only one (1) EC, the ECs of the other institutions participating in the project do not have knowledge of the project. In such cases, only the reviewing EC can take on those elements of monitoring a research project that are commonly performed by ECs.

Per the G-NatlStmt, if the EC or institution has reason to believe that continuance of a research project would compromise participants' welfare, or if the conditions of ethics approval for the project are not being adhered to, it should immediately seek to establish whether ethical approval for the project should be suspended or withdrawn. If an institution or EC considers that suspension of research is necessary, the instruction to stop should come from the management of the institution. If ethics approval for a research project is suspended, the researcher, the institution(s), and, where possible, the participants should be informed of the suspension.

As indicated in the G-NatlStmt, ECs may require researchers to amend research procedures to protect participants. If an EC determines that such changes cannot achieve that end, the EC may decline to grant an extension to project approval or decide to withdraw approval for the research. Where ethics approval for a research project is withdrawn:

The researcher, the institution(s), and, where possible, the participants should be informed of the withdrawal
Continuation of the research project is subject to re-application and re-approval by the EC

See the G-NatlStmt for more details on institutional and EC responsibilities regarding research monitoring.

External Ethics Approval and the National Mutual Acceptance Scheme

The G-NatlStmt encourages the minimization of unnecessary duplication of ethics review, including for research conducted in multiple Australian jurisdictions or across international boundaries. Institutions may accept an ethics review conducted by an entity external to the institution (including overseas review bodies) and should determine their criteria for this acceptance.

Per the G-NatlStmt, researchers who wish to submit evidence of ethics approval by an external EC in support of single ethics review should be aware of existing national or international programs, protocols, policies, standards, and guidance that may be relevant to the institutional decision to accept the review. To facilitate the efficient ethics review of research, researchers must inform any EC of:

All sites at which the research will be conducted
Any information on local site circumstances that is relevant to the ethics review
Any other body that will be considering ethical issues related to the research
Any previous decisions to approve, re-consider, or deny approval of the research by another review body in Australia or elsewhere

See the G-NatlStmt for more information on external ethics approval.

As described in AUS-21 and AUS-41, the National Mutual Acceptance (NMA) scheme further supports the acceptance of a single scientific and ethical review of multicenter research conducted in publicly funded health services. All state and territory-certified public health organizations in Australia are part of the NMA scheme.

Per AUS-68, in order for ethics reviews of human research to be accepted under NMA, the EC conducting the review must be certified under the National Health and Medical Research Council (NHMRC) National Certification Scheme of Institutional Processes Related to the Ethical Review of Multi-centre Research (National Certification Scheme), and also be a “Certified Reviewing HREC” under the NMA scheme.

For more information on submissions to ECs under the NMA scheme and the National Certification Scheme, see the Submission Process and Oversight of Ethics Committees sections.

Exemption from Ethics Review

As stated in the G-NatlStmt, some research may be eligible for exemption from ethics review. Where appropriate, exemption is granted, or not, by the institution responsible for the research. Where there is no institution providing oversight of the research, researchers should request a grant of exemption from an EC. Research that may be eligible for exemption from ethics review includes research that carries a lower risk to participants or the community, and satisfies one (1) or more of the following conditions:

The research involves the use of collections of information or data from which all personal identifiers have been removed prior to being received by the researchers, and where researchers explicitly agree: (i) not to attempt to re-identify those with whom the information or data is associated; (ii) to take all reasonable steps to prevent re-identification of the information or data for unauthorized purposes or access to the information or data by those who are not authorized; and (iii) that any sharing of any research data during or after the project will not create any additional risks of re-identification of the information or data
The research is restricted to surveys and observation of public behavior using information that was or will be collected and recorded without personal identifiers and is highly unlikely to cause distress to anyone associated with the information or the outcomes of the research
Is conducted as part of an educational training program in which the research activity is for training purposes only and where any outcomes or documentation are for program use only
The research uses only information that is publicly available through a mechanism set out by legislation or regulation and that is protected by law, such as mandatory reporting information, information obtained from registries of births and deaths, coroner’s investigations, or reports of the Australian Bureau of Statistics

The G-NatlStmt indicates that institutions or other granting bodies must keep a record of any decision to grant exemption from ethics review. See the G-NatlStmt for more information on ethics review exemption.

CTN Scheme, CTA Scheme, and FAQs

State and territory ethics review processes

Health Privacy

Clinical trials involving therapeutic goods, The CTN and CTA schemes, and Responsibilities under the CTN and CTA schemes (Role of Human Research Ethics Committees (HRECs))

3

Terms and SOP 05

Purpose, Scope and Limits of this Document, and Sections 1 (Introduction and Guidelines), 2, 3 (Introduction), 4, and 5 (Chapters 5.1-5.2 and 5.4-5.5)

Part 3 (12 and 12AA-12AD) and Schedule 5A

Last content review/update: May 16, 2024

Overview

According to GAfREC, the International Council for Harmonisation’s Guideline for Good Clinical Practice E6(R2) (GBR-113), and GBR-9, the primary scope of information assessed by ethics committees (ECs) within the United Kingdom (UK) Health Departments’ Research Ethics Service (RES) (GBR-62) relates to maintaining and protecting the dignity and rights of research participants and ensuring their safety throughout their participation in a clinical trial. (Note: ECs are known as research ethics committees (RECs) in the UK). GAfREC specifies that ethical review is required for research proposals that involve investigational products (IPs), material consisting of human cells, and other situations that are described in GAfREC.

As per GAfREC, the MHCTR, the MHCTR2006, the MHCTR2006-No2, and GBR-113, ECs must pay special attention to reviewing informed consent and to protecting the welfare of certain classes of participants deemed to be vulnerable. (See the Vulnerable Populations; Children/Minors; Pregnant Women, Fetuses & Neonates; Prisoners; and Mentally Impaired sections for additional information about these populations).

As indicated in GAfREC, the MHCTR, the MHCTR2006, GBR-113, and GBR-9, ECs are responsible for ensuring an independent, timely, and competent review of all ethical aspects of the clinical trial protocol. They must act in the interests of the potential research participants and the communities involved by evaluating the possible risks and expected benefits to participants; confirming the suitability of the investigator(s), facilities, and methods; and verifying the adequacy of confidentiality and privacy safeguards. See GAfREC, the MHCTR, the MHCTR2006, and GBR-9 for detailed ethics review guidelines.

GBR-112 indicates that certain ECs are flagged for special expertise including gene therapy or stem cell clinical trials; Phase 1 studies in healthy volunteers; Phase 1 studies in participants; research involving adults lacking capacity; research involving children; research involving prisoners or prisons; or fast-track ECs.

Role in Clinical Trial Approval Process

As described in GBR-9, GBR-66, and GBR-95, the type of EC responsible for approval (known as a “favorable opinion” in the UK) within the RES depends on the type of research being conducted. Per GAfREC and GBR-9, ECs are recognized or established by the United Kingdom Ethics Committee Authority (UKECA) to conduct reviews of clinical trials for IPs (known as clinical trials for investigational medicinal products (CTIMPs) in the UK). Per GAfREC, RES-recognized ECs established under Health Department policy within each of the four (4) UK nations (England, Northern Ireland, Scotland, and Wales) review research studies other than IP clinical trials. Also see GBR-64 for definitions of EC terminology and GBR-111 and GBR-112 to search for ECs within the RES.

As indicated in the MHCTR, the MHCTR2006, and GAfREC, IP applications require the favorable opinion of a UKECA-recognized EC, and approval by the Medicines and Healthcare Products Regulatory Agency (MHRA) prior to the sponsor or the designated legal representative initiating the trial. The G-CTApp states that all new clinical trial applications must be prepared, submitted, and reviewed via the combined review process, wherein a single application route and coordinated review by MHRA and the EC leads to a single UK decision. New clinical trial applications for combined review are prepared and electronically submitted to the new combined review section of Integrated Research Application System (IRAS) (GBR-125). Per GBR-78, IRAS does not change the requirements for review, including authorizations or signatures, of any regulatory authority or National Health Service (NHS) body. Therefore, it requires different authorizations depending on the type of study and the applicable review bodies. According to GBR-9, submissions of the electronic application must be made to IRAS on the same day that a booking is made to schedule an EC review through the NHS REC’s Online Booking Service (GBR-95).

According to the MHCTR, GAfREC, and GBR-9, for all studies, only one (1) EC review (referred to as the “main EC”) is needed for a project taking place in the UK, regardless of the number of sites. Furthermore, GBR-9 states that the Chief Investigator (CI) should be based in the UK and that the REC may agree exceptionally to an application being submitted by a CI based outside the UK, but should consider as part of the ethical review whether adequate arrangements are in place for supervision of the study in the UK. The ethical review includes an assessment of the suitability of each site or sites at which the research is to be conducted in the UK. The site assessment is not a separate ethical review, but forms part of the single ethical review of the research. Management permission is still required from the organization responsible for hosting the research before it commences at any site. In the case of international studies, an application must be made to an EC in the UK, whether or not the study has a favorable ethical opinion from a committee outside the UK, and whether or not it has started outside the UK.

Per GBR-68, unless an application is being processed under the proportionate review service, the applicant should attend the EC meeting if possible. The EC will notify the sponsor of its decision, usually within 10 working days of the EC meeting. GBR-9 indicates that the EC should reach one (1) of the following decisions on any application reviewed at a full meeting or a proportionate review sub-committee meeting:

A final opinion, which may be either favorable with standard conditions, favorable with additional conditions, or unfavorable
Provisional opinion with request for further information, which means the EC may decide that a final opinion cannot be issued until further information or clarification has been received from the applicant

The MHCTR, GBR-9, and GBR-68 state that the EC must give its opinion within 60 calendar days of receipt of a valid application. When an EC requires further information before confirming its opinion, it may give a provisional opinion and may make one (1) written request for further information, clarification, or changes to documentation. The time required for the EC to receive a complete response to its request does not count against the 60-day timeline. Certain studies, including gene therapy studies, will take 90 days, or 180 days if a specialist group or committee is consulted. For other exceptions, see GAfREC and the MHCTR. (See the Submission Process and Timeline of Review sections for detailed submission process requirements.)

Per GBR-116, the Health Research Authority (HRA), on behalf of the UK, offers a fast-track research ethics review. Fast-track ethics review is open to global clinical trials and Phase 1 trials, whether the sponsor is commercial or non-commercial. This includes:

Any CTIMP led from the UK with at least one (1) other country participating
Any CTIMP led from outside the UK which could be placed in any country and the UK is competing for participation (including any only taking place in the UK)
Any Phase 1 or Phase 1/2 CTIMP in healthy volunteers or participants

Fast-track ethics review is not available for any CTIMP involving a gene therapy medicinal product, any CTIMP funded by the US Department of Health and Human Services, and any other type of clinical trial or research study.

Per GBR-9, the EC’s favorable ethical opinion applies for the stated duration of the study, except where action is taken to suspend or terminate the opinion. The MHCTR, GAfREC, and IRAS (GBR-78) require the applicant to identify an expected end date for the study. A change to the definition of the end of the study is a substantial amendment. Extension of the study beyond the period specified in the application form is a non-substantial amendment.

GBR-9 describes EC processes related to reviewing and approving clinical trial amendments and any related notifications. The sponsor of a CTIMP may make an amendment to a clinical trial authorization, other than a substantial amendment, at any time after the trial has started. These do not need to be notified. If the amendment is substantial, the sponsor is required to submit a valid amendment to the MHRA and/or the REC that gave the favorable opinion of the trial. Where the sponsor requests an ethical opinion on a CTIMP, the EC should provide this in all cases within 35 calendar days of receiving a valid amendment. If the opinion is unfavorable, the sponsor may then modify the proposed amendment. A written notice of the modification should be sent to the main EC at least 14 calendar days before it is due to be implemented. The EC may then give an unfavorable opinion on the modified amendment within 14 calendar days, otherwise it may be implemented. See GBR-9 and GBR-98 for guidance on what changes qualify as a substantial amendment, which requires notification to the EC and MHRA. GBR-9 states that while the EC is not responsible for proactive monitoring, it has a duty to keep the favorable ethical opinion under review in the light of progress reports and significant developments and may review the opinion at any time. If information raises concerns about the suitability of the site or investigator, the favorable opinion may be reviewed.

Introduction (Purpose and Scope), Terminology (Glossary), and Sections 1, 3, 5, 6, and 10.9

Foreword, 1.27, 2, and 3

Search Research Ethics Committee

2.3, 3, 4.3, and 5.4

Combined review of clinical trials of investigational medicinal products

Amendment of the Clinical Trials Regulations; Amendment of the Adults with Incapacity (Scotland) Act 2000

Amendment of Regulation 12 of the Principal Regulations; and Part 2 (Conditions Based on Article 3 of the Directive)

Part 1 (2 and 3), Part 3 (11, 12, 14, 15, 17, and 18), Schedule 2, and Schedule 3 (Part 1)

Ethics Committee Fees

Last content review/update: May 2, 2024

The G-NatlStmt indicates that when establishing an ethics committee (EC) (Human Research Ethics Committee (HREC) in Australia), an institution must set out and publicize its terms of reference, including its schedule of fees charged, if any, for ethics review. The institution is responsible for ensuring that its EC operates in accordance with the G-NatlStmt, which includes being satisfied that any fees charged for EC review do not discourage research that the institution has an obligation to support.

Section 5 (Chapter 5.1)

Last content review/update: May 16, 2024

As set forth in GAfREC, ethics committees (ECs) are not permitted to charge an application fee or seek any other financial contribution or donation for reviewing research proposals. Additionally, EC members receive no payment for contributing to the application review process at scheduled meetings or for attending these meetings.

4.3

Oversight of Ethics Committees

Last content review/update: May 2, 2024

Overview

As per the TGAct, the G-TrialsSOP, and the G-CTHandbook, the National Health and Medical Research Council (NHMRC) is responsible for receiving applications from ethics committees (ECs) (Human Research Ethics Committees (HRECs) in Australia) to be registered. The NHMRC was established by the NHMRCAct. Per the NHMRCAct, the NHMRC’s activities are designed to raise the standard of individual and public health throughout Australia; to foster the development of consistent health standards between the various states and territories; to foster medical and public health research and training throughout Australia; and to foster consideration of ethical issues relating to health.

Research Governance

Pursuant to the G-NatlStmt, institutions may fulfill their research governance responsibilities by establishing and overseeing different levels of ethics review. One (1) or more institutions can individually or jointly establish an EC or any other ethics review body. Institutions that establish an EC are responsible for adequately resourcing and maintaining it, including providing sufficient administrative support.

According to the G-NatlStmt, institutions should ensure that all ethics review processes and the criteria that are used for determining the appropriate process are clear, transparent, and published to enable researchers to submit their research proposals efficiently.

The G-NatlStmt further states that institutions should clearly publicize their policy for access to their EC or other ethics review processes by researchers who are not affiliated with the institution. Additionally, institutions should regularly assess all their ethics review processes, including the criteria for allocating research to different levels of review, to ensure that those processes continue to enable the institution to meet its responsibilities under the G-NatlStmt. Where possible this assessment should be informed by the documented experience of research participants and/or by involving participants or the wider community in the assessment.

Furthermore, as delineated in the G-NatlStmt, institutions should have in place an auditing process to confirm that research is being reviewed at the levels of review that their criteria require and research is being exempted from review only in accordance with the criteria set out in the G-NatlStmt. See the Scope of Review section for more information on exemption criteria.

Registration, Auditing, and Accreditation

According to the G-NatlStmt, institutions that have responsibility for oversight of research and maintain ECs must register their ECs with the NHMRC. ECs that are not associated with institutions must register themselves with the NHMRC.

Per AUS-20, registration means that the EC has notified the NHMRC of its existence and declared that it meets the requirements of the G-NatlStmt. In order to review and monitor clinical trials of unregistered therapeutic goods, an EC must be notified to the NHMRC, and constituted and operating in accordance with the G-NatlStmt. Forms for registering an EC, notifying the NHMRC of changes to the EC, or terminating an EC’s registration are available at AUS-20.

As per the G-NatlStmt, an institution and its EC must report annually, or upon request, to the NHMRC. The NHMRC, through the Australian Health Ethics Committee (AHEC), will review the activities of ECs to ensure conformance with the G-NatlStmt. Reportable information may include:

Membership/membership changes
Number of meetings
Confirmation of participation in meetings by members in minimum membership categories
The number of research proposals presented, the number approved, the number requiring modification prior to approval, and the number rejected
Monitoring procedures that are in place and any problems encountered with monitoring of projects
Complaints procedures and number of complaints handled
Any other relevant policies, procedures, or processes as determined by the NHMRC

The G-NatlStmt further indicates that failure to comply with the requirements of the G-NatlStmt may result in the EC being removed from the list of ECs registered with NHMRC. See AUS-20 for more information and the list of registered ECs.

National Certification Scheme

According to AUS-21, the NHMRC developed the National Certification Scheme of Institutional Processes Related to the Ethical Review of Multi-centre Research (National Certification Scheme) to enable the single ethics and scientific review of human research occurring at multiple institutions in Australia. Under this scheme, certified institutions can have their ethics review accepted by other institutions participating in the research project. As part of the National Certification Scheme, certified institutions and their ECs are required to report to the NHMRC on their multicenter research activities.

As per AUS-21, the NHMRC assesses each institution’s interest in certification on a case-by-case basis. Certification respects institutional decisions about research governance matters, including whether research should be conducted at a given site. Before commencing steps to apply for certification, institutions should contact HREC.admin@nhmrc.gov.au.

For more information on the National Certification Scheme and the NHMRC’s continuous certification process, see AUS-21.

As stated in AUS-68, EC certification under the National Certification Scheme is required in order for ethics reviews of human research to be accepted under the National Mutual Acceptance (NMA) scheme. The NMA scheme facilitates single scientific and ethical review of clinical trials conducted in participating jurisdiction’s public health organizations. See the Scope of Review section for more information on NMA.

Role of Human Research Ethics Committees (HRECs)

Terms

Section 5 (Introduction and Chapters 5.1 and 5.8)

Part 1 (3) and Part 2 (5B, 5C)

Chapter 1 (3)

Last content review/update: May 16, 2024

Overview

As stated in GAfREC and GBR-9, the United Kingdom (UK)-wide Research Ethics Service (RES) (GBR-62) provides proportionate and responsive ethical review of research through its “recognized” ethics committees (ECs), known as research ethics committees (RECs) in the UK. Per the MHCTR, the MHCTR2006, and GAfREC, the UK Ethics Committee Authority (UKECA) is the statutory body that recognizes ECs for the review of clinical trials of investigational products (CTIMPs). The UK Health Departments have authorized England’s Health Research Authority (HRA) to perform some of the RES functions (more details below).

As indicated in the MHCTR and GBR-9, the UKECA recognizes two (2) types of ECs for new CTIMPs:

Type 1: Reviews Phase 1 clinical trials of investigational products (IPs) taking place at any site in the UK, where the sponsor has no knowledge of any evidence that the product has effects likely to be beneficial to the participants of the trial, and the participants are healthy and not suffering from the disease or condition to which the trial relates.
Type 3: Reviews clinical trials of IPs taking place at any site in the UK, including first-in-person studies involving people with the target disease or condition to which the trial relates.

As stated in GAfREC, the HRA performs the following EC oversight activities on behalf of the UKECA:

Develops and manages a national training program for ECs
Develops, implements, and maintains standard operating procedures (SOPs) for ECs and provides advice and support to ECs on procedural issues
Develops a quality assurance program, including accreditation of ECs, based on regular monitoring and audit of their operation and performance
Provides guidance and advice to assist ECs in their work and encourage consistency of approach to common issues in research ethics
Acts for UKECA to provide a national mechanism for operational advice and assistance to ECs recognized to review and approve clinical trials
Acts for UKECA to handle appeals against the unfavorable opinions of ECs in respect of CTIMPs
Acts for UKECA to transfer to a successor EC the functions of an EC that has ceased to operate or that has been varied, abolished, or had its recognition revoked
Acts for UKECA to reallocate to ECs applications made to the Gene Therapy Advisory Committee which do not require its review

Further, per GAfREC, the following oversight functions are the responsibility of UKECA for the purposes of clinical trials:

Establishes or recognizes ECs
Establishes or recognizes ECs to act in relation to such descriptions or classes of research as it considers appropriate
Abolishes or revokes the recognition of ECs that it has established or recognized
Monitors the extent to which ECs adequately perform their functions, including through annual reports from ECs it has recognized
Approves standing orders and SOPs for EC business and operations, as well as variations and revocations to these orders and procedures

Registration, Auditing, and Accreditation

Per GAfREC, HRA, acting for UKECA, develops a quality assurance program to encourage a consistently high level of service to applicants, including accreditation of ECs, based on regular monitoring and audit of their operation and performance.

GBR-123 indicates that HRA implements a rolling accreditation program to audit UK ECs against standards as detailed in GAfREC and GBR-9. ECs are issued with an audit decision: full accreditation, accreditation with conditions (low-risk non-compliance identified requiring an action plan), or provisional accreditation (high- and low-risk issues requiring an action plan). Published bi-annually, HRA’s latest accreditation report is at GBR-124. In addition, quality control checks are undertaken, and results are shared with management teams. For example, operational managers observe EC meetings and provide a check against agreed-upon standards relating to meeting conduct and minute taking. Findings from the meeting observations are shared with the EC chair and staff and collated to identify common themes to inform improvements. For more information about quality assurance, contact quality.assurance@hra.nhs.uk.

Introduction (Purpose and Scope), Implementation, Terminology (Glossary), and Sections 1, 2, and 3

Accreditation Scheme for Research Ethics Committees and Quality Control

1.3, 2.1, 2.3, 3.3, 5.4, Glossary, Annex C, Annex D, Annex E, and Annex F

Part 2 (Conditions Based on Article 3 of the Directive)

Part 2, Part 3 (12), and Schedule 2

Submission Process

Last content review/update: May 2, 2024

Overview

In accordance with the G-CTHandbook, the G-TrialsSOP, and AUS-47, Australia requires the sponsor to obtain clinical trial authorization from the Therapeutic Goods Administration (TGA) for the supply of unapproved therapeutic goods for clinical trials for experimental purposes in humans. The sponsor can apply under two (2) regulatory schemes—the Clinical Trial Notification (CTN) scheme and the Clinical Trial Approval (CTA) scheme.

Under either regulatory scheme, per the TGR, the G-CTHandbook, the G-TrialsSOP, and AUS-47, an ethics committee (EC) (Human Research Ethics Committee (HREC) in Australia) must approve the research protocol. The G-NatlStmt further specifies that any research that involves greater than low risk must be reviewed by an EC. AUS-47 indicates that the review and approval/authorization by an EC and institution may be conducted in parallel to the CTN form submission to the TGA, but it is the sponsor’s responsibility to ensure that all relevant approvals and authorizations are in place before commencement of the trial.

According to AUS-40, all public and private health organizations must also undertake a site-specific assessment (SSA) of each research project. This allows the institution to consider whether the project is suitable for the site, and whether it has the capacity to conduct the research at that site. Per the G-TrialsSOP, the SSA and ethics review may occur in parallel. However, EC approval must be obtained and submitted to the research governance officer (RGO) of each participating institution before institutional authorization is granted. While there is no submission language requirement stated in the requirements, the official language of Australia is English.

Regulatory Submission

Per AUS-17, sponsors may request pre-submission meetings with the TGA. See AUS-17 for the applicable forms.

CTN Scheme

According to AUS-47 and AUS-30, CTN forms are submitted online through the TGA Business Services (TBS) webpage (AUS-36). The sponsor must have or obtain a TGA Client Identification Number.

As per AUS-49, to submit the online CTN form successfully through AUS-36, the sponsor must accept a declaration to assume responsibility for the trial. After accepting the declaration, a webpage will advise the sponsor that the CTN submission has been successful. According to AUS-47, the TGA does not send an acknowledgement letter by email since this information is available for viewing and printing via the online portal. The TGA advises clinical trial sponsors to obtain and save a printout of notification at each stage of the submission process.

AUS-49 indicates that the sponsor may delegate duties and correspondence with the TGA to an authorized agent, which is able to create and submit a CTN on behalf of a sponsor. If an agent has submitted a CTN on the sponsor’s behalf, the sponsor will not have access to view or vary the CTN. Access is only granted to the agent.

See AUS-30 and AUS-49 for additional information on using and submitting the online form.

CTA Scheme

According to AUS-47, the sponsor must complete and submit two (2) forms (AUS-56 and AUS-57) to the TGA via email at clinical.trials@health.gov.au. Supporting data for the CTA application should be provided in electronic format, preferably on USB or CD-ROM via post. The trial commencement notification form (AUS-57) must be sent to the TGA within 28 days of commencing supply of the unapproved therapeutic goods.

Per AUS-47, those with queries regarding the CTA scheme are encouraged to contact the TGA directly at clinical.trials@health.gov.au.

Ethics Review Submission

AUS-46 indicates that the National Health and Medical Research Council (NHMRC) developed the Human Research Ethics Application (HREA) form (AUS-9) as a concise application to facilitate timely and efficient ethics review for research involving humans. The HREA assists researchers in considering the ethical principles of the G-NatlStmt in relation to their research and is accepted by institutions that participate in the National Mutual Acceptance (NMA) scheme, which facilitates single ethics review by multiple public health organizations for most human research.

According to the G-CTHandbook, trial sponsors and researchers should use the HREA unless advised otherwise. AUS-19 contains resources for using the HREA.

Per AUS-46, research proposals should be submitted to ECs associated with public health institutions in New South Wales, Queensland, South Australia, Australian Capital Territory, and Victoria, as well as Mater Research, via the Research GEMS system (AUS-55), the Ethical Review Manager (ERM) website (AUS-8), and/or the Research Ethics and Governance Information System (REGIS) (AUS-10), depending on which jurisdictions are involved. For research in the Northern Territory, Tasmania, or Western Australia, the EC should be contacted for their local submission requirements.

The G-CTHandbook further states that ECs have a high level of independence and are responsible for establishing their own processes for receiving research proposals.

Research Governance

According to the G-NatlStmt, institutions should publish (such as on their website) clear policies and procedures for institutional authorization of research. As noted in the G-CTHandbook, individual jurisdictions have specific requirements as a part of their SSA and authorization processes. South Australia sites use the online SSA form found in the Research GEMS system (AUS-55), while the ERM website (AUS-8) is used for SSA form submission for Mater Research, Queensland, and Victoria. New South Wales and the Australian Capital Territory use REGIS (AUS-10) for site governance applications.

Authorised Agent and Manual Submission

CTN Scheme, CTA Scheme, Clinical Trials Guidance, and FAQs

About this Handbook, Clinical Trials Involving Therapeutic Goods (Determine if the product is ‘unapproved’), The Australian Regulatory Environment, The CTN and CTA schemes, and Responsibilities under the CTN and CTA schemes (Role of Human Research Ethics Committees (HRECs))

Terms and SOP 05

Purpose, Scope and Limits of this Document, and Section 5 (Chapter 5.5)

Part 3 (12 and 12AA-12AD) and Schedule 5A

Last content review/update: May 16, 2024

Overview

In accordance with the MHCTR, the MHCTR2006, the G-CTApp, and GBR-9, the United Kingdom (UK) requires the sponsor or the designated legal representative to obtain clinical trial authorization from the Medicines and Healthcare Products Regulatory Agency (MHRA) prior to initiating the trial. Per G-CTApp and G-IRASCombRev, the UK’s combined review process offers a single application route and coordinated/parallel review from MHRA and the ethics committee (EC) leading to a single UK decision for clinical trials.

Note: G-CTApprovedCountries and the MHCTR-EUExit list the countries where a clinical trial sponsor or their legal representative may be established; these countries are initially European Union (EU) and European Economic Area (EEA) countries.

Combined Review Submission

Per G-CTApp and G-IRASCombRev, all new clinical trials applications of investigational products (CTIMPs) must be prepared, submitted, and reviewed via the combined review process using the Integrated Research Application System (IRAS) (GBR-125). For support and getting started, users should review GBR-72 and contact the combined review team at cwow@hra.nhs.uk. Step-by-step instructions are provided in G-IRASCombRev. As delineated in GBR-9, applications submitted via the combined review service are submitted jointly by the chief investigator and the sponsor. Per GBR-116, applicants seeking fast-track review of clinical trial applications must also apply via combined review on GBR-125. Per the G-CTApp, MHRA’s notification scheme enables a more streamlined and risk-proportionate approach to processing clinical trial authorization for “initial” applications. The scheme only applies to clinical trial applications for Phase 4 and certain Phase 3 clinical trials deemed to be of lower risk. Interest in the notification scheme should be registered via the combined review process (GBR-125). Per G-ATMP, all advanced therapy medicinal products must submit clinical trial applications using the same processes as all other medicines. See Scope of Review section for fast-track eligibility criteria.

Per GBR-122, for studies that were submitted before combined review, these applicants should continue to submit amendments and reports for these studies at IRAS via GBR-78’s log-in. HRA will update sponsors and applicants with full instructions and plenty of notice for any planned changes in the future, such as the migration of existing, ongoing studies. See GBR-122, for additional details on the migration of existing materials in IRAS. GBR-72 includes learning resources and a video on the combined review process.

G-IRASCombRev contains a step-by-step guide to combined review submission. The following is an overview of the steps:

Finalize protocol and supporting documents
New users create IRAS account and create a new project and allocate roles
Complete project details, study information, and clinical trial dataset in IRAS and upload supporting documentation
Send application to the sponsor to review and authorize
Book an EC online and submit application

G-IRASCombRev indicates that when selecting an EC meeting that is not the first available meeting, the 60-day regulatory clock for both the EC and the MHRA will start on the cutoff date for the meeting that is chosen, which is 14 days before the meeting date. Once booked, the EC booking page will update to show the confirmed booking details. The applicant will then be able to scroll down the page to select the option to “submit to the regulators.” See G-IRASCombRev for detailed step-by-step instructions.

For overall help during the submission process, see the CTapp-Issues which identifies common issues with validation and assessment of clinical trial applications and how to avoid them.

Other regulatory information aside from new clinical trial applications are to be submitted pursuant to the G-MHRASubmiss. These submittals include substantial amendments for existing clinical trials, end-of-trial notifications, and developmental safety update reports (DSURs). The G-CTAuth-GBR also states that clinical trials not approved or yet transitioned over to the combined review process should continue to use the online MHRA Submissions portal (GBR-13). The steps for gaining access to GBR-13 are contained in the G-MHRASubmiss and GBR-11.

For overviews of submittals to MHRA, see GBR-18. Also see the Initiation, Agreements & Registration section for information on obtaining a trial identification number during trial registration.

As described in GBR-78, other relevant approvals can be sought on the IRAS site. For example, applicants can request inclusion in the National Institute for Health and Care Research Clinical Research Network (NIHR CRN) Portfolio, which comprises high-quality clinical research studies that receive support services from the Clinical Research Network in England.

Per G-CTApp, MHRA supports the conduct of trials with complex innovative designs such as umbrella, basket, platform, and master protocol plus submodules. When submitting a clinical trial application for a trial with innovative designs that involve prospective major adaptations, the sponsor must justify the choice of a complex trial design, ensure that each adaptation as well as the entire trial are safe and scientifically sound, and describe how the integrity of trial results will be maintained throughout the conduct of the trial. See G-CTApp for example scenarios of when it is appropriate to propose major adaptations via submission of a substantial amendment request. Before submitting an application for authorization of a trial with a complex innovative design and/or an amendment requesting approval of major adaptations, sponsors are recommended to establish a dialogue with the MHRA and seek advice.

As delineated in the MHCTR, the clinical trial application and accompanying material must be provided in English.

Terminology (Glossary) and Sections 1.1-1.2 and 14

Combined Review - What will happen to ongoing CTIMP studies submitted in the standard system?

CI Checklist Before Seeking Approval, CTA Submission, and Ethics Submission

Help (Preparing and Submitting Applications)

Apply to conduct a clinical trial for an advanced therapy medicinal product

2

Trial Sponsor and legal Representative, Combined review of clinical trials of investigational medicinal products, Documents to send with your application, New notification scheme, and Requesting approval of trials with complex innovative designs

Amending your trial protocol or other documentation

2

Amendment of Regulation 12 of the Principal Regulations; and Part 2 (Conditions Based on Article 3 of the Directive)

Part 1 (3) and Part 3 (12, 14, 17, and 18)

Submission Content

Last content review/update: May 2, 2024

Regulatory Authority Requirements

Clinical Trial Notification (CTN) Scheme

As delineated in AUS-49, the following information must be submitted to the Therapeutic Goods Administration (TGA) through the online form on the TGA Business Services (TBS) webpage (AUS-36):

Sponsor name and address
Sponsor declaration
Notification fee (See Regulatory Fees section)
Organization-nominated contact’s name, phone number, and email
An optional alternative contact, which may be chosen from the contacts for the agent or sponsor organization submitting the CTN
Protocol number
Expected trial start and completion dates
Potential use of restricted goods
Study title and description
“This Trial” check boxes indicating whether the trial involves the use of a medicine, a medical device, and/or a biological
Trial type
Whether the trial is a first in human trial
Whether the trial, in part or as a whole, has been halted/stopped/withdrawn or rejected in another country due to safety concerns
Total number of trial participants
Therapeutic area
Investigational product (IP) details
Whether it is a multi-center trial
Whether the trial is being conducted in other countries
Preceding trial details
Trial site details

See AUS-49 for detailed descriptions of each required item.

Clinical Trial Approval (CTA) Scheme

AUS-47 states that the CTA scheme application consists of two (2) forms – Part 1: the application (AUS-56), and Part 2: Notification of the conduct of a trial under the CTA scheme (AUS-57).

The Part 1 CTA application form (AUS-56) requires general information (sponsor name, data details, and sponsor declaration) and details on the medicine (active ingredient)/biological be submitted to the TGA.

The Part 2 CTA application form (AUS-57) requires trial sponsor information (name and client ID code), the IP or biological, and the notification type, as well as trial and trial site details (title of study and trial type). The form also requires signed certifications from the sponsor, the principal investigator (PI), the ethics committee (EC) (Human Research Ethics Committee (HREC) in Australia), and the authority approving the conduct of the trial.

Ethics Committee Requirements

Per the G-CTHandbook, the EC and the institution are responsible for establishing what information should be provided in support of an application. The EC should request any additional information that it believes is necessary to undertake review of the proposed research. Unless advised otherwise, trial sponsors and researchers should use the Human Research Ethics Application (HREA) for submitting proposals for research involving humans to ECs.

AUS-46 indicates that the HREA assists researchers in considering the ethical principles of the G-NatlStmt in relation to their research. The G-NatlStmt requires that those who conduct and approve human research to consider:

How the research question/theme is identified or developed
The alignment between the research aims and methods
How the researchers and the participants will engage with one another
How the research data or information are to be collected, stored, and used
How the results or outcomes will be communicated
What will happen to the data and information after the project is completed

For more information on the HREA, see the Submission Process section.

The G-NatlStmt further specifies that in an application for review of their research, researchers should determine and state in plain language:

The research question or questions that the project is intended to explore
The potential benefit of exploring the question or questions including to whom that potential benefit is likely to flow, and whether that benefit is a contribution to knowledge or understanding, improved social or individual wellbeing, or the skill and expertise of researchers
The basis for that potential benefit as described in either relevant literature or a review of prior research unless, due to the novelty of the question, there is scarce literature or prior research
How the design and methods of the project will enable adequate exploration of the research questions and achieve the aims of the research
How the design of the project will maintain respect for the participants
Where relevant, that the research meets the requirements of any relevant regulations or guidelines authorized by law (such as those related to privacy and reporting requirements for disclosure of child abuse)
Whether or not the project has been reviewed by a formally constituted academic, scientific, or professional review process, and, if so, the outcome of that review

Research Governance

According to the G-NatlStmt, institutions should publish (such as on their website) clear policies and procedures for institutional authorization of research. See the Research GEMS system (AUS-55), the Ethical Review Manager (ERM) (AUS-8), and the Research Ethics and Governance Information System (REGIS) (AUS-10) websites for public health organization site-specific assessment (SSA) forms, which may differ between institutions and states or territories.

Clinical Protocol

The G-TrialsSOP indicates that where the investigator is responsible for the protocol development, the investigator must ensure the protocol follows the outline in the AU-ICH-GCPs. Specific content of a protocol will vary depending on the research area, the level of risk to participants, the phase of the research and study design, and whether a medicinal product or a device or a therapeutic intervention is being researched. If satellite sites for a teletrial are involved in the study, no specific additional wording is required in the protocol, as relevant considerations will be addressed in other study-specific documents which may be annexed to the protocol.

The AU-ICH-GCPs provides the following outline of the protocol:

General information (protocol title, identifying number, and date; contact information for the sponsor, medical expert, investigator(s), trial site(s), qualified physician(s), and laboratory and/or institutions involved in the study)
Background information
Objectives and purpose
Trial design
Selection, withdrawal, and treatment of participants
Assessment of efficacy
Assessment of safety
A description of the statistical methods to be used in the trial
Direct access to source data and documents
Quality control and quality assurance
Ethical considerations
Data handling and recordkeeping
Financing and insurance
Publication policy

Creating a New CTN Form

CTA Scheme and FAQs

Responsibilities under the CTN and CTA schemes (Role of Human Research Ethics Committees (HRECs))

SOP 04

Sections 3 (Introduction and Chapter 3.1) and 5 (Chapter 5.1)

Last content review/update: May 16, 2024

Regulatory Authority Requirements

As specified in the G-CTApp, a clinical trial submission package to the Medicines and Healthcare Products Regulatory Agency (MHRA) should contain the following documents:

Cover letter (when applicable, the subject line should state that the submission is for a Phase 1 trial and is eligible for a shortened assessment time, or if it is submitted as part of the notification scheme); this letter should clearly highlight the Purchase Order (PO) number to help the MHRA invoice and allocate payments promptly and efficiently
Clinical trial application form in PDF and XML versions
Protocol document
Investigator’s brochure (IB)
Investigational medical product dossier (IMPD) or a simplified IMPD
Summary of scientific advice obtained from the MHRA or any other regulatory authority, if available
Manufacturer’s authorization, including the importer’s authorization and Qualified Person declaration on good manufacturing practice for each manufacturing site if the product is manufactured outside the European Union (EU) (See G-ImportIMPs and the Manufacturing & Import section for more information)
Copy of the United Kingdom (UK) or the European Medicines Agency’s decision on the pediatric investigation plan and the opinion of the pediatric committee, if applicable
Content of the labelling of the investigational product (IP) (known as investigational medicinal product (IMP) in the UK) (or justification for its absence)

Ethics Committee Requirements

As per the MHCTR, the International Council for Harmonisation’s Guideline for Good Clinical Practice E6(R2) (GBR-113), ECs require the chief investigator (CI) to submit the following documentation for ethics approval:

Application for an EC opinion
A summary of the trial, including justification, relevance, and methodology to be used
Research hypothesis
Statistical analysis and justification for the numbers of participants to be recruited
Protocol
IB
Peer review process details
Sponsor name and contact information
Financial arrangements for the trial (e.g., funding sources, participant reimbursement, compensation provisions in the event of trial-related injury or death, and insurance or indemnity coverage for sponsor and investigator(s)) (See the Insurance & Compensation section for additional information)
Terms of agreement between sponsor and participating institution(s)
Material to be used (including advertisements) to recruit potential research participants (See the Initiation, Agreements & Registration section for additional information on participant recruitment)
Informed consent form and copies of materials to be provided to participants (See the Required Elements section for additional information)
Participant treatment plans
Benefit/risk assessment for participants
Investigator(s) Curriculum Vitaes (CVs)
Trial design and suitability of facilities

Further, to help with planning before seeking EC approval, GBR-18 provides a checklist for CIs.

Clinical Protocol

Per GBR-9, the protocol describes the objectives, design, methodology, statistical considerations and organization of a clinical trial. According to GBR-113, the clinical protocol should contain the following elements:

Protocol summary
Sponsor or designated representative name and contact information
Investigator(s) CV(s) and contact information
IP description (See the Investigational Products topic for detailed coverage of this subject)
Form, dosage, route, method, and frequency of administration; treatment period
Trial objectives and purpose
Trial design, random selection method, and blinding level
Participant selection/withdrawal
Participant treatment
Summary of potential risks and known benefits to research participants
Safety and efficacy assessments
Adverse event reporting requirements (See the Safety Reporting section for additional information)
Statistics and methods to track trial data
Sponsor specifications for direct access to source data/documents
Quality control/quality assurance procedures and practices
Ethical considerations
Data management and recordkeeping
Financing and insurance details
Publication policy

For complete protocol requirements, refer to GBR-113.

Terminology (Statutory Definitions Relating to CTIMPs)

3.1 and 6

CI Checklist Before Seeking Approval

Documents to send with your application

Part 3 (12, 14, 15, 17, and 18) and Schedule 3 (Parts 1 and 2)

Timeline of Review

Last content review/update: May 2, 2024

Overview

In accordance with the G-CTHandbook, the G-TrialsSOP, and AUS-47, the Therapeutic Goods Administration (TGA) is responsible for authorizing the supply of unapproved therapeutic goods for clinical trials under two (2) regulatory schemes—the Clinical Trial Notification (CTN) scheme and the Clinical Trial Approval (CTA) scheme. According to the TGR, the G-CTHandbook, the G-TrialsSOP, and AUS-47, under either regulatory scheme, an ethics committee (EC) (Human Research Ethics Committee (HREC) in Australia) must approve research protocols. The G-NatlStmt further specifies that any research that involves greater than low risk must be reviewed by an EC. AUS-47 indicates that the review and approval/authorization by an EC and institution may be conducted in parallel to the CTN form submission to the TGA, but it is the sponsor’s responsibility to ensure that all relevant approvals and authorizations are in place before commencement of the trial.

According to AUS-40, all public and private health organizations must also undertake a site-specific assessment (SSA) of each research project. Per the G-TrialsSOP, the SSA and ethics review may occur in parallel.

Regulatory Authority Approval

AUS-47 states that the TGA’s target time to process online CTNs is five (5) to seven (7) working days, but the agency tries to process the notification as soon as possible. This timeframe does not include the time taken for TGA finance to match the payment (if required) to a submission. For information on how to check the status of a CTN, see AUS-49.

No timeline information is available for applications under the CTA scheme. Per AUS-47, parties that are considering submitting a CTA application are strongly encouraged to contact the TGA at clinical.trials@health.gov.au for advice regarding the application process.

Ethics Committee Approval

The EC review and approval process timeline varies by institution. However, according to the G-NatlStmt, the institutional EC must implement standard operating procedures that promote good ethics review, including timely consideration of applications.

Research Governance

The G-GovHndbk indicates that ethical review and site assessment, both components of research governance, are two (2) distinct processes relating to the ethical approval and institutional authorization of research involving humans. However, because evidence of EC approval is a component of the site assessment process, institutional authorization of a research project cannot be given until EC approval has been provided. The G-TrialsSOP further specifies that EC approval must be obtained and submitted to the research governance officer (RGO) of each participating institution before institutional authorization is granted.

While some parts of the research governance review must occur after the EC review, the G-GovHndbk recommends that as part of the national approach to single ethical review, institutions establish processes to facilitate parallel review. Project documentation processes related to site assessment may be considered as falling into these categories:

That which can be assessed independent of ethical review, such as evidence of research qualifications, supporting department approval forms, contracts, budgets, and insurance and indemnity documents
That which is subject to ethical review, but can be submitted prior to or in parallel with ethical review to enable independent assessment of other documentation, such as initial project application documents
That which can only be assessed subsequent to ethical approval, such as approved project application documents, fully signed regulatory documents, and a certificate of ethical approval

See the G-GovHndbk for additional National Health and Medical Research Council (NHMRC) guidance on best practices in the governance of multicenter human research as part of the national approach to single ethical review.

The NHMRC also developed the GPP-SiteAssess to help institutions streamline the research governance process and shorten clinical trial start-up times. See the GPP-SiteAssess for more information.

CTN Scheme, CTA Scheme, and FAQs

Responsibilities under the CTN and CTA schemes (Role of Human Research Ethics Committees (HRECs))

Report of the pilot of the Good Practice Process – Executive summary

Terms and SOP 05

Purpose, Scope and Limits of this Document and Section 5 (Chapter 5.1)

Part 3 (12 and 12AA-12AD) and Schedule 5A

Last content review/update: May 16, 2024

Overview

Per G-CTApp and G-IRASCombRev, all new clinical trials applications for investigational products (CTIMPs) must be prepared, submitted, and reviewed via the combined review process. Combined review offers a single application route and coordinated/parallel review from the Medicines and Healthcare Products Regulatory Agency (MHRA) and the ethics committee (EC) leading to a single United Kingdom (UK) decision for clinical trials.

Combined Review

Per the G-CTApp and GBR-72, the initial combined review assessment will be completed within 30 days of being submitted. The G-CTApp indicates that applications for healthy volunteer trials and sponsor-determined phase 1 trials in non-oncology participants may qualify for a shortened assessment time and MHRA will work with the EC to expedite these applications. The MHRA and the EC will inform applicants of the outcome of a submission. If there are grounds for non-acceptance of the application, the applicant will have the opportunity to respond, usually within 14 days, though this may be extended on request. Communication informing the applicant of the MHRA and EC decisions following receipt of the responses will usually be sent within 60 days of receiving the original valid application. If an extension to the response date has been agreed to, then this will impact the final decision timeline. Notification of the decision relating to a gene therapy, somatic cell therapy (including xenogenic cell therapy) product, tissue engineered product, or products containing genetically modified organisms will be sent within 90 days of receiving the original application unless otherwise advised.

The G-CTApp states that the MHRA uses automated electronic communication. To ensure receipt of MHRA correspondence, applicants should add MHRA_CT_Ecomms@mhra.gov.uk to their safe sender email list. MHRA will only send official correspondence to the named applicant email address. According to the MHCTR, if the sponsor or the designated representative does not receive a request for additional information from the MHRA within 30 days, the clinical trial application is treated as authorized.

Regarding the new notification scheme, the G-CTApp states that this pathway enables a more streamlined and risk-proportionate approach to processing clinical trial authorization for “initial” applications for Phase 4 and certain Phase 3 clinical trials deemed to be of lower risk. Applications submitted under this scheme will be processed by the MHRA within 14 calendar days from the application received effective date, provided the sponsor can demonstrate the trial meets the inclusion criteria. Authorization by the MHRA will be granted unless any criterion is not suitably met. If the MHRA determines the application does not meet the criteria, an objection decision will be communicated within 14 calendar days from the application received effective date, and the application will continue under the full authorization assessment with a decision communicated within the 30-day statutory timeframe.

In addition, as stated in the G-CTApp, certain first-in-human (Phase 1) trials of investigational products with higher risk or greater elements of uncertainty require the MHRA to seek advice from the Clinical Trials, Biologicals, and Vaccines Expert Advisory Group (CTBV EAG) of the Commission on Human Medicines (CHM) before approval for the trial can be given. See the G-CTApp for detailed requirements.

Initial Process Review and Timelines

Combined review of clinical trials of investigational medicinal products, New notification scheme, Assessment of your submission, and Applications that need expert advice

Initiation, Agreements & Registration

Last content review/update: May 2, 2024

Overview

In accordance with the G-TrialsSOP, the G-CTHandbook, and AUS-47, clinical trials involving unapproved therapeutic goods can only commence under the Clinical Trial Notification (CTN) scheme or the Clinical Trial Approval (CTA) scheme. According to the G-GovHndbk and the G-TrialsSOP, under either scheme, both institutional ethics committee (EC) (Human Research Ethics Committees (HRECs) in Australia) approval and research governance authorization are required before a research project can commence at a site.

Research Governance

Per the G-GovHndbk, research must be governed by the institution at all stages of a project. Ethical review and site assessment, both components of research governance, are two (2) distinct processes relating to the ethical approval and institutional authorization of research involving humans. According to AUS-40, all public and private health organizations must undertake a site-specific assessment (SSA) of each research project. This allows the institution to consider whether the project is suitable for the site, and whether it has the capacity to conduct the research at that site. Pursuant to the G-NatlStmt, authorization of research by the institution should consider, but not re-review, any issues raised during the ethics review of the research proposal, and each institution should have a process or processes for assessing the risk level of the research. These processes may involve seeking advice from relevant clinical or administrative staff, members of an EC, or a full meeting of the EC. All research should be developed, reviewed, authorized, conducted, and monitored in accordance with a research governance framework as described in an institution’s policy. For more information on institutional responsibilities, see the Site/Investigator Selection section.

The G-TrialsSOP states that in the case of a teletrial, the principal investigator (PI) must ensure that a robust site assessment is undertaken that fully quantifies the capabilities of each satellite site to inform the extent to which trial related activities can be delegated to the site. This may include a pre-commencement assessment before a specific trial is proposed so that the process of trial start up is expedited when a suitable trial is identified.

Per the G-TrialsSOP, prior to a study’s commencement, the PI must:

Submit the primary site's Clinical Trial Research Agreement (CTRA), EC approval, the SSA form, evidence of any relevant good clinical practice (GCP) training, and any other required documentation to the institution’s research governance officer (RGO)
Ensure all documentation and correspondence pertaining to the submission and approval processes is filed in the study master file (SMF) (see Appendix 8 of the G-TrialsSOP)
Ensure each satellite site completes and submits to their RGO a clinical trial sub-contract and a SSA form
Await site specific RGO authorization before any study related activity can occur at that site
Ensure the satellite site files all documentation in the satellite site study file (SSSF)

The G-TrialsSOP further states that prior to the initiation of a study, the investigator must also mutually agree with the sponsor on a scheduled date, time, and location for a study initiation visit at the participating site to ensure the site is prepared to commence the study. In the case of a teletrial, this may be at the primary site only, or could include (remotely) the satellite site(s) as determined by the study complexity by the sponsor/PI.

See the G-TrialsSOP for more information on site initiation requirements for primary and satellite sites.

The G-GovHndbk further indicates that in the national approach to single ethical review, site assessment and project authorization are the responsibility of each institution participating in a multicenter human research project while ethical review is provided by a single EC using certified ethical review processes. Each institution collaborating in a multicenter project utilizing the outcome of a single ethical review must individually authorize the commencement of research at their institution. To avoid unnecessary delays in research commencing at all collaborating centers and sites, each institution should consider relevant local matters prior to or in parallel with ethical review.

Clinical Trial Agreement

As delineated in the AU-ICH-GCPs, the sponsor must sign an agreement between all involved parties, including investigators, institutions, contract research organizations, and others for documentation purposes. Further, the sponsor should obtain the investigator’s/institution's agreement:

To conduct the trial in compliance with good clinical practice, with the applicable regulatory requirement(s), and with the protocol agreed to by the sponsor and given approval/favorable opinion by the EC
To comply with procedures for data recording and reporting
To permit monitoring, auditing, and inspection
To retain the trial-related essential documents until the sponsor informs the investigator/institution these documents are no longer needed

The sponsor and the investigator/institution should sign the protocol, or an alternative document, to confirm this agreement.

For the purposes of the G-TrialsSOP, the CTRA for the primary site and the sub-contract for each satellite site constitute part of a research governance application, which is submitted to the RGO. The CTRA covers matters such as confidentiality, intellectual property, ownership of data, insurance, and indemnity. The Medicines Australia CTRA (see AUS-38) is the recommended standard form.

Clinical Trial Registration

The G-NatlStmt requires that clinical trials be registered on a publicly accessible register complying with international standards before recruitment of the first participant. For information on these standards, see the World Health Organization (WHO)’s International Clinical Trials Registry Platform (ICTRP) (AUS-67). Per AUS-15, the Australian and New Zealand Clinical Trials Registry (ANZCTR) (AUS-12) recommends applying for registration at the same time as ethics submission.

CTN Scheme and CTA Scheme

The CTN and CTA schemes

1.17, 5.1.2, 5.6.3, and 8.2.6

Terms; SOPs 03, 05, and 06; and Appendix 8

Sections 3 (Chapter 3.1) and 5 (Chapter 5.1)

Last content review/update: May 16, 2024

Overview

In accordance with the MHCTR, the MHCTR2006, and GAfREC, a clinical trial can only commence after the sponsor or the designated representative receives authorization from the Medicines and Healthcare Products Regulatory Agency (MHRA) and the chief investigator (CI) receives an approval from a recognized ethics committee (EC). In addition, GBR-9 clarifies that a favorable EC opinion does not imply that research activity at sites can begin. Confirmation of management permission or approval from relevant care organization(s) to proceed with the research also needs to be in place. In addition, if the EC issued a favorable opinion with additional conditions, the clinical trial cannot start until these conditions are met. GBR-18 indicates that once all the relevant approvals are in place, all documentation has been finalized, and all participating sites have the information they need, the trial can begin. This process is often achieved by holding a start-up meeting at each site so that the CI ensures all technical aspects of a trial and protocol requirements are fully understood by relevant site staff. Trial-specific training (protocol and procedures) and review of trial conduct (e.g., safety reporting) is often undertaken at this stage. For clinical trials of an investigational product (IP), this communication should also include pharmacy staff, if applicable, so that they can confirm all requirements are in place before dispensing IPs to participants.

See GBR-40 for information about DigiTrials, which supports clinical trials in England to provide safe, authorized access to patient data to help set up trials. DigiTrials includes recruitment and feasibility services to identify whether there are enough suitable participants, as well as participant communication and outcomes services.

Per the MHCTR and GBR-18, specific documentation, including MHRA licensing, must be in place before an IP can be released for a clinical trial.

As stated in the MHCTR, clinical trials should be conducted in compliance with the International Council for Harmonisation’s Guideline for Good Clinical Practice E6(R2) (GBR-113), and laboratory practices for IPs must comply with the UK-GLPs. Per the CTIMP-Condtns, MHRA assumes that the trial will commence within 12 months of the date of the favorable ethical opinion. The EC must be notified of the trial start date with evidence of the authorization. Further, the trial should not commence at any site until management permission has been obtained from the organization responsible for the care of the participants at the site. If the trial does not commence within 12 months of the favorable opinion being issued, the sponsor should send the EC a written explanation for the delay. A further written explanation should be sent after 24 months if the research has still not commenced. If the trial does not commence within 24 months of the favorable opinion being issued, the EC may recommend to the MHRA that the clinical trial authorization should be suspended or terminated. See CTIMP-Condtns for additional information on standard conditions for clinical trials.

Per GBR-78, all project-based research must also have governance and legal compliance approvals from the appropriate lead United Kingdom (UK) Health Department. The Integrated Research Application System (IRAS) (GBR-78) facilitates this process. As described in GBR-67, approval from the Health Research Authority (HRA) is required for all National Health Service (NHS) project-based research led from England or Wales. HRA and Health and Care Research Wales (HCRW) approval brings together the assessment of governance and legal compliance. For any new studies that are led from Scotland or Northern Ireland but have English and/or Welsh NHS sites, the national research and development coordinating function of the lead nation will share information with the HRA and HCRW assessment teams, who can issue HRA and HCRW approval for English and Welsh sites and thereby retain existing compatibility arrangements. Studies led from England or Wales with sites in Northern Ireland or Scotland will be supported through existing UK-wide compatibility systems, by which each country accepts the centralized assurances, as far as they apply, from national coordinating functions without unnecessary duplication. For more information on HRA’s assessment criteria and standards for approval, see GBR-29.

Clinical Trial Agreement

According to GBR-107 and GBR-70, contracts and agreements should be in place prior to the initiation of a trial. GBR-107 provides model templates for industry-sponsored clinical trials with the NHS/Department of Health and Social Care (DHSC) participants in hospitals throughout the UK Health Services, which encompasses England, Northern Ireland, Scotland, and Wales. Applicants are advised to use the templates without modification. Any proposed modifications will not be accepted unless first agreed to by the UK Contracting Leads. Proposing modifications to the templates is likely to result in significant delay.

GBR-107 also provides the model non-commercial agreement (mNCA) template to meet the requirements of non-commercial sponsors and the NHS/DHSC bodies undertaking the research. This agreement has been developed as a single, UK-wide agreement template, meaning that it can be used irrespective of where the sponsor and research site are established. It is designed to be used without modification or negotiation. The mNCA has been developed for a range of interventional research scenarios, including clinical trials, medical device studies, research using participant data, and research using human tissue. The terms and conditions are suitable for all such scenarios and only the completion of highlighted sections, including the schedules of the agreement, will differ depending on the study involved.

Additional details and templates are available in GBR-107 and GBR-70.

Clinical Trial Registration

As per the GBR-102 and the G-CTApp, the sponsor or investigator is required to register the clinical trial in a publicly accessible database as a condition of a favorable ethical opinion. Registration should occur before the first participant is recruited and no later than six (6) weeks after recruitment of the first participant. To help researchers meet the UK’s transparency requirements, GBR-102 indicates that the HRA will automatically register approved clinical trials with the International Standard Randomised Controlled Trial Number (ISRCTN) Registry (GBR-47) to ensure that information is publicly available. ISRCTN is the UK’s preferred clinical trials registry. HRA’s commitment to register clinical trials on behalf of sponsors and researchers is in line with the “Make It Public” research transparency strategy (see GBR-55).

Per GBR-18, each clinical trial must have a unique trial number. Clinical trials with sites in the European Union (EU), the European Economic Area (EEA), or Northern Ireland should also apply for a European number. Per GBR-87, as of January 31, 2023, all new clinical trials with sites in Europe should register on the new Clinical Trials Information System (CTIS) (GBR-39). GBR-39 specifies that by January 31, 2025, any ongoing trials must be transitioned from EudraCT (GBR-87) to GBR-39. For more information, see the EudraCT transition fact sheet (GBR-16). CTIMP-Condtns indicates that for clinical trials involving sites in both the UK and the EU, a record in EU’s GBR-39 does not satisfy the public registry condition because the UK component of the trial will not be visible in CTIS (GBR-39). Failure to register is a breach of the clinical trial conditions unless a deferral has been agreed to.

Per GBR-102, HRA also recognizes any registry covered by the World Health Organization (WHO) or the International Committee of Medical Journal Editors (ICMJE), such as clinicaltrials.gov (GBR-49). For any submissions prior to December 31, 2021, the applicant should have registered their clinical trial on an established international register.

6

Terminology (Glossary) and Sections 1, 3, and 14

1.17, 5.1.2, and 8.2.6

About NHS DigiTrials and NHS DigiTrials - our services

CI Checklist Before Seeking Approval, CTA Submission, Final Trial Management Documentation, Trial Registration, and Trial Begins

Help (Preparing and Submitting Applications)

2-3

3.2

Registration of your clinical trial, Combined review of clinical trials of investigational medicinal products, Documents to send with your application, and Assessment of your submission

7

Amendment of Regulation 12 of the Principal Regulations; and Part 2 (Conditions Based on Article 3 of the Directive)

Part 3 (12, 13, and 18)

Safety Reporting

Last content review/update: May 2, 2024

Safety Reporting Definitions

According to the G-SftyRpt, the following definitions provide a basis for a common understanding of Australia’s safety reporting requirements:

Adverse Event (AE) – Any untoward medical occurrence in a patient or clinical trial participant administered a medicinal product and that does not necessarily have to have a causal relationship with this treatment
Adverse Reaction (AR) – Any untoward and unintended response to an investigational medicinal product related to any dose administered
Unexpected Adverse Reaction (UAR) – An adverse reaction, the nature or severity of which is not consistent with the applicable product information (e.g., investigator's brochure (IB) for an unapproved investigational medicinal product)
Serious Adverse Event (SAE) or Serious Adverse Reaction (SAR) – Any adverse event/adverse reaction that results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in persistent or significant disability or incapacity, or is a congenital anomaly or birth defect
Suspected Unexpected Serious Adverse Reaction (SUSAR) – An adverse reaction that is both serious and unexpected
Significant Safety Issue (SSI) – A safety issue that could adversely affect the safety of participants or materially impact the continued ethical acceptability or conduct of the trial
Urgent Safety Measure (USM) – A measure required to be taken in order to eliminate an immediate hazard to a participant’s health or safety (Note: This type of SSI can be instigated by either the investigator or sponsor and can be implemented before seeking approval from ethics committees (ECs) or institutions)

Safety Reporting Requirements

Investigator Responsibilities

As specified in the G-SftyRpt, the investigator is responsible for recording and assessing all AEs that occur at the site. The investigator is also required to inform the sponsor of all SAEs, and all USMs instigated by the site, within 24 hours of becoming aware of the event. All safety critical events must be reported to the sponsor, and for reported deaths, the investigator should supply the sponsor with any additional requested information. Further, the investigator must report to the institution all SSIs and SUSARs arising from the local site within 72 hours of becoming aware of the event.

However, the G-TrialsSOP states that the investigator must also report any SUSARs to the sponsor within 24 hours of becoming aware of the event, and USMs instigated by the investigator or site must be reported to the sponsor within 72 hours. Furthermore, the investigator must report all other significant issues to the sponsor within 15 days of instigating or becoming aware of the event. The investigator must notify the sponsor promptly regarding any changes significantly affecting the conduct of the trial, and/or increasing the risk to participants. The investigator must also be available to meet with the sponsor to discuss study progress, issues, and safety.

The G-TrialsSOP requires that within 72 hours of instigating or becoming aware of the event, the investigator must notify the institution of:

USMs
SUSARs arising from the local site
Any information received from the sponsor that may be new and have an impact on the continued ethical acceptability of the trial or may indicate the need for amendments to the trial protocol, including monitoring of safety

The G-TrialsSOP indicates that for satellite site(s) in teletrials, staff must report safety issues directly to the sponsor as per the timelines specified in the clinical trial protocol and the safety monitoring plan or similar document, in the same way as the primary site. Certified copies of the relevant safety reports/documentation generated at the satellite site must be sent to the primary site for filing in a study master file.

According to the G-TrialsSOP, the principal investigator (PI) must ensure that study staff, including those at teletrial satellite sites, are trained in the protocol, investigator’s brochure (IB), study procedures, and AE/SAE reporting. The PI must also ensure that a system for safety reporting duties is in place for all study staff. For more information on investigator responsibilities related to standard operating procedures (SOPs), see the G-TrialsSOP.

Sponsor Responsibilities

As delineated in the G-SafetyDataMgt, the G-SftyRpt, and the G-CTHandbook, the sponsor is required to expedite reporting of SUSARs to the Therapeutic Goods Administration (TGA).

The G-SafetyDataMgt indicates that other situations requiring expedited reporting may include information that might materially influence the benefit-risk assessment of an investigational product, or that would be sufficient to consider changes in the administration or conduct of a clinical trial.

According to the G-SftyRpt and the G-TrialsSOP, expedited reporting requires the sponsor to file reports to the TGA in the following specified timelines:

For an Australian SUSAR that is fatal or life-threatening, immediately, but no later than seven (7) calendar days, with any follow-up information within eight (8) calendar days
For all other Australian SUSARs, no later than 15 calendar days after becoming aware of the case

The G-SftyRpt and the G-TrialsSOP further indicate that the TGA, the EC, and investigators must also be notified of all SSIs that adversely affect the safety of participants, or materially impact the continued ethical acceptability or conduct of the trial. SSIs that meet the definition of a USM should be reported within 72 hours, and all other SSIs should be reported within 15 calendar days of the sponsor being made aware of the issue. It is strongly recommended that the sponsor contact the TGA within 24 hours of a USM being taken, and if initial contact is by telephone, it should be followed up with a written notification provided by e-mail within 72 hours. See AUS-53 for additional information on SSIs and USMs.

Per the G-SftyRpt, submitting individual reports of AEs, SAEs, and SUSARs to ECs, institutions, and investigators are no longer required. However, according to the G-TrialsSOP, the sponsor must provide the EC with an updated IB at least annually that supports trial oversight, depicts a clear picture of the evolving trial safety profile, and provides evidence that the sponsor is conducting its safety monitoring appropriately.

The G-CTHandbook and the G-SftyRpt further require the sponsor to maintain records of all other single case AEs and submit them to the TGA upon request. The G-CTHandbook indicates that the TGA does not require sponsors to submit individual SUSARs from outside Australia. Sponsors should continually monitor the safety of their clinical program and advise the TGA of any SSIs that arise from their analysis of overseas reports, or of any action that has been taken by another country’s regulatory agency. Investigators and ECs should also be informed of this information, and sponsors must be able to provide the TGA with the clinical details of any individual overseas AE reports if requested.

According to the G-TrialsSOP, the sponsor’s plans for safety data monitoring should be documented in a safety monitoring plan or similar document and be given to the PI prior to commencement of the clinical trial. The plan must be continually reviewed and updated during the trial, as real-time assessments of safety data are performed, and outcomes are made available.

Other Safety Reports

The G-SftyRpt delineates that the sponsor must provide the EC with an annual safety report including a clear summary of the evolving trial safety profile. The annual safety report should generally include:

A brief description and analysis of new and relevant findings
For investigational products (IPs) not on the Australian Register of Therapeutic Goods (ARTG) (AUS-22), a brief analysis of the safety profile of the IP and its implications for participants
A brief discussion of the implications of the safety data to the trial’s risk-benefit ratio
A description of any measures taken or proposed to minimize risks

A Development Safety Update Report (DSUR) or other similar document may also serve as the annual safety report. See the G-SftyRpt for more information.

Form Completion & Delivery Requirements

As per the G-CTHandbook, all SUSARs from Australian sites must be reported to the TGA using one (1) of three (3) formats:

The Electronic Data Interchange (EDI) functionality, which allows sponsors to submit AE reports directly from their system to the TGA (more information can be found at AUS-26)
The online reporting form, which can be accessed from AUS-51
The CIOMS Form I (AUS-4) or the TGA’s Blue Card Adverse Reaction Reporting Form (AUS-3)

Per AUS-3, the Blue Card form may be emailed to adr.reports@tga.gov.au or mailed to Pharmacovigilance and Special Access Branch, Reply Paid 100, Woden ACT 2606. More information about reporting to the TGA may be found at AUS-7.

See AUS-37 for the SSI/USM reporting form.

Safety reporting to TGA for CTN and CTA trials

Introduction, Definitions and Terminology Associated with Clinical Safety Experience, Standards for Expedited Reporting, and Attachment 1

Summary of Main Changes to Reporting Requirements and Part 1 - Investigational Medicinal Product (IMP) Trials (C. An Overview of Safety Monitoring and Reporting Responsibilities)

SOPs 02, 05, and 12

Last content review/update: October 25, 2024

Safety Reporting Definitions

According to GBR-1 and GBR-64, the following definitions provide a basis for a common understanding of the United Kingdom’s (UK’s) safety reporting requirements:

Adverse Event or Adverse Experience (AE) – Any untoward medical occurrence in a participant, including occurrences which are not necessarily caused by or related to that product
Adverse Drug Reaction (ADR) – Any untoward and unintended response in a participant to an investigational medicinal product which is related to any dose administered to that participant
Serious Adverse Event (SAE), Serious Adverse Drug Reaction (SADR), or Unexpected SADR – Any AE, ADR, or unexpected ADR that results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, or a congenital anomaly/birth defect
Unexpected Adverse Drug Reaction (ADR) – An adverse reaction where the nature or severity is inconsistent with the applicable product information
Suspected Unexpected Serious Adverse Reaction (SUSAR) – A suspected serious adverse reaction, which is also “unexpected,” meaning that its nature and severity are not consistent with the information about the medicinal product in question

Per the G-CTAuth-GBR, the Medicines and Healthcare Products Regulatory Agency (MHRA) advises that the guidance on reference safety information (RSI) contained in GBR-30 (developed by the Clinical Trials Facilitation Group of the Heads of Medicines Agencies (HMA)) remains applicable. For clinical trials that are being conducted in the UK, an RSI cannot be used for expectedness until the RSI has been approved by the MHRA. Additional SUSARs that occur before the new RSI is approved should be reported in the usual expedited manner. If sponsors wish to harmonize the implementation date of an RSI in a trial that includes European Union (EU) and UK sites, then they can use the date when approval is granted in all member states and the UK. In the interest of efficiency and harmonization for multinational trials, the MHRA recommends that amendments including changes to the RSI are submitted to the UK and EU at the same time. The RSI in place at the time the SUSAR occurred should be used to assess expectedness for follow-up reports.

Safety Reporting Requirements

Per GBR-99, a sponsor or investigator may take appropriate urgent safety measures (USMs) to protect research participants against any immediate hazard to their health or safety, without prior authorization from a regulatory body. The main ethics committee (EC), and the MHRA for clinical trials for investigational medicinal products (CTIMPs), must be notified immediately (no later than three (3) days) in the form of a substantial amendment that such measures have been taken and the reasons why. GBR-9 states that for trials which have been submitted via the combined review service, one USM notification is made via the combined review part of the Integrated Research Application System (IRAS) (GBR-125) and received by the MHRA. No additional notification is required directly to the EC. GBR-32 reaffirms this stating that SUSARs and safety reports for CTIMPs that were approved by combined review should be submitted to the MHRA only. If the safety report requires action, the MHRA will instruct the study team to submit a substantial amendment. Any other SUSARs or annual safety report submitted UK wide will be acknowledged by email by the EC. The submitted cover report for the SUSAR or annual safety report will not be signed and returned, and the email will act as the formal acknowledgement.

In addition, the G-CTAuth-GBR states that the sponsor should call the MHRA’s Clinical Trials Unit at 020 3080 6456 to discuss the issue with a safety scientist, ideally within 24 hours of measures being taken, but no later than three (3) days. If key details are not available during the initial call, then the sponsor should inform the MHRA no later than three (3) days from the date the measures are taken by email to clintrialhelpline@mhra.gov.uk. Written notification in the form of a substantial amendment is also required. The substantial amendment covering the changes made as part of the USM is anticipated within approximately two (2) weeks of notification to the MHRA. Any potential reason for delay of substantial amendment submission should be discussed and agreed upon with the MHRA at the time of initial notification or through a follow-up call. Submission of the substantial amendment must not be delayed by additional changes outside of those taken and required as an urgent safety measure. Unrelated and unacceptable changes may result in rejection. For more details on how submissions should be made using MHRA Submissions, see G-CTAuth-GBR.

Investigator Responsibilities

As specified in the MHCTR, GBR-1, and GBR-30, the investigator is responsible for reporting all SAEs/SADRs immediately to the sponsor. The report may be made orally or in writing and followed by a detailed report no later than 24 hours after the event. When the reported event results in a participant’s death, the investigator must provide the sponsor with any requested information. According to the MHCTR, in cases where reporting is not immediately required according to the protocol or the Investigator’s Brochure (IB), the investigator should report an SAE/SADR within the appropriate timeframe based on the trial requirements, the seriousness of the SAE/SADR, and protocol or IB guidelines. Per GBR-1, the investigator and the sponsor share responsibility for the assessment and evaluation of adverse events with regard to seriousness, causality, and expectedness.

See GBR-18 for a safety reporting flowchart that gives an overview of the investigator’s expedited safety reporting requirements to the sponsor for a clinical trial in the UK.

Sponsor Responsibilities

According to the MHCTR, the G-CTAuth-GBR, and the MHCTR-EUExit, the sponsor is required to record and report all relevant information about fatal or life-threatening SUSARs as soon as possible, but no later than seven (7) calendar days to the MHRA, to the institution in which the trial is being conducted, and to the EC. Any additional relevant information should be sent within eight (8) days of the initial report. The sponsor must also report any non-fatal or non-life threatening SUSARs no later than 15 calendar days following first awareness of the event. Per GBR-1, the investigator and the sponsor share responsibility for the assessment and evaluation of adverse events with regard to seriousness, causality, and expectedness. Per the G-CTAuth-GBR, sponsors must report all UK-relevant SUSARs to the MHRA. The agency’s definition of ‘UK-relevant’ includes:

SUSARs originating in the UK for a trial
SUSARs originating outside the UK for a trial
If the sponsor is serving as a sponsor of another ongoing trial outside the UK involving the same medicinal product
SUSARs involving the same medicinal product if the sponsor of the trial outside the UK is either part of the same mother company or develops the medicinal product jointly, on the basis of a formal agreement, with the UK sponsor

Per GBR-18, sponsors should develop formal, written processes for the management of adverse events and safety reports, including the handling of both expedited reports and annual safety reporting.

Other Safety Reports

Per the G-CTAuth-GBR, sponsors must submit Development Safety Update Reports (DSURs) to the MHRA. The DSUR should consider all new available safety information received during the reporting period. The DSUR should include:

A cover letter listing all relevant clinical trial numbers of trials covered by the DSUR and an email address for correspondence (Note: per GBR-18, every clinical trial with a European site must include a European number. GBR-87 indicates that as of January 31, 2023, all new clinical trials with sites in Europe should use the Clinical Trials Information System (CTIS) (GBR-39)
An analysis of the participant’s safety in the concerned clinical trial(s) with an appraisal of its ongoing risk/benefit
A listing of all suspected serious adverse reactions (including all SUSARs) that occurred in the trial(s)
An aggregate summary tabulation of SUSARs that occurred in the concerned trial(s)

As stated in the G-CTAuth-GBR, at the end of the DSUR reporting period, the sponsor may assess the new safety information that has been generated and submit any proposed safety changes to the IB as a substantial amendment. This amendment must be supported by the DSUR and approved before the RSI is changed. A shortened DSUR is available for approved trials under MHRA’s notification scheme that are not part of a multi-study development program. Phase 4 national (UK only) trials of licensed products, which commanded a low fee from the MHRA, and where all participants have completed treatment and are only in the follow-up stage will also be suitable for submission of a short format DSUR. As an alternative to producing a full DSUR for these trials, the Health Research Authority Annual Progress Report (GBR-27) may be used.

The MHRA and Health Canada jointly released DSUR-UK_Canada to strengthen participant safety in clinical trials by improving the quality of DSURs. To increase the transparency of the data included in DSURs, the MHRA and Health Canada are requiring that the region-specific section of the DSUR explain how safety data were reviewed during the reporting period. Specifically, the region-specific section of the DSUR should include a summary description of the processes used by the sponsor to review the worldwide safety data of the investigational product (IP) (e.g., regular analyses of accumulating data, in-house safety review meetings, proposal of specific pharmacovigilance activities, or substantial modifications of the protocol). In addition, the region-specific section must describe how each safety signal (i.e., an event with an unknown causal relationship to the IP) identified during the reporting period was evaluated, as well as how a decision was made regarding the signal itself.

See the G-CTAuth-GBR, the MHCTR, GBR-1, GBR-18, GBR-30, and GBR-99 for detailed reporting requirements for the investigator and sponsor.

Form Completion & Delivery Requirements

Per the G-CTAuth-GBR, SUSARs during clinical trials should be reported to the MHRA in one (1) of the following ways:

Individual Case Safety Reports (ICSR) Submissions (GBR-126) (which replaces the EudraVigilance website (EVWEB)) – The ICSR Submissions route is used to submit single reports. (Note that per GBR-127, MHRA also decommissioned the eSUSAR reporting platform.)
MHRA Gateway (which replaces the EudraVigilance Gateway) – To gain access to the MHRA Gateway, which is used to submit bulk reports, users must first register via MHRA Submissions (GBR-13). The steps for gaining access to MHRA Submissions are contained within the G-MHRASubmiss and GBR-11.

See the Regulatory Fees section for information on fees for annual safety reporting and DSURs. See the G-CTAuth-GBR and GBR-99 for more details on submittal and delivery requirements.

4 and 5

10

Changes to SUSARs and annual safety reports

CI Checklist Before Seeking Approval, Trial Registration, Safety Reporting, and Urgent Safety Measures

SUSAR

Reference Safety Information – updated guidance, Suspected Unexpected Serious Adverse Reactions (SUSARs), Development Safety Update Reports (DSURs), and Urgent Safety Measures

14

Part 5

Progress Reporting

Last content review/update: May 2, 2024

Interim and Annual Progress Reports

As per the AU-ICH-GCPs, the G-NatlStmt, and the G-TrialsSOP, the investigator(s) is responsible for submitting progress reports to the ethics committee (EC) (known as Human Research Ethics Committee in Australia) annually, or more frequently if requested. The AU-ICH-GCPs and the G-TrialsSOP state that if there are significant changes in trial conduct or safety, the investigator should submit a written report to the sponsor, the EC, and where applicable, the institution. The G-NatlStmt indicates that at regular periods (reflecting the degree of risk, and at least annually), researchers should provide reports to the relevant EC(s) and institution(s), including information on:

Progress to date
The security of project-related data and information
Compliance with the approved proposal
Compliance with any conditions of approval

According to the G-NatlStmt, progress report forms should be designed to collect information that can provide meaningful assistance to reviewers in determining whether continuation of ethics approval is warranted. See the G-NatlStmt for more details.

Final Report

AUS-47 indicates that for trials conducted under the Clinical Trial Approval (CTA) scheme, the CTA clinical trial completion advice form (AUS-58) is used to notify the Therapeutic Goods Administration (TGA) of the trial completion. AUS-58 indicates that upon completion, the form may be emailed to the TGA at clinical.trials@tga.gov.au (preferred) or faxed to 02 6232 8112.

Per AUS-49, for trials conducted under the Clinical Trial Notification (CTN) scheme, a completion advice should be submitted through the TGA Business Services (TBS) webpage (AUS-36). The completion advice must include the date the trial was completed at all Australian sites, as well as the completion reason. See AUS-49 for additional information on the completion advice.

The AU-ICH-GCPs and the G-TrialsSOP indicate that the investigator should provide the EC with a final clinical study report. As per the G-TrialsSOP, the investigator must also notify the research governance officer that the trial has been terminated/closed. At the completion of the project, a report with the same information as described above for progress reports (per G-NatlStmt) must also be provided to the relevant EC(s) and institution(s), but it should include information on the outcome of the completed research.

Submitting a Completion Advice

CTA Scheme

4

SOP 05

Section 5 (Chapter 5.4)

Last content review/update: October 25, 2024

Interim and Annual Progress Reports

As indicated in the G-CTAuth-GBR and GBR-9, the investigator and the sponsor share responsibility for submitting progress reports to the ethics committee (EC), as required, on the status of a clinical trial and for submitting a final study report upon the trial’s completion. These requirements comply with the progress and final reporting requirements delineated in the International Council for Harmonisation’s Guideline for Good Clinical Practice E6(R2) (GBR-113).

In accordance with GBR-32 and GBR-65, it is no longer a requirement to submit annual progress reports to the EC. However, GBR-65 states that depending on the type of approval, a progress report may be requested to track progress.

In addition, GBR-65 states that if the study was reviewed by an EC in Scotland or Northern Ireland, an annual progress report should be submitted 12 months after the date on which the favorable ethics opinion was given, except in the following instances:

If the study is expected to run for less than two (2) years in duration
If the study received a proportionate review
If the study received a favorable ethics opinion from an EC in England or Wales

Furthermore, GBR-65, states that if a study was given a favorable ethics opinion by an EC in Scotland or Northern Ireland, there are separate forms for submitting progress reports, depending on the type of research. The form for clinical trials of investigational medicinal products (GBR-27) should be completed in typescript and authorized by the Chief Investigator (CI) or the sponsor/sponsor representative. An electronic copy should be emailed to the EC within 30 days of the end of the reporting period.

See the Regulatory Fees section for information on fees for annual progress reports.

Final Report

As per the MHCTR and the G-CTAuth-GBR, the sponsor must notify the Medicines and Healthcare Products Regulatory Agency (MHRA) and the EC in writing that a clinical trial has ended within 90 days of the conclusion of the trial. As indicated in GBR-128, all project-based research (not research tissue banks or research databases) that has been reviewed by an EC needs to submit a final report within 12 months of the end of the study. The final report should be completed and submitted in the combined review part of Integrated Research Application System (IRAS) (GBR-125). When completing the final report form, IRAS guides the user with instructions next to each question.

The G-CTAuth-GBR further specifies that a declaration of the end of a clinical trial should be sent to the MHRA within 90 days of the global end of the trial and within 15 days of the global premature end of the trial. The submission must include an end of trial form (GBR-133) and a cover letter. Note that only the global end-of-trial notification is required to be submitted. However, a facility may inform the MHRA of the local (UK) end of trial via the end-of-trial notification form, but these local notifications will not be officially acknowledged and the MHRA Submissions automatic email confirmation should be considered as evidence of submission. If a local end of trial is submitted, the MHRA would still expect to receive relevant safety updates and substantial amendments for the ongoing trial until the global end of trial notification is received. An exemption to this requirement must be requested via a substantial amendment for approval. The amendment must clearly state to what documents the proposal relates and provide a robust rationale for the request. All safety documentation must be submitted unless there are no other trials ongoing with the same product in the UK. Any trial activities (such as follow-ups, visits) must be completed before the submission of the global end-of-trial declaration form. It is not possible to submit amendments to the trial or the Development Safety Update Report (DSUR) once the global end-of-trial declaration form has been received by the MHRA. If the end-of-trial declaration has been received within a reporting period, or within 60 days following the data lock point, the corresponding DSUR will not be required.

Per the G-CTAuth-GBR, the timeframe for publishing the summary of results is within one (1) year of the end of trial. Sponsors should publish summary results within this timeframe in the public register(s) where they registered the clinical trial. While it is not required to submit this clinical trial summary report to the MHRA, sponsors must send a short confirmation email to CT.Submission@mhra.gov.uk once the results-related information has been uploaded to the public register and provide the relevant link.

As per GBR-9, the investigator is also required to submit a summary of the final study report to the main EC within one (1) year of the trial’s conclusion. GBR-20 clarifies that the form in GBR-20 should be used for this submittal, which includes submitting a lay summary of results. This is a UK-wide final report for all project-based research studies that have been reviewed by an EC within the UK Health Departments’ Research Ethics Service (GBR-62). The information contained in this final report helps the Research Ethics Service to monitor whether the research was conducted in accordance with the EC’s favorable opinion and applicable transparency requirements. Per the GBR-120, sponsors should include a plain language summary of their findings in the final report, which will be published on HRA’s website alongside the study research summaries. See GBR-120 for guidance on writing a good plain language summary for a general audience.

Per the G-PIPs, UK marketing authorization holders who sponsor a study that involves the use of the authorized medicinal product in the pediatric population, must submit to the MHRA results of the study within six (6) months after the trial ended. Additional requirements and submittal details are in the G-PIPs and the G-PIPsProcess.

Terminology (Glossary), and Sections 1 and 14

4.10 and 4.13

Final report on the research

End of Trial

Legal Background and Scope

Part 3 (Section 27)

Definition of Sponsor

Last content review/update: May 2, 2024

As per the AU-ICH-GCPs and the G-TrialsSOP, a sponsor is defined as an individual, company, institution, or organization that takes responsibility for the initiation, management, and/or financing of a clinical trial. As stated in the AU-PIC-S-GMP-Guide, sponsors undertake the ultimate responsibility for all aspects of the clinical trial, including the quality of investigational products (IPs).

In accordance with the AU-ICH-GCPs, Australia permits a sponsor to transfer any or all of its trial-related duties and functions to a contract research organization (CRO). Any trial-related duties and functions transferred to a CRO should be specified in a written agreement, and the sponsor should ensure oversight of such transferred responsibilities. Any trial-related duties and functions not specifically transferred to and assumed by a CRO are retained by the sponsor. The AU-ICH-GCPs further indicates that the sponsor retains overall responsibility for the trial data’s quality and integrity, as well as the conduct of the trial. As stated in the G-TrialsSOP, the sponsor is also responsible for ensuring that appropriate approvals are obtained prior to the commencement of the clinical trial, that conditions of any approvals are adhered to during the course of the clinical trial, and that the ethics principles of research merit and integrity, justice, beneficence, and respect are applied to the conduct of clinical trials.

According to the G-CTHandbook, if the investigator initiates and organizes the trial, the role of trial sponsor is assumed. If another party (such as a pharmaceutical company) provides the IP or other support for an investigator-led trial, that party is not required to assume the sponsor role.

As per the G-CTHandbook, the G-TrialsSOP, and AUS-47, a sponsor must be an Australian entity.

FAQs

Determine if the product is ‘unapproved’ and Role of trial sponsors

1.53 and 5.2

Annex 13 (Principle)

Terms

Last content review/update: May 16, 2024

As per the MHCTR, the MHCTR2006, the G-CTApp, GBR-103, GBR-9, GBR-2, and the International Council for Harmonisation’s Guideline for Good Clinical Practice E6(R2) (GBR-113), the sponsor is defined as an individual, company, institution, or organization who takes ultimate responsibility for the initiation, management, and financing (or arranging the financing) of a trial. The sponsor must ensure that the trial design meets appropriate standards and arrange for the trial to be properly conducted and reported. In addition, per GBR-101, the sponsor is the individual, organization, or partnership that takes on overall responsibility for proportionate, effective arrangements being in place to set up, run, and report a research project.

In accordance with GBR-113, the United Kingdom (UK) also permits a sponsor to transfer any or all of its trial-related duties and functions to a contract research organization (CRO) and/or institutional site(s). However, the ultimate responsibility for the trial data’s quality and integrity always resides with the sponsor. Any trial-related responsibilities transferred to a CRO should be specified in a written agreement. The CRO should implement quality assurance and quality control. Per the G-CTApp, G-SubtlAmndmt, and the GBR-103, the clinical trial sponsor or legal representative needs to be established in the UK or a country on an approved country list which initially includes the European Union (EU)/European Economic Area (EEA) countries per G-CTApprovedCountries. A change in sponsor or legal representative for a UK trial is a substantial amendment requiring submission to both the MHRA and the ethics committee. GBR-103 specifies that the legal representative:

May be an individual person or a representative of a corporate entity
Does not have to be a legally qualified person
Should be willing to act as the agent of the sponsor in the event of any legal proceedings instituted (e.g., for service of legal documents)
Should be established at an address in the UK or a country on the approved country list
Does not assume any of the legal liabilities of the sponsor(s) for the trial by virtue of the role of legal representative and does not therefore require insurance or indemnity to meet such liabilities; but may, in some cases, enter into specific contractual arrangements to undertake some or all of the statutory duties of the sponsor in relation to the trial, in which case the legal representative would also be regarded as a co-sponsor and would then require insurance or indemnity cover

The MHCTR also permits two (2) or more parties to take responsibility for the sponsor’s functions. When this applies, the MHCTR requires one (1) of the parties to submit the clinical trial application for authorization to the Medicines and Healthcare Products Regulatory Agency (MHRA), and to specify who is responsible for carrying out the following functions:

Communications relating to substantial amendments, modified amendments, and trial conclusion
Communications relating to urgent safety measures
Pharmacovigilance reporting

Basic Principles

Terminology (Statutory Definitions Relating to CTIMPs)

5.1 and 5.2

Responsibilities (9.10)

Changes to the trial sponsor/legal representative

2

Trial Sponsor and legal Representative

Amendment of Regulation 3 of the Principal Regulations; Amendment of Regulation 12 of the Principal Regulations; and Part 2 (Conditions Based on Article 3 of the Directive)

Part 1 (3)

Site/Investigator Selection

Last content review/update: May 2, 2024

Overview

As set forth in the AU-ICH-GCPs, the sponsor should select the investigator(s) and the institution(s) for the clinical trial, taking into account the appropriateness and availability of the study site and facilities. The sponsor must also ensure that the investigator(s) are qualified by training and experience. Prior to entering into an agreement with the investigator(s) and the institution(s) to conduct a study, the sponsor should provide the investigator(s) with the protocol and an investigator’s brochure.

According to the G-TrialsSOP, the principal investigator (PI) must ensure that all required staff who assist with the clinical trial are informed about and trained on the protocol, any investigational product (IP), and their research-related duties and functions. This can be in the form of an initiation meeting held by any communication means, including face-to-face, videoconference, telehealth, etc. The PI must also have sufficient time to properly conduct and complete the research within the specified period, as well as an adequate number of qualified staff and adequate facilities for the foreseen duration of the research. When a teletrial is being conducted, the PI, who is always at the primary site and never at the satellite site, remains responsible for the trial across the cluster. For more information on PI site staff training and qualification requirements, see the G-TrialsSOP.

See AUS-64 for additional clinical trial and researcher resources.

Research Governance

The G-NatlStmt indicates that institutions must ensure that any human research for which they are responsible is designed, reviewed, approved, authorized, conducted, and monitored in accordance with the G-CodeConduct and the G-NatlStmt, along with any policies that they have developed that form part of their research governance framework. Each institution should be satisfied that the human research for which it is responsible meets both relevant ethical standards and scholarly or scientific standards, and ensure that those conducting the research (i) are either adequately experienced and qualified, or supervised; (ii) understand the need to assess risks to their own safety and that of participants; and (iii) are aware they are free to withdraw from research on conscientious grounds. Institutions should publish (such as on their website) clear policies and procedures for ethics review and approval and institutional authorization of research. They may establish their own processes for ethics review of research or use the review processes of another institution or external ethics review body.

Per AUS-63, the Australian Commission on Safety and Quality in Health Care developed the National Clinical Trials Governance Framework (AUS-63), which embeds clinical trials into routine health service provisions and strengthens the clinical and corporate governance arrangements for parties that deliver clinical trials. All jurisdictions have agreed to implement the framework in health service organizations, meaning the organizations will be assessed concurrently for clinical and corporate services and clinical trial service provisions. The framework describes the systems and processes that should be in place to implement an effective governance system considering local needs, values, and the context in which services are provided. For more information about implementation timing and assessments under the National Safety and Quality Health Service (NSQHS) standards, see AUS-63.

Foreign Sponsor Responsibilities

As per the G-CTHandbook, the G-TrialsSOP, and AUS-47, a sponsor must be an Australian entity.

Data Safety Monitoring Boards

G-DSMB indicates that the sponsor may establish a Data Safety Monitoring Board (DSMB) to review accumulating trial data in order to monitor the progress of a trial. The role of a DSMB is to provide advice on safety and/or trial conduct issues by making recommendations to the sponsor or trial steering committee on whether to continue, modify, or stop a trial. Per the AU-ICH-GCPs, the DSMB should have written standard operating procedures (SOPs) and maintain written records of all its meetings.

According to the G-TrialsSOP, the sponsor may utilize a DSMB or independent individuals (e.g., a medical monitor) to:

Review accruing trial safety data in either an unblinded or blinded manner to assess treatment exposure
Access, assess, and review emerging efficacy data for the trial
Assess the balance of risks and benefits within the trial
Document the outcome of these reviews

Multicenter Studies

As delineated in the AU-ICH-GCPs, in the event of a multicenter trial, the sponsor must ensure that:

All investigators conduct the trial in strict compliance with the protocol that was agreed to by the sponsor and the Therapeutic Goods Administration (TGA) (if required), and that was approved by the ethics committee (EC)
The case report forms (CRFs) capture the required data at all multicenter trial sites
The responsibilities of coordinating investigator(s) and the other participating investigators are documented prior to the start of the trial
All investigators are given instructions on following the protocol, on complying with a uniform set of standards to assess clinical and laboratory findings, and on completing the CRFs
Communication among investigators is facilitated

As noted in the G-TeletrialPrncpls, Australian jurisdictions agree that “traditionally” multicenter clinical trials assume one (1) PI per geographic site, differing from teletrials. However, for the purposes of teletrials, multicenter trials may include some sites that have satellite sites supervised under teletrial guidance, including the Clinical Oncology Society of Australia (COSA)’s Australasian Tele-trial Model (AUS-2), the G-TeletrialPrncpls, and the G-TrialsSOP. Sponsor responsibilities in teletrials, as described in the G-TrialsSOP, are discussed throughout the Australia profile alongside other clinical trial regulations and guidance. See each section of the Sponsorship topic for additional applicable information.

Role of trial sponsors

What is a DSMB and what is its role?

5

Introduction, Terms, SOP 03, and SOP 12

Section 5 (Chapter 5.1)

Last content review/update: May 16, 2024

Overview

As set forth in the International Council for Harmonisation’s Guideline for Good Clinical Practice E6(R2) (GBR-113), the sponsor is responsible for selecting the investigator(s) and the institution(s) for the clinical trial, taking into account the appropriateness and availability of the study site and facilities. The MHCTR2006 indicates that the sponsor must also ensure that the investigator(s) are qualified by training and experience. Additionally, the sponsor must define and allocate all study related duties and responsibilities to the relevant parties participating in the study. GBR-9 states that the chief investigator (CI) should be based in the United Kingdom (UK). In rare cases when this is not required, adequate arrangements must be in place for supervision of the study in the UK.

As delineated in the MHCTR, the MHCTR2006, and GBR-113, prior to entering into an agreement with the investigator(s) and the institution(s) to conduct a study, the sponsor should provide the investigator(s) with the protocol and an investigator’s brochure. Per GBR-113, if a multicenter trial is going to be conducted, the sponsor must organize a coordinating committee or select coordinating investigators. Per GBR-18, for clinical trials of investigational products (CTIMPs) conducted at National Health Service (NHS) sites, the addition of a new site and/or addition or change of a principal investigator (PI) is no longer considered a substantial amendment. No changes have been made to the classification of amendments relating to new sites/change of PI at non-NHS sites. If a site is added in a nation not previously involved in a study, this should be indicated in the combined review section (GBR-125) of the Integrated Research Application System (IRAS) for CTIMPs, and made clear in a cover letter when submitting the amendment to the lead nation.

GBR-113 recommends establishing a Data Monitoring Committee (DMC) to assess the progress of 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 trial.

Per GBR-63, researchers working with NHS/Health and Social Care in Northern Ireland (HSC) organizations across England, Northern Ireland, Scotland, and Wales should use the UK Local Information Pack, which provides one (1) consistent package to support study setup and delivery across the UK. For help with preparing and submitting these packages and site-specific information, see GBR-106.

Foreign Sponsor Responsibilities

GBR-103 provides that if a sponsor(s) is not established in the UK or on an approved country list (which initially includes European Union (EU)/European Economic Area (EEA) countries), it is a statutory requirement to appoint a legal representative based in the UK or a country on the approved country list for the purposes of the trial. Per the G-CTApprovedCountries, the UK published a list of countries where a sponsor of a clinical trial, or their legal representative, may be established; currently listed countries are those in the EU and EEA. The G-SubtlAmndmt delineates that a change in sponsor or legal representative for a UK trial is a substantial amendment requiring submission to both the Medicines and Healthcare Products Regulatory Agency (MHRA) and the ethics committee (EC), pursuant to the guidelines in the G-CTAuth-GBR. Where the sponsor is from the rest of the world, and the legal representative is established in the UK, and there are sites in the EU/EEA, the sponsor will need to assign an EU/EEA legal representative for these sites via a substantial amendment to the relevant EU/EEA competent authorities. No amendment submission to the MHRA is required where the sponsor or legal representative for an ongoing trial is established in the EU/EEA as the UK will continue to accept this approval. Further, no amendment will need to be submitted in the UK if the sponsor retains the UK legal representative for the UK study. Similarly, no amendment will need to be submitted in the UK if a sponsor remains in the UK and a legal representative is added to cover EU/EEA sites.

Additional foreign sponsor requirements are listed in Section 5.2 of GBR-113.

Data Safety and Monitoring Board

Per GBR-18, the chief investigator should ensure that arrangements are made for a data safety and monitoring board (known as a data monitoring committee (DMC) in the UK). GBR-113 recommends establishing a DMC to assess the progress of 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 trial.

Multicenter Studies

Per GBR-18, for multicenter trials, the careful selection and evaluation of investigator sites is critical for the successful completion of a trial within budget, timelines, and to ensure the generation of high-quality data. When undertaking site selection, the preparation of ‘reserve’ investigator sites (so that the trial may be extended to these sites if recruitment issues arise) should be considered as part of proactive trial planning. Factors that should influence investigator site selection include:

Interest in the research question
Experience and qualifications of the investigator
Sufficient staff to conduct the study and their experience and qualifications
Availability of a suitable patient population
Adequate time to conduct and oversee the trial
Adequate facilities
Previous track record with similar trials
Geographic location
Contractual and budgetary negotiations and arrangements

Per GBR-18, for multicenter trials, the CI must ensure that each PI is provided with all relevant, version-controlled documents before commencing recruitment. Further, it is good practice to ensure the PI signs a protocol signature page to confirm receipt and their agreement to comply with the current version of the protocol. The trial master file should be held at the coordinating site and copies of relevant documents should be kept at each participating site in an investigator site file.

Further, as delineated in GBR-113, in the event of a multicenter clinical trial, the sponsor must ensure that:

All investigators conduct the trial in strict compliance with the protocol agreed to by the sponsor
The case report forms (CRFs) are designed to capture the required data at all multicenter trial sites
Investigator responsibilities are documented prior to the start of the trial
All investigators are given instructions on following the protocol, complying with a uniform set of standards to assess clinical and laboratory findings, and completing the CRFs
Communication between investigators is facilitated

1.1

5.23, 5.5, 5.6, 6, and 7

CI Checklist Before Seeking Approval, Addition of New Sites & Investigators, Final Trial Management Documentation, Feasibility & Investigator Selection, Final Protocol, and Trial Master File

Preparing and Submitting Application (Site-specific information)

Changes to the trial sponsor/legal representative

2

Amending your trial protocol or other documentation

Insertion of Regulation 3A of the Principal Regulations, Insertion of Regulation 29A of the Principal Regulations, and Part 2 (Principles based on Articles 2 to 5 of the GCP Directive)

Part 1 (3) and Part 3 (15)

Insurance & Compensation

Last content review/update: May 2, 2024

Insurance

The AU-ICH-GCPs and the G-NatlStmt state that the sponsor should provide insurance in accordance with applicable regulatory requirements. In addition, according to the G-NatlStmt, institutions must ensure that sponsors have insurance arrangements in accordance with applicable regulatory requirements. The federal documents cited here do not explicitly require insurance.

Per the G-GovHndbk, the institution and investigator are responsible for managing risks of any proposed research, including providing appropriate insurance coverage.

Compensation

Injury or Death

According to the G-NatlStmt, institutions must ensure that sponsors have indemnity and compensation arrangements in accordance with applicable regulatory requirements, and that arrangements are in place to compensate trial participants for harm resulting from negligence in research. The AU-ICH-GCPs further indicates that the sponsor must explain to participants the compensation and/or treatment available to them in the event of trial-related injuries. The federal documents cited here do not explicitly require indemnity.

The G-TrialsSOP states that if the investigator is notified or becomes aware that a trial participant intends to make a claim against the institution or sponsor for injuries arising as a result of participating in a clinical trial undertaken at the institution (or any of the satellite sites under supervision by the institution in a teletrial), the investigator must promptly notify the following parties in writing that such an action is intended:

The institution’s authority
The coordinating principal investigator (CPI)/principal investigator (PI)/associate investigator, as relevant
The sponsor

In addition, if the institution is notified or becomes aware that a trial participant intends to make a claim for compensation against the institution or sponsor for injuries arising as a result of participating in a clinical trial undertaken at the institution (or any of the satellite sites under supervision by the institution in a teletrial), the institution must promptly notify the institution’s insurer in writing that such an action is intended.

See AUS-39 for indemnity and injury compensation guidelines for commercially-sponsored trials.

Trial Participation

The G-NatlStmt states that it is generally appropriate to reimburse participants for the costs associated with taking part in research including travel, accommodations, and parking. Sometimes participants may also be paid for time involved. However, payment may not be disproportionate to the time involved, or include other incentives that encourage participants to take risks. Further, payment or reimbursement decisions should consider customs and practices of the community in which the trial will be conducted.

According to the G-ResearchPayment, any proposal for payment of participants should be considered by the ethics committee (EC) reviewing the research. The EC should be provided with a payment plan that includes:

A rationale for the proposed payments
The method and timing of any disbursements, including how they have been calculated, and
Information about how prospective participants will be advised of the provision of payment

Payment of participants is ethically appropriate if it is equitable and proportionate to the burden of the research, and does not:

Undermine a participant’s capacity to provide voluntary and informed consent
Unduly influence a participant to accept a risk or burden that is greater than they would otherwise accept in everyday living or to compromise their fundamental values
Unduly influence a participant to make false representations about or conceal information that is relevant to their eligibility for the research, their contribution to the research, or the risks related to participation

To minimize the likelihood of a payment acting as an undue influence, the G-ResearchPayment further indicates that payment of participants should generally be limited to reimbursement of documented expenses and remuneration for time and inconvenience. Payment may be offered as an incentive to participate in cases where the research offers little or no benefit to individuals or where the research requires the participation of target populations that are difficult to recruit. In these cases, adequate processes must be in place to promote valid consent. For more information and examples of payment models, see the G-ResearchPayment.

According to the AU-ICH-GCPs, payments to a participant should be prorated and not wholly contingent on completion of the trial by the participant.

Post-Trial Access

Per the G-NatlStmt, researchers must make clear to the participant if there are any intended therapeutic benefits from the trial, and if the treatment will be available only through participation in the trial. In addition, researchers must make it clear to the participant whether they will have access to the treatment or information they received after completion of the trial.

3, 4, 5, and 8

Guidance Statements

IV

SOP 05

Sections 2 (Chapter 2.2), 3 (Chapter 3.1), and 5 (Chapter 5.1)

Last content review/update: May 16, 2024

Insurance

As set forth in the MHCTR and the MHCTR2006, it is a legal requirement for an insurance and indemnity provision to be made to cover the liability of the investigator and sponsor for trial-related injuries. The MHCTR does not ascribe responsibility to the sponsor or the designated representative to obtain insurance and indemnity. However, GBR-2, GBR-103, GBR-101, and GBR-18 state that the sponsor or the designated representative is responsible for ensuring adequate insurance and indemnity arrangements are in place to cover the sponsor’s and the investigator’s potential liability, and for providing a copy of this coverage in the clinical trial application submission.

In addition, according to GBR-2, the sponsor or the designated representative must ensure that the research covered by the National Health Service (NHS)’s indemnity policy is in place for each publicly funded participating study site. See GBR-33 for detailed information on the NHS indemnity responsibilities for clinical negligence involving investigators and participants. GBR-33, specifically addresses the sponsor’s or the designated representative’s requirement to insure or indemnify the investigator participating in industry-sponsored Phase 1 clinical trials.

The International Council for Harmonisation’s Guideline for Good Clinical Practice E6(R2) (GBR-113) also guides sponsors on providing insurance.

Compensation

Injury or Death

As specified in the MHCTR, the sponsor or the designated representative is responsible for providing compensation to research participants and/or their legal heirs in the event of Phase 1 trial-related injuries or death. According to GBR-33, the sponsor must have agreed with the research participant to provide compensation for injury whenever a causal relationship with participation is demonstrated. This undertaking can be provided directly by the sponsor through the consent process, or through authorizing the contract research organization (CRO) or investigator on behalf of the sponsor. In addition, the sponsor should follow these practices:

If the health or wellbeing of the participant deteriorates significantly as a result of taking part in the study, the sponsor will compensate the volunteer, irrespective of the ability of the participant to prove fault on the part of the sponsor or anyone else connected with the study.
The amount of compensation should be calculated by reference to the amount of damages that would commonly have been awarded for similar injuries by an English court had liability been proven. The amount of compensation may be reduced if the volunteer is partly responsible for the injury or if the volunteer is separately compensated under any other insurance policy.
The sponsor and participant agree to refer any dispute about whether compensation is payable or the amount of such compensation to an arbitrator with power to consult a barrister of 10 years’ standing on any issue of law, including the amount of damages to be paid.
Participants should be given a copy of the relevant Association of the British Pharmaceutical Industry (ABPI) guidelines and should be invited to seek clarification of any aspect of the undertaking that is not clear to them.
Participants may make a claim through the investigator, and the sponsor should aim to respond sympathetically and promptly.

GBR-113 also provides guidance for sponsors on providing compensation to research participants in the event of trial-related injuries or death. The sponsor must explain to participants the compensation and/or treatment available to them in the event of trial-related injuries.

3, 4, and 6

Introduction and Basic Principles

5.8

CI Checklist Before Seeking Approval (Trial Planning Phase) and Final Trial Management Documentation

Responsibilities

Part 2 (Conditions Based on Article 3 of the Directive)

Part 3 (15), Part 4 (8), and Schedule 1 (Part 1 (1) and (16))

Risk & Quality Management

Last content review/update: May 2, 2024

Quality Assurance/Quality Control

As per the TGR and the AU-ICH-GCPs, the sponsor should implement a system to manage quality throughout all stages of the trial process, focusing on trial activities essential to ensuring participant protection and the reliability of trial results.

According to the AU-ICH-GCPs, the quality management system should use a risk-based approach that includes:

Identifying processes and data that are critical to ensure participant protection and the reliability of trial results during protocol development
Identifying risks to critical trial processes and data
Evaluating the identified risks against existing risk controls
Deciding which risks to reduce and/or accept
Documenting quality management activities and communicate to those involved in or affected by these activities
Periodically reviewing risk control measures to ascertain whether the implemented quality management activities are effective and relevant
Describing the quality management approach implemented in the trial and summarize important deviations from the predefined quality tolerance limits and remedial actions taken in the clinical study report

The G-RBMgmtMntring provides further guidance on the application of risk-based trial processes, particularly as a reference to sponsors of non-commercial trials.

The AU-ICH-GCPs further indicates that the sponsor is responsible for implementing and maintaining quality assurance (QA) and quality control (QC) systems with written standard operating procedures (SOPs) to ensure that trials are conducted and data generated, recorded, and reported in compliance with the protocol, the AU-ICH-GCPs, and the applicable regulatory requirements. The sponsor is responsible for obtaining agreement from all involved parties to ensure direct access to all trial-related sites, source data/documents, reports for monitoring and auditing purposes, and inspection by domestic and foreign regulatory authorities. The sponsor should implement a system to manage quality throughout all stages of the trial process, and QC should be applied to each stage of data handling to ensure that all data are reliable and have been correctly processed. Any agreements between the sponsor and investigator, or with any other parties involved in the clinical trial, should be written, either within the protocol or in a separate agreement.

Responsible Research Conduct

The G-CodeConduct outlines principles, responsibilities, and expectations for institutions and researchers to facilitate responsible research practices. Australian institutions must establish and maintain good governance and management practices for responsible research conduct. In addition, researchers must comply with the relevant laws, regulations, disciplinary standards, ethics guidelines, and institutional policies related to responsible research conduct. Compliance with the G-CodeConduct is a requirement to receiving funding from the National Health and Medical Research Council (NHMRC) or the Australian Research Council (ARC).

The G-CodeBreaches describes the preferred model for institutions to use to investigate and manage potential code breaches, to determine any corrective actions, and when a finding of research misconduct may be made. The Australian Research Integrity Committee uses the G-CodeBreaches as a guide for reviewing how NHMRC- and ARC-funded institutions manage potential code breaches.

The G-RptBreachGCP requires the sponsor to notify the reviewing ethics committee (EC) (Human Research Ethics Committee (HREC) in Australia) within seven (7) days of confirming a serious breach of good clinical practice (GCP). A serious breach is defined as one that is likely to affect to a significant degree: the safety or rights of a trial participant or the reliability and robustness of the data generated in the trial. Sponsors should also develop documented processes for managing serious breaches. The G-TrialsSOP notes that although all deviations or breaches of the protocol must be reported by the investigator to the sponsor, only serious breaches must be reported to the EC. Serious breaches should also be reported by the principal investigator (PI) to their institution, as they may have an impact on medico-legal risk, the responsible conduct of research, or adherence to contractual obligations.

The supplementary guidance G-RptBreachGCP should be read alongside the G-CodeConduct and the G-CodeBreaches.

Monitoring Requirements

As part of its QA system, the AU-ICH-GCPs notes that the sponsor should ensure the trial is monitored and audited. The purpose of the audit should be to evaluate trial conduct and compliance with the protocol, SOPs, the AU-ICH-GCPs, and other applicable regulatory requirements. The sponsor should appoint auditors to review the clinical trial. The sponsor should ensure that the auditors are qualified by training and experience, and the auditor’s qualifications should be documented. The sponsor must also ensure that the audit is conducted in accordance with its own SOPs and that the auditor’s observations are documented.

Per the G-TrialsSOP, the PI must ensure audit/inspection readiness throughout the study, have oversight of any audit or inspection of the trial at both primary and satellite sites, and ensure any deficiencies identified through audit or inspection are actively managed to ensure continuous improvement.

The TGR further states that the sponsor must provide a written assurance to comply with any trial-related requests by an authorized Therapeutic Goods Administration (TGA) officer(s), which includes allowing inspection of clinical trial sites. The PI is required to comply with requests and answer any questions the authorized officer(s) may have.

Premature Study Termination/Suspension

As per the G-CTHandbook, procedures following the TGA’s revocation of approval under the Clinical Trial Approval (CTA) scheme or a breach of the conditions of the Clinical Trial Notification (CTN) scheme would be determined on a case-by-case basis based on the impact on participants and their ongoing safety. The AU-ICH-GCPs states that if a trial is prematurely terminated or suspended, the sponsor should promptly inform the investigator(s), institution(s), the EC, and the TGA. The sponsor should provide the reason(s) for the termination or suspension. Additionally, as indicated in the G-CTHandbook, the sponsor must notify all sites in the case of a multicenter trial. A lead EC in a multicenter study will need to liaise with the sites and sponsor when determining which, if any, are affected and the actions they need to apply.

According to the G-TrialsSOP, if a trial is prematurely terminated or suspended for any reason, the investigator must:

Promptly inform the sponsor, EC, research governance officer, associate investigator, any satellite site, and the TGA by providing a detailed written explanation of the premature termination or suspension
Promptly inform the trial participant and the participant’s primary care physician where the trial participant has consented, of the termination or suspension and, if applicable, of the investigational product (IP) and dose that was administered
Assure appropriate therapy and follow up for the participant’s continued care

As per the G-NatlStmt, if an institution or EC considers that suspension of research is necessary, the instruction to stop should come from the management of the institution. Where ethics approval for a research project is suspended:

The institution must ensure that the researcher promptly suspends the research and makes arrangements to meet the needs of participants, such as ensuring that appropriate counselling support or the provision of standard care continues
The research may not be resumed unless: (i) the research is modified to provide sufficient protection or participants or address the concerns that led to the suspension; or (ii) the researcher establishes to the satisfaction of the EC that continuation of the research will not compromise participants’ welfare; and (iii) the institution authorizes the continuation of the research

The G-NatlStmt further indicates that if ethics approval for a research project is withdrawn, the researcher must promptly halt the research, make arrangements to meet the needs of participants, and notify the institution that these steps have been taken.

Responsibilities under the CTN and CTA schemes

Preamble, Responsibilities of institutions, and Responsibilities of researchers

Introduction

5

SOPs 02, 05, and 13

Section 5 (Chapter 5.4)

Background and Scope

Part 3 (12AB and 12AC)

Last content review/update: October 25, 2024

Quality Assurance/Quality Control

As stated in the MHCTR, the MHCTR2006, and GBR-92, the sponsor is responsible for maintaining quality assurance (QA) and quality control (QC) systems with written standard operating procedures (SOPs) to ensure that trials are conducted and data are generated, recorded, and reported in compliance with the protocol and the International Council for Harmonisation’s Guideline for Good Clinical Practice E6(R2) (GBR-113). The sponsor is required to obtain agreement from all involved parties to ensure direct access to all trial related sites, source data/documents, reports for monitoring and auditing purposes, and inspection by domestic and foreign regulatory authorities. QC should be applied to each stage of data handling to ensure that all data are reliable and have been correctly processed. The sponsor must also obtain the investigator(s) and the institution(s) agreement to:

Conduct the trial in compliance with GBR-113 and the protocol agreed to by the sponsor and approved by the ethics committee (EC)
Comply with data recording and reporting procedures
Permit monitoring, auditing, and inspection
Retain essential documents until the sponsor informs them that they are no longer needed

MHCTR2006 requires the sponsor to notify the Medicines and Healthcare Products Regulatory Agency (MHRA) of serious breaches of good clinical practice (GCP) or the trial protocol. A serious breach is defined as one that is likely to affect to a significant degree: the safety or physical or mental integrity of the trial participants; or the scientific value of the trial. Per G-MHRA-SeriousBreaches, the sponsor or delegated party should notify the MHRA GCP Inspectorate within seven (7) days of becoming aware of a serious breach. Further, the sponsor should investigate and take action simultaneously after the MHRA notification. Notifications should primarily be sent to the following email address: GCP.SeriousBreaches@mhra.gov.uk.

Per the G-RiskAssmt, MHRA recommends that a risk assessment is undertaken for all clinical trials. Phase 1 trials are required to have a documented risk assessment process and to produce a risk assessment for all proposed trials. The risk assessment should be done as early as possible to help the sponsor identify whether the sponsor wishes to proceed with sponsorship and the potential category of IP for eventual marketing authorization. An early risk assessment will also identify the study management requirements, which can assist in the planning and resourcing aspects of the trial (e.g., identification of trial monitoring requirements so that these can be budgeted for in any funding application). There is no requirement to submit risk assessments to the MHRA or the ethics committee (EC). However, any safety monitoring produced because of the risk assessment must be described in the protocol. Finally, information contained in the risk assessment may prove useful in completing the application form for approvals, particularly for the EC application. See the G-RiskAssmt for details on how to conduct the risk assessment.

See GBR-10 for best practices in improving clinical trial setup to reduce timelines and increase citizens’ access to research. Also see GBR-34 for investigator training and guidance on implementing people-centered research.

Monitoring Requirements

Per GBR-18, the sponsor must develop an audit plan to assess and assure the reliability and integrity of the clinical trial systems against all relevant written standards. The following activities and checks could include the following:

Interview staff to assess whether they are appropriately trained; understand their role(s); and are working to all relevant standards, the protocol, and SOPs.
Tour the facility to assess if there are adequate resources and if the equipment is fit for its intended use.
Review documents to evaluate whether data reported is verifiable from source data and that written records confirm that the trial was conducted appropriately.

Auditors must be independent of the trial team and appropriately trained for their role. Their findings and observations must be documented in a formal audit report. Any deficiencies identified during an audit must be followed up with appropriate corrective and preventive actions wherever possible.

Per GBR-18, the MHRA may conduct inspections to ensure the clinical trial is being conducted in compliance with good clinical practice (GCP) as prescribed in GBR-92 and GBR-113. The MHRA takes a risk-based approach to inspections depending on the type of trials and risk rating. Once an inspection has been completed, a formal report outlining the findings will be sent to the inspected organization. A response to this report (describing any corrective and preventive actions) must be produced. See GBR-92 for pre-inspection checklists and other resources. Per G-RiskAssmt, GCP Inspectors will review risk assessments. The risk assessment should provide the rationale behind trial management/monitoring and GCP activities applied, or not, to the trial.

Finally, the sponsor’s audits and inspections should be conducted in compliance with GBR-113, which calls for a systematic, prioritized, risk-based approach to monitoring clinical trials. The extent and nature of monitoring is flexible and permits varied approaches that improve effectiveness and efficiency. The sponsor may choose on-site monitoring, a combination of on-site and centralized monitoring, or where justified, centralized monitoring. The sponsor should document the rationale for the chosen monitoring strategy (e.g., in the monitoring plan). The G-Ovrsight provides additional guidance to assist sponsors and those conducting trials on implementing adequate oversight and monitoring processes for clinical trials.

Premature Study Termination/Suspension

The G-CTAuth-GBR states that the MHRA has the authority to suspend or terminate a trial. In addition, the sponsor can contact the MHRA to put a trial on temporary halt or terminate a trial. If a sponsor suspends a trial temporarily, the MHRA must be notified. Sponsors of clinical trials of investigational products (CTIMPs) must use the combined review part of the Integrated Research Application System (IRAS) (GBR-125) to submit this notification as a substantial amendment. Per GBR-122, for studies that were submitted before combined review, these applicants should continue to submit this notification at IRAS via GBR-78. The G-CTAuth-GBR indicates the notification should be made as a substantial amendment using the amendment tool, clearly explaining what has been stopped and the reasons for the suspension. To restart a trial that has been temporarily suspended, you must make the request as a substantial amendment using the notification of amendment form, providing evidence that it is safe to restart the trial.

Per the G-CTAuth-GBR and GBR-18, to terminate a CTIMP, the sponsor must notify (as a substantial amendment) the MHRA and the EC via the combined review part of IRAS (GBR-125). For studies that were submitted before combined review, the submission should be made at GBR-78, using the end-of-trial form (GBR-133). GBR-128 specifies that for CTIMPs, the declaration of end of trial must be sent to the MHRA within 15 days of the global premature end of trial. Before declaring an end of the study, sponsors should review the plans that were approved by the EC for use of tissue and data collected in the course of the study, providing information to participants, and dissemination of results. If changes need to be made to these agreed upon arrangements, the sponsor should consider whether an amendment is required before submitting the end of study notification. GBR-65 also states that if research is terminated early or is temporarily suspended, then all relevant review bodies should be notified within 15 days.

According to GBR-113, if it is discovered that noncompliance significantly affects or has the potential to significantly affect participant protection or reliability of trial results, the sponsor should perform a root cause analysis and implement appropriate corrective and preventive actions. Further, the sponsor should also inform the EC promptly and provide the reason(s) for the termination or suspension.

5.0, 5.1, 5.2, 5.18, 5.19, 5.21, and 6.10

Ongoing Management & Monitoring, MHRA Inspection, Audit, Temporary Halt, Early Termination, and End of Trial Declaration

Early termination or temporary halt of research

Suspend or Terminate a Trial and End of Trial

Amendment of Regulation 31 of the Principal Regulations and Part 2 (Principles Based on Articles 2 to 5 of the GCP Directive)

Part 3 (15), Part 4 (28), Part 6 (36 and 38), and Schedule 7 (Parts 2 and 3)

Data & Records Management

Last content review/update: May 2, 2024

Electronic Data Processing System

When using electronic trial data handling systems, the sponsor must ensure and document that the electronic data processing system conforms to its established requirements for completeness, accuracy, reliability, and consistent intended performance, and that standard operating procedures (SOPs) are maintained for using these systems. Refer to the AU-ICH-GCPs for additional information.

Records Management

According to the G-CodeConduct and the G-DataInfoMgt, institutions must provide access to facilities for the safe and secure storage and management of research data, records, and primary materials.

The G-DataInfoMgt requires that institutional policy include guidance for managing research data and primary materials that addresses the following:

Ownership, stewardship, and control
Storage, retention, and disposal
Safety, security, and confidentiality
Access by interested parties

Furthermore, institutional policies on ownership of, and access to, databases and archives must require that:

Researchers are informed of relevant confidentiality agreements and restrictions on the use of research data
Computing systems are secure
Information technology personnel understand their responsibilities for network security and access control
Those holding primary material, including electronic material, understand their responsibilities for security and access

The G-CodeConduct and the G-DataInfoMgt further state that researchers must retain clear, accurate, secure, and complete records of all research including research data and primary materials. Additionally, the G-NatlStmt indicates that when multiple researchers are collaborating on the collection, storage, and/or analysis of data or information, they should agree to the arrangements for custodianship, storage, retention, and destruction of those materials, as well as the rights of access, rights to analyze/use and re-use the data or information, and the right to produce research outputs based upon them.

According to the G-TrialsSOP, the investigator must maintain adequate source documents and trial records, including all key observations on each of the trial participants. The investigator must also store all trial related documents in a study master file (SMF) and take measures to prevent accidental or premature destruction of these documents. In the case of a teletrial, the SMF is stored at the primary site, and the principal investigator (PI) must have control of all essential documents and records generated by the investigator(s), institution, and satellite site(s) before, during, and after the trial. The PI must also establish the maintenance rules of the SMF and relationship between the primary site’s SMF and any satellite site study files. For more information on the SMF, see the G-TrialsSOP.

As set forth in the annotated AU-ICH-GCPs, the Therapeutic Goods Administration (TGA) requires that the sponsor retain records for 15 years following the completion of a clinical trial. However, product liability is the overriding consideration, and the sponsor should be able to produce records at any time, including possibly beyond the life of a product, in the event of an adverse event claim. The sponsor should inform the investigator(s) and the institution(s) in writing when trial-related records are no longer needed.

Data Management Plan

According to the G-NatlStmt and the G-DataInfoMgt, researchers should create a data management plan, which should be developed as early as possible in the research process and should include details regarding:

Physical, network, system security, and any other technological security measures
Policies and procedures
Contractual and licensing arrangements and confidentiality agreements
Training for members of the project team and others, as appropriate
The form in which the data or information will be stored
The purposes for which the data or information will be used and/or disclosed
The conditions under which access to the data or information may be granted to others
What information from the data management plan, if any, needs to be communicated to potential participants

The G-NatlStmt states that in the data management plan, researchers should also clarify whether they will seek extended or unspecified consent for future research, or permission from a review body to waive the requirement for consent. In addition, the security arrangements specified in the plan should be proportional to the risks of the research project and the sensitivity of the information.

In accordance with the G-NatlStmt, researchers must comply with all relevant legal and regulatory requirements that pertain to the data or information collected, used, or disclosed as well as the conditions of the consent provided by participants. Data, information, and biospecimens used in research should be disposed of in a manner that is safe and secure, consistent with the consent obtained and any legal requirements, and appropriate to the research design.

The G-NatlStmt indicates that in the absence of justifiable ethical reasons and to promote access to the benefits of research, researchers should collect and store data, or information generated by research projects, in such a way that they can be used in future research projects. A justification must be provided when a researcher believes there are valid reasons for not making data or information accessible. More details are provided in the G-NatlStmt.

In addition, for details related to secondary use and sharing of data or information, see the G-NatlStmt.

Preamble, Responsibilities of Institutions, and Responsibilities of Researchers

5

Responsibilities of Institutions and Responsibilities of Researchers

SOPs 07 and 08

Section 3 (Chapter 3.1)

Last content review/update: May 16, 2024

Electronic Data Processing System

To safeguard personal data within electronic health record (EHR) systems, G-EHRAccess provides guidance on updating these systems to ensure access by sponsors and their representatives (e.g., monitors and investigators) is limited to only the records of clinical trial participants and that this access is auditable. See G-EHRAccess for details on system security, remote access, document sharing, consent, and other considerations.

According to GBR-113, when using electronic trial data handling processing systems, the sponsor must ensure and document that the electronic data processing system conforms to the sponsor’s established requirements for completeness, accuracy, reliability, and consistency of intended performance. To validate such systems, the sponsor should use a risk assessment approach that takes into consideration the system’s intended use and potential to affect human participant protection and reliability of trial results. In addition, the sponsor must maintain standard operating procedures (SOPs) that 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. With respect to the use of these computerized systems, the responsibilities of the sponsor, investigator, and other parties should be clear, and the users should receive relevant training.

Records Management

As set forth in GBR-113, sponsor-specific essential documents should be retained until at least two (2) years after the last approval of a marketing application, until there are no pending or contemplated marketing applications, or at least two (2) years have elapsed since the formal discontinuation of the investigational product’s clinical development. The sponsor should inform the investigator(s) and the institution(s) in writing when trial-related records are no longer needed.

However, per the MHCTR2006, the sponsor and the Chief Investigator must ensure that the documents contained in the trial master file are retained for at least five (5) years following the trial’s completion. The documents must be readily available to the Medicines and Healthcare Products Regulatory Agency (MHRA) upon request and be complete and legible. The sponsor should ensure that trial participant medical files are also retained for at least five (5) years after the trial’s conclusion.

In addition, GBR-113 states that the sponsor and investigator/institution should maintain a record of the location(s) of their respective essential documents including source documents. The storage system used during the trial and for archiving (irrespective of the type of media used) should allow for document identification, version history, search, and retrieval. The sponsor should ensure that the investigator has control of and continuous access to the data reported to the sponsor. The investigator/institution should have control of all essential documents and records generated by the investigator/institution before, during, and after the trial.

1.65, 5.18, and 8

Part 2 (Principles Based on Articles 2 to 5 of the GCP Directive)

Personal Data Protection

Last content review/update: May 2, 2024

Responsible Parties

Per AUS-70, the PrivacyAct regulates how certain health service providing organizations collect and handle personal information, including health information. It also includes provisions that generally allow an individual to access information held about them.

According to the PrivacyAct, agencies and organizations as defined in the PrivacyAct must comply with the Act and the Australian Privacy Principles (APP), found in Schedule 1, and are referred to as APP entities.

Data Protection

Per the PrivacyAct’s APP, an APP entity must have a clearly expressed and up-to-date policy about the management of personal information by the entity. Individuals must have the option of not identifying themselves or of using a pseudonym, and an APP entity must not collect sensitive information about an individual unless the individual consents to the collection of the information.

The APP outline further requirements for the consideration of personal information privacy; the collection of personal information; dealing with personal information; the integrity of personal information; and access to, and correction of, personal information. For the full list of APP, see Schedule 1 of the PrivacyAct.

Consent for Processing Personal Data

The PrivacyAct’s APP indicate that if an APP entity holds personal information about an individual that was collected for a particular purpose, the entity must not use or disclose the information for another purpose unless consent is obtained from the individual. There are limited exceptions to this requirement, which can be found in Schedule 1 of the PrivacyAct.

AUS-70 notes that in certain circumstances, the PrivacyAct permits the handling of health information and personal information for health and medical research purposes, where it is impracticable for researchers to obtain individuals' consent, recognizing: the need to protect health information from unexpected uses beyond individual healthcare, and the important role of health and medical research in advancing public health. To promote these ends, the Office of the Australian Information Commissioner (OAIC) approved the National Health and Medical Research Council (NHMRC)’s legally binding guidelines, G-PrivacyAct95 and G-PrivacyAct95A, which researchers must follow when handling health information for research purposes without individuals' consent. The guidelines also assist ethics committees (ECs) (known as the Human Research Ethics Committees in Australia) in deciding whether to approve research applications. The guidelines are:

G-PrivacyAct95, which sets out procedures that ECs and researchers must follow when personal information is disclosed from a federal agency for medical research purposes
G-PrivacyAct95A, which provides a framework for ECs to assess proposals to handle health information held by organizations for health research (without individuals' consent). It ensures that the public interest in the research activities substantially outweighs the public interest in the protection of privacy

See the PrivacyAct, the G-PrivacyAct95, and the G-PrivacyAct95A for more information.

Part II (6), Part III (15 and 16B), and Schedule 1

Last content review/update: May 16, 2024

Responsible Parties

For purposes of data protection requirements, the UK-GDPR, the UK-DPAct, and the G-GDPR delineate that the sponsor acts as the “controller” in relation to research data. This is because the sponsor determines what data is collected for the research study through the protocol, case report form, and/or structured data fields in a database. GBR-7 provides guidance on key data protection requirements to consider in the post-Brexit environment. Among other things, it describes how data can continue to flow to and from the United Kingdom (UK), as well as controller responsibilities.

Data Protection

Per the UK-GDPR, the UK-DPAct, the G-GDPR, and GBR-89, the sponsor (known as the “controller” in data protection legislation) must comply with the following principles of the data protection legislation:

Lawfulness, fairness, and transparency
Purpose limitation
Data minimization
Accuracy
Storage limitation
Integrity and confidentiality (security)
Accountability

The sponsor must show that each data processing activity has a lawful basis under this legislation, in addition to the common law basis. For health and social care research, the lawful basis is determined by the data controller’s organization type:

For universities, National Health Service (NHS) organizations, Research Council institutes, or other public authority, the processing of personal data for research should be a “task in the public interest.”
For commercial companies and charitable research organizations, the processing of personal data for research should be undertaken within “legitimate interests.”

As described in the G-GDPR, with regard to transparency, the sponsor should understand whether personal data is collected indirectly from a third party or directly, as these determine the actions to take to comply with data protection requirements. In most cases, the sponsor will need to provide transparency information about the legal basis and other details of processing personal data. See the table in G-GDPR, which sets out the specific transparency requirements for personal data. In addition, GBR-100 contains a series of templates by the Health Research Authority (HRA) with suggested transparency language. Further, the sponsor should take measures to ensure data is processed securely, giving consideration to security, storage, and pseudonymization/anonymization when possible. For details on complying with security and storage requirements, see GBR-100.

Per the UK-GDPR and the UK-DPAct, the data protection legislation introduces a duty requiring public authorities or bodies to appoint a data protection officer (DPO); a DPO may be required for non-public entities if they carry out certain types of processing activities. The DPO assists the sponsor with monitoring internal compliance, informs and advises on data protection obligations, provides advice regarding Data Protection Impact Assessments (DPIAs), and is a point of contact for participants and the supervisory authority. See G-GDPR for guidance related to DPIAs.

For more information on data protection requirements following the UK’s transition out of the European Union (EU), see GBR-7.

Consent for Processing Personal Data

Per the UK-GDPR, UK-DPAct, and G-GDPR, consent to participate in research is not the same as consent as the legal basis for processing personal data under the data protection legislation. Per the G-GDPR, for the purposes of the UK-GDPR, the legal basis for processing data for health and social care research should not be consent. This means that requirements in the UK-GDPR relating to consent do not apply to health and care research. Per the G-GDPR, even though consent is not the legal basis for processing personal data for research, the common law duty of confidentiality still applies, so consent is still needed for people outside the care team to access and use confidential information for research.

As delineated in the UK-GDPR, the UK-DPAct, the G-GDPR, and GBR-89, participants have the right to be informed about the collection and use of their personal data. This is a key transparency requirement under the data protection legislation. The UK-GDPR specifies what data individuals have the right to be informed about (i.e., privacy information). In addition, as delineated in the UK-GDPR, the UK-DPAct, the G-GDPR, and GBR-89, the participant has certain data rights, which are limited by a range of exemptions. These exemptions must be balanced with what is fair to participants. As indicated in the G-GDPR, exemptions to data subject rights are not automatic, but must be considered on a study-by-study basis. It is important, therefore, to take into account the relevance of data rights to a particular study in the Participant Information Sheet (PIS) when offering or limiting the rights available to research participants. If data rights have been previously offered or limited to participants that are not appropriate under UK-GDPR, then the PIS may need to be revised as a non-substantial amendment.

As indicated in the G-GDPR and GBR-100, the HRA has developed a series of templates with transparency language to help organizations comply with the data protection legislation. The requirements vary depending on the point of collection of personal data (directly or indirectly) and the timing of the study. Also see GBR-129 for guidance from the UK Information Commissioner’s Office.

UK-US Data Bridge

As explained in GBR-22, under the “UK Extension to the EU-US Data Privacy Framework” (GBR-23), businesses in the UK can transfer personal data to certified U.S. organizations without further safeguards as defined in the GBR-23. US organizations that have been certified can opt in to receive data from the UK through the UK-US data bridge. Per GBR-19, before transferring personal data, UK organizations must verify that the receiving US organization is certified pursuant to GBR-23. Sensitive personal data must be appropriately identified as sensitive when transferred under the UK-US data bridge to ensure it receives appropriate protections under the framework. Under the UK extension, sensitive personal information includes genetic data, biometric data for the purpose of uniquely identifying a natural person, and data concerning sexual orientation. See GBR-22, GBR-23, and GBR-19 for additional information about the UK Extension to the Data Privacy Framework.

Principles, Lawful Basis for Processing, Individual Rights, Accountability and Governance

Part 1, Part 2 (Chapter 2), and Schedules 2-4

Documentation Requirements

Last content review/update: May 2, 2024

Obtaining Consent

In all Australian clinical trials, valid consent is required from each participant in accordance with the requirements set forth in the AU-ICH-GCPs and the G-NatlStmt. According to the AU-ICH-GCPs, if requirements specified in the G-NatlStmt appear to differ from those specified in the AU-ICH-GCPs, the Therapeutic Goods Administration (TGA) recommends compliance with the G-NatlStmt.

As per the AU-ICH-GCPs, the informed consent form (ICF) (also referred to as a participant information sheet and consent form (PICF) in Australia) is viewed as an essential document that must be reviewed and approved by an institutional ethics committee (EC) (known as a Human Research Ethics Committee in Australia) and kept on file before the trial commences. (See the Required Elements section for details on what should be included in the form.)

According to the G-TrialsSOP, the principal investigator (PI) for any research project retains overall responsibility for ensuring a participant’s consent has been obtained in the correct manner prior to the participant’s entry into the project. This includes where consent is obtained from participants at satellite sites in a teletrial. The PI can delegate the duty for obtaining consent to a suitably qualified associate investigator at the PI’s discretion, but the PI remains responsible for any delegated activity. Furthermore, the investigator must ensure that institutional authorization is obtained, inclusive of approval by an appropriate EC, for all written information and any other media used to provide information to potential participants prior to their usage to obtain consent from any participant.

The AU-ICH-GCPs states that the investigator must provide detailed research study information to the participant or legal representative/guardian. The ICF content should be as non-technical as practical and understandable to the participant or legal representative/guardian. The G-TrialsSOP further indicates that the ICF and relevant EC-approved participant information documents can be provided in person, by telehealth, or by telephone and email or weblink. If informed consent is obtained by telephone, this must be recorded on the ICF and in the participant’s health and medical record, and/or source document, stating (as an example): “The protocol was discussed with [participant’s name] via telephone on [DD/MM/YYYY].”

According to the G-TrialsSOP, e-consent may be the preferable option for teletrials, as consent signatures can be obtained contemporaneously at both primary and satellite sites. For more information on obtaining consent using telehealth, see the G-TrialsSOP.

As per the AU-ICH-GCPs, the ICF content should be clearly presented orally, or in a written language that is easy to understand, and commensurate with the age and comprehension level of the research participant. The participant and legal representative/guardian should also be given adequate time to consider whether to participate. According to the G-NatlStmt, information should also be presented to potential participants in ways that help them make informed choices. To this end, the researcher should take into account cultural and language barriers, the need for accurate and reliable translation, the participant’s educational background, the participant’s age and maturity level, and whether there is a visual, hearing, or communication impairment. See AUS-65 for researcher guidance on how to talk to potential participants.

Furthermore, as delineated in the G-TrialsSOP, the PI or delegate must assess the potential participant’s understanding of what they are agreeing to, that they are aware of the purpose of the study, what will be involved, and any risks that may exist. The participants must demonstrate that they fully understand the implications of decisions that may be made within the course of the research.

Per the G-NatlStmt, where a potential participant lacks the capacity to consent, a person or appropriate statutory body exercising lawful authority for the potential participant should be provided with relevant information and decide whether the individual will participate. That decision must not be contrary to the individual’s best interests. Researchers should bear in mind that the capacity to consent may fluctuate, and even without that capacity, people may have some understanding of the research and the benefits and burdens of their participation. Additionally, within some communities, decisions about participation in research may involve not only individuals but also properly interested parties such as formally constituted bodies, institutions, families, or community elders. See the Emergencies, Vulnerable Populations, Children/Minors, Prisoners, and Mentally Impaired sections for additional information about these populations.

As per the AU-ICH-GCPs, none of the oral and written information concerning the research study, including the written ICF, should contain any language that causes the participant or legal representative/guardian to waive or to appear to waive their legal rights, or that releases or appears to release the investigator(s), the institution, the sponsor, or their representative(s) from liability for negligence. Per the G-NatlStmt, no person should be subject to coercion or pressure in deciding whether to participate in a trial.

The G-NatlStmt indicates that consent may be:

Specific – limited to the specific project under consideration
Extended – given for the use of data or tissue in future research projects that are: (i) an extension of, or closely related to, the original project; or (ii) in the same general area of research (for example, genealogical, ethnographical, epidemiological, or chronic illness research)
Unspecified – given for the use of data or tissue in any future research

The G-NatlStmt further states that when unspecified consent is sought, its terms and wide-ranging implications should be clearly explained to potential participants. When such consent is given, its terms should be clearly recorded. Subsequent reliance, in a research proposal, on existing unspecified consent should describe the terms of that unspecified consent. See the G-NatlStmt for more information on consent to future use of data and tissue in research. Additionally, see the Consent for Specimen section for more information on consent related to use of tissue in research.

Re-Consent

According to the AU-ICH-GCPs and the G-TrialsSOP, any change in the ICF that is relevant to the participant’s consent should be approved by the EC prior to implementing any changes. The participant or legal representative/guardian should also be informed in a timely manner if new information becomes available that may be relevant to the participant’s willingness to continue participation in the trial. The communication of this information should be documented. The G-TrialsSOP further specifies that unless there is a significant safety concern, ECs will not usually require that participants be recontacted immediately since there are potential implications related to blinding. If approved by the EC, continued consent may be obtained verbally and recorded in the participant’s medical records and relevant documents. Re-consent may also be obtained by telephone if approved by an EC.

The G-NatlStmt notes that in some research, consent may occasionally need to be renegotiated or confirmed, especially where projects are complex or long-running, or participants are vulnerable. Research participants should be told if there are changes to the terms to which they originally agreed and given the opportunity to continue their participation or withdraw.

Language Requirements

Pursuant to the G-NatlStmt, methods for presenting research information to participants should take into account the need for accurate and reliable translation into the participant’s first language or dialect, as well as culture and its effects on the communication process. According to the G-TrialsSOP, in cases where translation is required, a professional interpreter should facilitate the process.

Documenting Consent

The AU-ICH-GCPs and the G-TrialsSOP state that the participant or legal representative(s)/guardian(s) and the investigator(s) must sign and date the ICF. Where the participant is unable to read or the legal representative/guardian is unable to read, an impartial witness should be present during the entire informed consent discussion. After the following steps have occurred, the witness should sign and date the ICF attesting that the information in the ICF was accurately explained to, and apparently understood by the participant or legal representative/guardian:

The written ICF and any other written information to be provided to the participant is read and explained to the participant or legal representative/guardian
The participant or legal representative/guardian has orally consented to the participant’s involvement in the trial, and has signed and dated the ICF, if capable of doing so

Before participating in the study, the participant or legal representative/guardian should receive a copy of the signed and dated ICF.

The G-TrialsSOP further indicates that where consent is obtained by telehealth or telephone, once the ICF is signed and dated by both the participant and the investigator (and any other person present, for example an interpreter), the participant must select the statement identifying that consent was obtained by telehealth or telephone with the name of the investigator. Similarly, the investigator must select the statement identifying that consent was obtained by telehealth or telephone with the name of the participant. For more information on informed consent documentation, see the G-TrialsSOP.

According to the G-NatlStmt, consent may be expressed orally, in writing, or by some other means (such as return of a survey or conduct implying consent), depending on the nature, complexity, and level of risk of the research, and the participant’s personal and cultural circumstances.

Waiver of Consent

The G-NatlStmt specifies that although voluntary consent is a requirement for every trial, the EC may approve an alteration to the consent requirements. Limited disclosure to participants of the aims and/or methods of research may be justifiable. However, only an EC can review and approve research that involves active concealment or planned deception or aims to expose illegal activity.

Per the G-NatlStmt, it may be appropriate to use an opt-out approach for participant recruitment when obtaining explicit consent is neither practical nor feasible. An opt-out approach is a method used in the recruitment of research participants where information is provided to the potential participant regarding the research and their involvement, and where their participation is presumed unless they take action to decline to participate. An EC may approve the use of an opt-out approach for research if the study satisfies all of the following conditions:

It involves only low risk to participants
The public interest in the proposed activity substantially outweighs the public interest in the protection of privacy
The research activity is likely to be compromised if the participation rate is not near complete, and the requirement for explicit consent would compromise the necessary level of participation
Reasonable attempts are made to provide participants with appropriate plain language information explaining the nature of the information to be collected, the purpose of collecting it, and procedure to decline participation or withdraw from the research
A reasonable time period is allowed between the provision of information to prospective participants and the use of their data so that an opportunity for them to decline to participate is provided before the research begins
A mechanism is provided for prospective participants to obtain further information and decline to participate
The data collected will be managed and maintained in accordance with relevant security standards
There is a governance process in place that delineates specific responsibility for the project and for the appropriate management of the data
The opt-out approach is not prohibited by state, federal, or international law

According to the G-NatlStmt, only an EC may grant a waiver of consent for research using personal information in medical research, or personal health information. However, other review bodies may grant a waiver of consent for other research. In order to help maintain public confidence in the research process, each institution must make publicly accessible summary descriptions of all its research projects for which consent has been waived.

As stated in the G-NatlStmt, an EC may waive the requirement for consent if the study satisfies all of the following conditions:

Involvement in the research carries no more than low risk to participants
The benefits from the research justify any risks of harm associated with not seeking consent
It is impracticable to obtain consent (for example, due to the quantity, age, or accessibility of records)
There is no known or likely reason for thinking that participants would not have consented if they had been asked
There is sufficient protection of their privacy
There is an adequate plan to protect the confidentiality of data
There is, where practicable, a plan for making information arising from the research available to participants in cases where the results have significance for their welfare
The possibility of commercial exploitation of derivatives of the data or tissue will not deprive the participants of any financial benefits to which they would be entitled
The waiver is not prohibited by state, federal, or international law

See the G-NatlStmt for more information on conditions for the opt-out approach or waiving consent.

1, 3, 4, and 8

SOP 09

Sections 2 (Chapters 2.2 and 2.3), 3 (Chapter 3.1), and 5 (Chapter 5.3)

Last content review/update: May 16, 2024

Obtaining Consent

In all United Kingdom (UK) clinical trials, a freely given informed consent must be obtained from each participant in accordance with the requirements set forth in the MHCTR, the MHCTR2006, and the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (GBR-113). As per the MHCTR, the MHCTR2006, and GBR-9, the informed consent form (ICF) is viewed as an essential document that must be reviewed and approved by an ethics committee (EC) recognized by the United Kingdom Ethics Committee Authority (UKECA) (henceforth referred to as a “recognized EC”) and operating according to standard operating procedures (GBR-9) issued by England’s Health Research Authority (HRA).) Refer to GBR-18 and GBR-69 for more on informed consent in the UK.

The MHCTR and G-ConsentPIS, state that the investigator(s) must provide detailed research study information to the participant or legal representative/guardian. The MHCTR and G-ConsentPIS also specify that the oral and written information concerning the trial, including the ICF, should be easy to understand and presented without coercion or unduly influencing a potential participant to enroll in the clinical trial. The participant and the legal representative/guardian, should also be given adequate time to consider whether to participate. Per G-ConsentPIS, the Participant Information Sheet (PIS) supports the consent process to help ensure participants have been adequately informed. In addition, the PIS forms part of the transparency information that must be provided to participants under the data protection legislation for the use and processing of personal data. (See the Personal Data Protection section for more information on data protection requirements.) For more guidance on the PIS, see the PrtInfoQty-Stds, the PrtInfo-DesignPrin, and GBR-14, which include FAQs, information principles, and standards.

Per GBR-31, the HRA guides researchers and ECs in taking a proportionate approach to seeking consent. A proportionate approach adopts procedures commensurate with the balance of risk and benefits so that potential participants are not overwhelmed by unnecessarily lengthy, complex, and inaccessible information sheets. Participants should be provided with succinct, relevant, truthful information in a user-friendly manner that promotes their autonomy. Specifically, the methods and procedures used to seek informed consent and the level of information provided should be proportionate to:

The nature and the complexity of the research
The risks, burdens, and potential benefits (to the participants and/or society)
The ethical issues at stake

Per GBR-113, none of the oral and written information concerning the clinical trial, including the written ICF, should contain any language that causes the participant or legal representative/guardian to waive or to appear to waive any legal rights, or that releases or appears to release the investigator, the institution, the sponsor, or their agents from liability for negligence.

Re-Consent

According to GBR-113, the EC should approve any change in the ICF due to a protocol modification before such changes are implemented. The participant or legal representative/guardian will also be required to re-sign the revised ICF and receive a copy of any amended documentation.

Per GBR-18, during a clinical trial, researchers should periodically reaffirm the willingness of participants to continue. If significant new information becomes available, participants should be reconsented using revised (and re-approved) consent documents so that their continued consent is confirmed.

Language Requirements

As stated in the MHCTR, applications to the EC and the Medicines and Healthcare Products Regulatory Agency (MHRA) and any accompanying material, such as the ICF content, should be presented in English.

Documenting Consent

The MHCTR states that the participant or legal representative/guardian, and the investigator(s) must sign and date the ICF. Where the participant is illiterate, or the legal representative/guardian is illiterate, verbal consent should be obtained in the presence of and countersigned by an impartial witness. As provided in G-ConsentPIS, consent can be documented electronically or in writing. A physical or electronic copy of the signed consent form will still need to be provided to the participant. To record consent electronically, electronic signatures will be needed. Because there are different forms and classifications of electronic signatures, the researcher should determine what is appropriate for the particular study. GBR-6 sets out the legal and ethical requirements for seeking and documenting consent using electronic methods (also known as eConsent in the UK), as well as expectations regarding the use of electronic signatures. eConsent enables potential research participants to be provided with the information they need to make a decision via a tablet, smartphone, or digital multimedia. It also enables their informed consent to be documented using electronic signatures. This approach can supplement the traditional paper-based approach or, where appropriate, replace it.

Waiver of Consent

No information is currently available.

1 and 2

2, 4.4, 4.8, 8.2, and 8.3

Informed Consent

Principles of consent - General principals and Role of Participant Information Sheets; Content - Participant Information Sheet and Consent Form; and Examples and Templates

Amendment of Regulation 3 of the Principal Regulations; Amendment of Regulation 12 of the Principal Regulations; Amendment of Regulation 15 of the Principal Regulations; Amendment of Schedule 1 to the Principal Regulations; Amendment of Schedule 3 to the Principal Regulations; and Part 2 (Principles Based on Articles 2 to 5 of the GCP Directive and Conditions Based on Article 3 of the Directive)

Part 1 (3), Part 3 (12, 15, 17, and 18), Schedule 1 (Part 1 (3) and Part 2), and Schedule 3 (Parts 1 and 3)

Required Elements

Last content review/update: May 2, 2024

Based on the AU-ICH-GCPs and the G-NatlStmt, both the informed consent discussion and the written informed consent form (ICF) (also referred to as a participant information sheet and consent form (PICF) in Australia) should include the following statements or descriptions, as applicable (Note: Each of the items listed below will not necessarily be found in both sources, which provide overlapping and unique elements):

That the trial involves research
The purpose of the trial
The trial treatment(s) and the probability for random assignment to each treatment
The trial procedures to be followed, including all invasive procedures
The participant's responsibilities
Those aspects of the trial that are experimental
The reasonably foreseeable risks or inconveniences to the participant and, when applicable, to an embryo, fetus, or nursing infant
The reasonably expected benefits, including to the wider community. When there is no intended clinical benefit to the participant, the participant should be made aware of this
The alternative procedure(s) or course(s) of treatment that may be available to the participant, and their important potential benefits and risks
The compensation and/or treatment available to the participant in the event of trial-related injury, including provision of services to participants adversely affected by the research
The amounts and sources of funding for the research, as well as financial or other relevant declarations of interests of researchers, sponsors, or institutions
The anticipated prorated payment, if any, to the participant for participating in the trial
The anticipated expenses, if any, to the subject for participating in the trial
That participation in the trial is voluntary and that the participant may refuse to participate or withdraw from the trial, at any time, without penalty or loss of benefits to which the subject is otherwise entitled
Any implications of withdrawal from the trial, and whether it will be possible to withdraw data
How the research will be monitored
That the monitor(s), the auditor(s), the ethics committee (EC), and the regulatory authority(ies) will be granted direct access to the participant's original medical records for verification of clinical trial procedures and/or data, without violating the confidentiality of the participant, to the extent permitted by the applicable laws and regulations and that, by signing a written informed consent form, the participant or legal representative/guardian is authorizing such access
That records identifying the 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 trial are published, the participant’s identity will remain confidential
That the participant or legal representative/guardian will be informed in a timely manner if information becomes available that may be relevant to the participant's willingness to continue participation in the trial
The person(s) to contact for further information regarding the trial and the rights of trial participants, and whom to contact in the event of trial-related injury
Contact details of a person to receive complaints and of the researchers
The foreseeable circumstances and/or reasons under which participation in the trial may be terminated
The expected duration of participation in the trial
The approximate number of participants involved in the trial
The likelihood and form of dissemination of the research results, including publication
Any other relevant information, including research-specific information required under other chapters of the G-NatlStmt

4.8.10

Section 2 (Chapter 2.2)

Last content review/update: May 16, 2024

Based on the MHCTR, the G-ConsentPIS, and the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (GBR-113), the informed consent form (ICF) should include the following statements or descriptions, as applicable (Note: Each of the items listed below will not necessarily be found in all sources, which provide overlapping and unique elements):

The study purpose, procedures, and duration
Study title and the study Integrated Research Application System (IRAS) ID are clearly displayed
Approximate number of participants involved in the trial
The participant’s responsibilities in participating in the trial
Trial treatment schedule and the probability for random assignment to each treatment
Experimental aspects of the study
Any foreseeable risks or discomforts to the participant, and when applicable, to an embryo, fetus, or nursing infant
Any benefits or prorated payment to the participant or to others that may reasonably be expected from the research; if no benefit is expected, the participant should also be made aware of this
A disclosure of appropriate alternative procedures or treatments, and their potential benefits and risks
Compensation and/or medical treatment available to the participant in the event of a trial-related injury
Any additional costs to the participant that may result from participation in the research
That participation is voluntary, the participant may withdraw at any time, and refusal to participate will not involve any penalty or loss of benefits, or reduction in the level of care to which the participant is otherwise entitled
The extent to which confidentiality of records identifying the participant will be maintained, and the possibility of record access by the Medicines and Healthcare Products Regulatory Agency (MHRA), the ethics committees (ECs), the auditor(s), and the monitor(s)
That the participant or legal representative/guardian will be notified if significant new findings developed during the study may affect the participant's willingness to continue
Individuals to contact for further information regarding the trial, the rights of trial participants, and whom to contact in the event of trial-related injury
Foreseeable circumstances under which the investigator(s) may remove the participant without consent

ICF examples and templates are provided in the G-ConsentPIS.

For more information about informed consent required elements, see GBR-18, GBR-113, GBR-100, GBR-31, and GBR-69.

1 and 2

4.4 and 4.8

Informed Consent

Principles of consent - General principles and Role of Participant Information Sheets; Content - Participant Information Sheet and Consent Form

Part 1 (3), Part 3 (12 and 15), and Schedule 3 (Parts 1 and 3)

Participant Rights

Last content review/update: May 2, 2024

Overview

In accordance with the AU-ICH-GCPs and the G-NatlStmt, Australia’s ethical standards protect participants’ rights and promote respect for human beings, research merit and integrity, justice, and beneficence. The G-NatlStmt further recognizes that state or territory authorities may have additional statutes regarding the use of human tissues, guardianship, and illegal and unprofessional conduct. Furthermore, a participant’s rights must be clearly addressed in the informed consent form (ICF) (also referred to as a participant information sheet and consent form (PICF) in Australia).

The Right to Participate, Abstain, or Withdraw

As stated in the AU-ICH-GCPs and the G-NatlStmt, the participant or the legal representative/guardian should be informed that participation is voluntary, that the participant may withdraw from the research study at any time, and that refusal to participate will not involve any penalty or loss of benefits to which the participant is otherwise entitled. The G-TrialsSOP further specifies that participants may withdraw their consent at any time without giving a reason.

Per the G-NatlStmt, the participant should be informed of any implications of withdrawal and whether it is possible to withdraw data.

The Right to Information

As per the AU-ICH-GCPs and the G-NatlStmt, a potential research participant or the legal representative/guardian has the right to be informed about the nature and purpose of the research study, its anticipated duration, study procedures, any potential benefits or risks, any compensation or treatment in the case of injury, and any significant new information regarding the research study.

The Right to Privacy and Confidentiality

According to the AU-ICH-GCPs and the G-NatlStmt, all participants must be afforded the right to privacy and confidentiality, and the ICF must provide a statement that recognizes this right. Privacy is also subject to national, state, and territory laws, including the PrivacyAct. As per the G-TrialsSOP, if telehealth is used, all measures must be taken to ensure privacy and confidentiality of the participant’s identity.

See the Personal Data Protection section for more details on personal information collection and handling requirements.

The Right of Inquiry/Appeal

The AU-ICH-GCPs and the G-NatlStmt state that the research participant or the legal representative/guardian should be provided with contact information for the individual responsible for addressing trial-related inquiries and/or rights.

AUS-45 provides information on who the participant or the legal representative/guardian may contact regarding a concern with the clinical trial. The options include contacting the researcher(s) directly, the ethics committee (EC) (known as Human Research Ethics Committee in Australia), the institution, the healthcare complaints entity in the state or territory, or the National Health and Medical Research Council (NHMRC). Concerns may also be reported to the Therapeutic Goods Administration (TGA). See AUS-45 for more information on the types of concerns that may be reported to each party.

See the G-NatlStmt for more information on institutional requirements for receipt of complaints.

The Right to Safety and Welfare

The AU-ICH-GCPs (which upholds the Declaration of Helsinki (AUS-52)) and the G-NatlStmt clearly state that a research participant’s right to safety and protection of health and welfare must take precedence over the interests of science and society.

See the Required Elements and Vulnerable Populations sections for additional information regarding requirements for participant rights.

Introduction, 2, and 4

SOP 09

Purpose, Scope, and Limits of this Document, Section 1, Section 2 (Chapters 2.2 and 2.3), and Section 5 (Chapter 5.7)

Part II

Last content review/update: May 16, 2024

Overview

In accordance with the MHCTR, the MHCTR2006, the G-ConsentPIS, and the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (GBR-113), the United Kingdom’s (UK’s) ethical standards promote respect for all human beings and safeguard the rights of research participants. The MHCTR states that a participant’s rights must also be clearly addressed in the informed consent form (ICF) and during the informed consent process.

The Right to Participate, Abstain, or Withdraw

As set forth in the MHCTR, the G-ConsentPIS, and GBR-113, the participant or legal representative/guardian should be informed that participation is voluntary, that they may withdraw from the research study at any time, and that refusal to participate will not involve any penalty or loss of benefits to which the participant is otherwise entitled.

The Right to Information

As delineated in the MHCTR, the G-ConsentPIS, and GBR-113, a potential research participant or legal representative/guardian has the right to be informed about the nature and purpose of the research study, its anticipated duration, study procedures, any potential benefits or risks, any compensation for participation or injury/treatment, and any significant new information regarding the research study.

Also see GBR-117 for an interactive web-based communications toolkit to help researchers and participants keep in touch after participation in a research study.

The Right to Privacy and Confidentiality

As per the MHCTR and GBR-113, the arrangements to protect participants’ privacy should be provided in the application to the ethics committee, and the ICF should inform potential participants of any potential risk to their confidentiality.

The Right of Inquiry/Appeal

The MHCTR and GBR-113 state that the research participant or legal representative/guardian should be provided with contact information for the sponsor and the investigator(s) to address trial-related inquiries.

The Right to Safety and Welfare

The MHCTR, the MHCTR2006, and GBR-113 state that a research participant’s rights, safety, and well-being must take precedence over the interests of science and society.

4.8

Principles and Content

Amendment of Regulation 3 of the Principal Regulations; Amendment of Schedule 1 to the Principal Regulations; and Part 2 (Principles Based on Articles 2 to 5 of the GCP Directive and Conditions Based on Article 3 of the Directive)

Part 1 (3 and 15), Schedule 1 (Parts 1, 2, and 5)

Emergencies

Last content review/update: May 2, 2024

The AU-ICH-GCPs states that in emergency situations, when prior consent of the participant is not possible, the consent of the legal representative/guardian, if present, should be requested. When prior consent of the participant is not possible, and the legal representative/guardian is not available, enrollment of the participant should require measures described in the protocol and/or elsewhere, with documented approval/favorable opinion by the ethics committee (EC) (known as the Human Research Ethics Committee in Australia), to protect the rights, safety, and well-being of the participant and to ensure compliance with applicable regulatory requirements, including the G-NatlStmt. Per the AU-ICH-GCPs, the participant or legal representative/guardian should be informed about the trial as soon as possible, and consent to continue and other consent should be requested, as appropriate.

The G-NatlStmt recognizes that in emergency care research, recruitment into a research project often must be achieved rapidly. Where the research involves emergency treatment and meets the G-NatlStmt’s requirements for research involving people highly dependent on medical care, consent for the research may be waived. See the Vulnerable Populations section for more information on people highly dependent on medical care, and the Documentation Requirements section for more details on waiver of consent.

4.8.15

Section 4 (Chapter 4.4)

Last content review/update: May 16, 2024

The MHCTR, the MHCTR2006-No2, the MHCTR-BSQ, and the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (GBR-113) make provisions to protect the rights of a research participant during the informed consent process when a clinical trial of an investigational product (IP) is complicated by medical emergencies. As delineated in the G-ConsentPIS and GBR-18, in an emergency, if the signed informed consent form (ICF) cannot be obtained from the research participant, the consent of the legal representative/guardian should be obtained. If the prior consent of the participant or legal representative/guardian cannot be obtained, the participant’s enrollment should follow measures specified in the protocol, and the ethics committee (EC) must provide documented approval in order to protect the participant’s rights, safety, and well-being. The participant or legal representative/guardian should provide consent as soon as possible.

The MHCTR-BSQ amends the MHCTR and creates an exception for minors participating in a trial where urgent treatment is required and prior consent cannot be obtained. This situation also requires the EC to issue its approval beforehand.

The MHCTR2006-No2 amends the MHCTR and creates an exception to the general rule in England, Northern Ireland, and Wales that incapacitated adults cannot be included in a clinical trial under medical emergencies. If the treatment to be provided is a matter of urgency and obtaining prior consent is not possible, incapacitated adult participants may be included in the trial once EC approval has been obtained. In Scotland, the provisions of Section 51 of the AIA2000 govern the inclusion of adults lacking capacity in research.

The G-ConsentPIS states that the United Kingdom allows adults not able to consent for themselves to be recruited into clinical trials without prior consent in emergency situations if the following conditions exist:

Treatment needs to be given urgently
It is also necessary to take urgent action to administer the drug (IP) for the purposes of the trial
It is not reasonably practicable to obtain consent from a legal representative
The procedure is approved by an EC
Consent is sought from a legal representative as soon as possible

4.8.15

Informed Consent

Principles of Consent - Emergency Research

Section 51

4 and Explanatory Note

2 and Explanatory Note

Schedule 1 (Parts 4 and 5)

Vulnerable Populations

Last content review/update: May 2, 2024

Overview

The AU-ICH-GCPs characterizes vulnerable populations as those who may be unduly influenced by the expectation, whether justified or not, of benefits associated with participation in a clinical trial, or of a retaliatory response for not participating. 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 subjects include patients with incurable diseases, residents of nursing homes, unemployed or impoverished persons, patients in emergency situations, homeless persons, nomads, refugees, minors, and those incapable of giving consent. Per the G-NatlStmt, people who may be involved in illegal activities, Aboriginal and Torres Strait Islander peoples, ethnic minority groups, and people in other countries are other groups for which specific ethical considerations are required.

People Highly Dependent on Medical Care

According to the G-NatlStmt, research involving people who are highly dependent on medical care may be approved where:

It is likely that the research will lead to increased understanding about, or improvements in, the care of this population
The requirements of relevant jurisdictional laws are taken into account
Either: 1) any risk or burden of the proposed research to this particular participant is justified by the potential benefits, or 2) where participants have capacity to consent, any risk or burden is acceptable to them and justified by the potential benefits of the research

The G-NatlStmt indicates that when a researcher is also the treating health professional, it should be considered whether an independent person should seek the consent of potential participants who are highly dependent on medical care. In addition, the participant and/or the participant’s relatives and an authorized representative should be informed of the participant’s inclusion in the research and of the option to withdraw from it without any reduction in quality of care.

The G-NatlStmt states that when neither the potential participant nor the legal representative/guardian can consider the proposal and give consent, an ethics committee (EC) (known as the Human Research Ethics Committee in Australia) may, having taken account of relevant jurisdictional laws, approve a research project without prior consent if:

There is no reason to believe that, were the participant or legal representative/guardian to be informed of the proposal, the participant would be unwilling to consent
The risks of harm to individuals, families, or groups linked to the participant, or to their financial or social interests, are minimized
The project is not controversial and does not involve significant moral or cultural sensitivities in the community

And, where the research is interventional, these additional conditions apply:

The research supports a reasonable possibility of benefit over standard care
Any risk or burden of the intervention to the participant is justified by its potential benefits
Inclusion in the research project is not contrary to the interests of the participant

The G-NatlStmt further provides specific requirements related to conducting research on participants in terminal care, which is characterized by the short remaining life expectancy of the participants and their vulnerability to unrealistic expectations of benefits. Terminal care research should be designed so that the benefits of research justify any burden, discomfort, or inconvenience to the participants; the prospect of benefit from research participation is not exaggerated; the needs and wishes of participants to spend time as they choose are respected; and the entitlement of those receiving palliative care to participate is recognized.

Aboriginal and Torres Strait Islander Peoples

The G-NatlStmt states that research involving Aboriginal and Torres Strait Islander Peoples must be reviewed and approved by an EC and include assessment and advice from: people who have networks with and/or knowledge of Aboriginal and Torres Strait Islander Peoples; and people familiar with the culture and practices of the relevant Aboriginal and Torres Strait Islander community(ies). In addition, the researcher should ensure the following:

Research methods are respectful and acknowledge the cultural distinctiveness of participating Aboriginal and Torres Strait Islander communities and groups
There is evidence of support for the research project from relevant Aboriginal and Torres Strait Islander communities or groups and the research methodology engages with their social and cultural practices
The research methods provide for mutually agreed mechanisms for recruitment, information provided about the research, notification of participants’ consent and of research progress, and final reporting
Procedures and actions have been taken to monitor and, where appropriate, minimize any potential negative consequences of the proposed research

For more information on research involving Aboriginal and Torres Strait Islander Peoples, see the G-AboriginalEthic, the G-EthicsRsrchTrackII, and the G-AIATSISCode.

People in Dependent Groups

The G-NatlStmt cautions that dependent or unequal relationships that might compromise the voluntary character of a participant’s decision should be considered. Examples of such relationships include caregivers and people with chronic conditions/disabilities; health care professionals and their patients; teachers and their students; prison authorities and prisoners; governmental authorities and refugees; employers/supervisors and their employees (including members of police and Defense Forces); and service-providers and especially vulnerable communities to whom the services are provided. Where potential participants are especially vulnerable or powerless, consideration should be given to the appointment of a participant advocate.

Per the G-NatlStmt, when a researcher and potential participant have a pre-existing relationship, it should be considered whether an independent person should seek the consent of the participant.

People Who May Be Involved in Illegal Activities

The G-NatlStmt provides specific requirements related to conducting research on participants who may be involved in illegal activities. Research that is intended to study or expose, or likely to expose, illegal activity should be reviewed and approved by an EC. Researchers should be satisfied that participants who are subject to criminal justice processes are aware that the research may discover illegal activity and do not have unrealistic expectations of benefit from their participation. Finally, research designed to expose illegal activity should only be approved where the illegal activity bears on the discharge of a public responsibility or the fitness to hold public office, the risks are justified by the benefits, and the research meets the other requirements in the G-NatlStmt.

People in Other Countries

The G-NatlStmt states that research involving people in other countries must be reviewed and approved by an EC and comply with the G-NatlStmt. The research design, protocol, and consent process should take into consideration the local cultural values, yet still result in participants being treated with no less respect and protection than what is provided in the G-NatlStmt. Additional details are provided in the G-NatlStmt.

1

Section 4 (Introduction and Chapters 4.1, 4.3-4.4, and 4.6-4.8)

Last content review/update: May 16, 2024

Overview

As per the MHCTR and the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (GBR-113), in all United Kingdom (UK) clinical trials, research participants selected from vulnerable populations must be provided additional protections to safeguard their health and welfare during the informed consent process.

Per GBR-131, vulnerability may be defined in different ways and may arise as a result of being in an abusive relationship, vulnerability due to age, potential marginalization, disability, and due to disadvantageous power relationships within personal and professional roles. Participants may not be conventionally vulnerable but may be in a dependent relationship that means they can feel coerced or pressured into taking part.

As stated in GBR-131, researchers must assess potential vulnerability within the context of the research, in terms of potential consequences from their participation (immediate and long-term) or lack of positive impact where this is immediately needed or expected. Further, researchers should make the participants aware of the limits to confidentiality and decide whether verbal or written consent will be more appropriate and protective of the participants’ interests. In addition, researchers should consider the following:

Participants’ vulnerability
Potential negative consequences or lack of personal benefits from their involvement in research where these are expected
Providing appropriate information to elicit freely-given informed consent for participation as well as information regarding data deposit and data re-use (where deposit is possible)
Limits to confidentiality and occasions where this may occur
Legal requirements of working with the specific population
Incentives and compensation for participation

In addition, GBR-131 states that when working with participants who are considered vulnerable, researchers may find themselves in a position of increased responsibilities or expectations. Researchers should endeavor to assess the likelihood of additional ethics issues and develop strategies and a framework of clear responsibilities they can refer to should such issues arise. They should also use their research ethics committee as a resource for advice and guidance. Researchers should be able to justify the approach they take in dealing with unforeseen ethics issues and maintain the integrity of the research.

As per GBR-131, in cases where research involves potentially vulnerable groups, every effort should be made to secure freely given informed consent that participants have actively provided. Every effort should be made to ensure that they have the time and opportunity to access support in their decision-making, for example by discussing their choice with a trusted adult or relative. Passive assent, including group assent (with consent given by a gatekeeper) should be avoided wherever possible, and every effort should be made to develop methods of seeking consent that are appropriate to the groups studied, using expert advice, support, and training, where necessary. Vulnerability should be considered on a case-by-case basis; many groups or individuals not traditionally considered as vulnerable could be exposed to issues from participating in research that make them vulnerable. See GBR-131 for additional resources and case studies.

See the Children/Minors; Pregnant Women, Fetuses & Neonates; and Mentally Impaired sections for additional information about these vulnerable populations.

1.61, 3.1, and 4.8

Schedule 1 (Parts 1, 4, and 5)

Children/Minors

Last content review/update: May 2, 2024

The FamLawAct defines a child as a person who is under 18 years of age. Per AUS-71, different states or territories may have specific legislation about a parent/guardian providing consent to medical treatment for a minor; otherwise, the FamLawAct has provisions that may apply.

According to AUS-71, children under 16 cannot give legal consent, which must be given by a parent/guardian, but they can and should be involved in the decision. Young people over 16 can give legal consent to medical treatment; however, they usually cannot provide legal consent to participate in research until they are 18. Nonetheless, some ethics committees (ECs) (known as Human Research Ethics Committees in Australia) do allow mature young people under 18 to give their consent for some kinds of research.

The AU-ICH-GCPs states that minors should be informed to the extent compatible with their maturity and understanding, and if capable, they should sign and personally date the informed consent form (ICF) (also referred to as a participant information sheet and consent form (PICF) in Australia). In accordance with the G-NatlStmt, consent requirements for conducting clinical trials follow the general requirements listed in the Required Elements section.

The G-NatlStmt states before including a child or young person in research, researchers must establish that there is no reason to believe that such participation is contrary to that child's or young person's best interest. Furthermore, a child or young person's refusal to participate in research should be respected wherever the child or young person has the capacity to give consent to that same research. Where a child or young person lacks this capacity, the child or young person’s refusal may be overridden by the judgement of the parent/guardian as to what is in the child's best interest.

The G-NatlStmt indicates that an EC may approve research to which only the child or young person consents if it is satisfied that:

The child or young person is mature enough to understand the relevant information and give consent
The research involves low risk
The research aims to benefit children or young people
The child or young person is estranged or separated from the parent/guardian and the researcher ensures the child or young person’s safety, security, and well-being in the research conduct; or it would be contrary to the best interests of the child or young person to seek consent from the parent/guardian, and the researcher ensures the child or young person’s safety, security, and well-being in the research conduct

In addition, as stated in the G-NatlStmt, children and young people who are not of sufficient maturity to consent should only participate in clinical studies when: the research is likely to advance knowledge about the health or welfare of, other matters relevant to, children and young people; or their participation is indispensable to the conduct of the research. When considering the inclusion of children and young people in research, the researchers and EC must consider their level of maturity to ensure adequate protections for their welfare.

Assent Requirements

AUS-71 indicates that when a parent/guardian gives consent for their child to take part in a clinical trial, researchers may also ask the child for their permission or agreement, also referred to as assent. The researchers must do this in an age-appropriate manner. Both the parent/guardian and the child should have the chance to ask any questions before agreeing to participate and at any time during a trial.

In order for a child to provide their consent or assent they must:

Understand the research process
Understand the purpose of the trial
Be told what they are expected to do or what will happen to them during the trial

Children should be able to express their views and any worries they might have about participating in a trial, and have their questions answered. Children should always be given information in a form that they can understand.

Furthermore, the G-NatlStmt states that except in cases involving standing parental consent, specific consent must be obtained from the child or young person whenever the child or young person has the capacity to make this decision, and either one (1) parent, except when the EC decides that the risks require the consent of both parents, or the child or young person’s parent/guardian.

Per the G-NatlStmt, researchers must respect the developing capacity of children and young people to be involved in decisions about participation in research. The child or young person's particular level of maturity has implications for whether consent is necessary and/or sufficient to authorize participation. However, it is not possible to attach fixed ages to each level of maturity, which may vary from child to child. The following guidelines on maturity and corresponding capacity to consent are provided:

Infants, who are unable to take part in discussion about the research and its effects
Young children, who are able to understand some relevant information and take part in limited discussion about the research, but whose consent is not required
Young people of developing maturity, who are able to understand the relevant information but whose relative immaturity means that they remain vulnerable; the consent of these young people is required, in addition to consent from a parent or guardian
Young people who are mature enough to understand and consent, and are not vulnerable through immaturity in ways that warrant additional consent from a parent or guardian

See the G-NatlStmt for more information on consent and assent involving children and young people.

Clinical trials and children

4

Section 4 (Chapter 4.2)

Part I-Preliminary (4 Interpretation)

Last content review/update: May 16, 2024

According to the MHCTR and GBR-4, a minor in the United Kingdom (UK) is an individual under 16 years of age.

As set forth in the MHCTR, the MHCTR2006, the G-ConsentPIS, GBR-4, GBR-9, and the International Council for Harmonisation’s Guideline for Good Clinical Practice E6(R2) (GBR-113), when the research participant is a minor, informed consent should be obtained from a parent/legal guardian. As per GBR-4, the researcher needs only to obtain consent from one (1) person with parental responsibility. GBR-130 further indicates that the parent/legal guardian must not be connected with the conduct of the trial, is suitable to act by virtue of their relationship with the child/young person, and is available and willing to do so. A legal representative should only ever be approached if someone with parental responsibility cannot be contacted prior to the proposed inclusion of the child/young person due to the urgent nature of the treatment provided as part of the trial. In this situation, a professional legal representative (e.g., a doctor) can be responsible for the medical treatment of the child/young person if they are independent of the study, or a person nominated by the healthcare provider.

Additionally, GBR-130 states that researchers must ensure that the parent/legal guardian:

Understand that they are being asked to give consent on behalf of the child/young person
Understand the objectives, risks, and inconveniences of the trial and the conditions under which it is to be conducted
Have been informed of the right to withdraw the child/young person from the trial at any time
Have a contact point where further information about the trial can be obtained

The MHCTR, the MHCTR2006, and GBR-4, state that a study may only be conducted on minors if several conditions are fulfilled including:

An ethics committee (EC), following consultation with pediatric experts, has endorsed the protocol
The parent/guardian has had an interview with the investigator(s) to understand the trial objectives and risks, been provided with a point of contact for further information, and been informed of the right to withdraw the minor from the trial at any time
No incentives or financial inducements are given to the minor or the parent/guardian except in the event of trial-related injury or loss
The trial relates directly to a condition from which the minor suffers, or is of such a nature that it can only be carried out on minors
The participant(s) will derive some direct benefit from their participation in the trial
The trial is necessary to validate data obtained in other trials involving persons able to give informed consent, or by other research methods
The trial has been designed to minimize pain, discomfort, fear, and any other foreseeable risk in relation to the disease and the minor’s stage of development

GBR-4 provides additional best practices:

Children and their parents (or those with parental responsibility) should be involved in the decision-making process around consent to take part in research, regardless of whether the child or young person is legally competent to give consent. This includes involving children or young people who are not considered competent to give consent.
Assent should be sought from a child who is not considered competent as long as this is practicable and the child is not too young.
In some situations, a young person who is competent may object to the involvement of their parents and their confidentiality should be respected.
Before giving consent, children and young people should be provided with age-appropriate information that enables them to understand participation in research. Information may be provided using a layered or staged approach so that it is more easily understood.
Children and young people should be given the opportunity to ask questions and to get support in their decision-making, such as talking to a trusted adult.
Good records should be kept of any discussions about consent and of the final decision.
Inducements and coercion must be avoided.
Seeking consent is a process and it is good practice to engage regularly with the child and family over the course of research to confirm they are willing to continue. In studies in which children who are not competent will become competent during the study period, then consent from young people should be sought as soon as possible after competency is reached. A decision about how this will be managed should be made at the start of the study and included in the protocol.

See the MHCTR, the MHCTR2006, GBR-4, and GBR-9 for detailed requirements. The G-ConsentPIS provides style guidance and suggestions for presenting age-appropriate information in the participant information sheet.

Assent Requirements

As indicated in GBR-4, whenever practical and appropriate, a child's assent should be sought before including them in research. Even when a child or young person is competent, it is still normally good practice to involve the family in the decision-making process; however, if the young person objects, researchers should respect their privacy.

As per GBR-4, for clinical trials of investigational products (IPs), it is usually inappropriate to ask very young children (e.g., under five (5) years old) to sign an assent form; however, their views should be considered. Researchers must make an informed judgment to determine when seeking assent is appropriate; the age of a child can only be taken as a guide. The child's developmental stage, knowledge of illness and experience of health care should also be considered. Although there is a danger that children can be asked to exercise greater autonomy than normal, this must be balanced with the potential loss of trust associated with denying their assent. Such judgment needs a framework of considerations for analysis, a record of observations, and discussions and a documented decision. In circumstances where seeking assent at the outset is not appropriate, the researcher could provide the child with information as and when required.

Guidance (Consent)

2.51-2.58

4.8.12

Clinical Trial of an Investigational Medicinal Product (Consent for under 16)

Style and Examples & Templates

Amendment of Schedule 1 to the Principal Regulations; Amendment of Regulation 15 of the Principal Regulations; and Part 2 (Conditions Based on Article 3 of the Directive)

Part 1 (2) and Schedule 1 (Part 4)

Pregnant Women, Fetuses & Neonates

Last content review/update: May 2, 2024

As per the G-NatlStmt, studies involving pregnant women, fetuses, and neonates require additional safeguards to ensure that the research assesses the risks to the pregnant women, fetuses, and neonates. The wellbeing and care of the woman who is pregnant and of her fetus always takes precedence over research considerations, and research involving a fetus or fetal tissue should be conducted in a manner that maintains a clear separation between the woman’s clinical care and the research. Additionally, research should be designed to minimize pain or distress for the fetus, include steps for monitoring for signs of fetal pain or distress, and include steps for suspending or ceasing the research if necessary.

In accordance with the G-NatlStmt, consent requirements for conducting clinical trials follow the general requirements listed in the Required Elements section. However, except for therapeutic innovative therapy cases, the process of providing information and obtaining consent for participating in research should be clearly separate from clinical care if the woman is pregnant and the fetus is in utero. Further, per the G-NatlStmt, the woman should be informed of the following:

That she should consider whether to seek consent to the proposed research from any other person (e.g., the other parent)
Whether it is possible to store the fetus or fetal tissues for later use in research
That she is free to withdraw her consent to the research at any time, whether before or after a termination or other loss of a fetus
Whether there is potential for commercial application of outcomes of the research, including the development of cell lines
That she will not be entitled to a share in the profits of any commercial applications
Whether fetal organs or stem cell lines developed from them will be exported to another country

In addition, the G-NatlStmt states that if, for research purposes, fetal cells are to be derived from the fetal tissue and stored or propagated in tissue culture, or tissues or cells are to be used in human transplantation, the woman's consent is required. Others whom the woman identifies may also need to be involved in decisions about these matters.

For requirements related to assisted reproductive technology, including research involving the creation of human embryos using precursor cells from a human embryo or a human fetus, see the G-EthicsART.

Section 4 (Chapter 4.1)

Last content review/update: May 16, 2024

The G-ConsentPIS states that researchers must give a clear warning to potential participants when there is a risk of harm to an unborn child and/or risk when breastfeeding. The Participant Information Sheet (PIS) should provide specific advice to potential participants about the risks of becoming pregnant, of fathering a child, or of breastfeeding while taking part in the research including the need for pregnancy testing, contraceptive requirements, and how to report a pregnancy during the study. The PIS should also provide information about what will happen if a participant becomes pregnant, including whether and how the researcher will monitor the pregnancy. This would include access to the mother's and/or child's notes, and any possible follow up of the child including post-natal examinations. For men, researchers must provide clear warnings and advice if the research treatment could damage sperm and consequently pose a risk to possible pregnancies. Specific advice for pregnant partners may be needed, including information on any compensation arrangements.

Further, the G-ConsentPIS finds that the risk of harm caused during pregnancy is most likely when recruiting young people to a clinical trial for an investigational medicinal product (CTIMP). In this case, there should be consent from someone over the age of 16, and the following should be done:

Discuss the risk of pregnancy, pregnancy testing, and the use of appropriate contraception with their parents (or their legal guardian) during the consent process and with young potential participants as part of the assent process
Consider local social beliefs
Involve pediatricians and the ethics committee in preliminary discussions if this is a concern
Consult young people when designing consent and writing information
Respect the young person's autonomy but encourage involvement of the parents
Be aware that in CTIMPs, it is the parents of children under 16 who legally provide consent, and this will include consent to pregnancy testing and discussion of contraception
Information needs to go beyond "We will do a pregnancy test…" to include what will happen in broad terms

In accordance with the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (GBR-113), informed consent requirements for conducting clinical trials with pregnant or nursing women or fetuses follow the general requirements listed in the Required Elements section. Specifically, the informed consent form should include a statement on the reasonably foreseeable risks or inconveniences to the participant, and when applicable, to an embryo, fetus, or nursing infant.

As set forth in GBR-35, any research studies involving women capable of becoming pregnant and breastfeeding women require additional safeguards to ensure the research conforms to appropriate ethical standards and upholds societal values. According to GBR-35, the following conditions are required for research to be conducted with this population:

Reproductive toxicology studies have been completed and the results support conducting a trial, or there is a good reason not to conduct the reproductive toxicology studies and/or the risk of pregnancy is minimized (e.g., because she agrees to adhere to a highly effective method of contraception); Women using a hormonal contraceptive, such as “the pill,” should use an alternative method of contraception until the possibility of an interaction with the investigational product has been excluded
The female participant is not pregnant according to her menstrual history and a pregnancy test, and is not at risk of becoming pregnant during, and for a specified interval, after the trial
The female participant is warned about the potential risks to the developing child should she become pregnant, and she is tested for pregnancy during the trial, as appropriate
The female is tested for pregnancy before dosing starts and possibly during the trial, as appropriate

Content - Participant Information Sheet

Prisoners

Last content review/update: May 2, 2024

The G-NatlStmt refers to prisoners and prison authorities as an example of people who may be in dependent or unequal relationships.

Per the G-NatlStmt, a research study involving people in dependent or unequal relationships (such as prisoners) should, wherever possible, invite prospective participants to discuss their participation with someone who is able to support them in making their decision. If prospective participants are especially vulnerable, researchers should consider appointing a participant advocate.

Section 4 (Chapter 4.3)

Last content review/update: May 16, 2024

Per the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (GBR-113), prisoners are considered vulnerable because incarceration could affect their ability to make a voluntary decision regarding participation in research. A research study involving prisoners should ensure that these prospective participants are informed and are given the opportunity to make their own decisions without any interference from a higher authority. The ethics committee must also ensure that the study will be independently monitored to assure the dignity and rights of the prisoners involved in the research.

1.61

Mentally Impaired

Last content review/update: May 2, 2024

Cognitive Impairment, Intellectual Disability, or Mental Illness

The G-NatlStmt discusses the requirements for research involving participants with cognitive impairment, intellectual disability, and mental illness together, noting that many of the ethical issues they raise about research participation are similar. An ethics committee (EC) (known as Human Research Ethics Committee in Australia) must review and approve research involving such participants, except where the research uses collections of non-identifiable data and involves negligible risk.

Per the G-NatlStmt, the research design should take into account factors that may affect the capacity to receive information, to consent to the research, or to participate in it. Additionally, care should be taken to determine whether the participant’s cognitive impairment, intellectual disability, or mental illness increases the susceptibility to some forms of discomfort or distress. Ways of minimizing effects of this susceptibility should be described in the research proposal.

As delineated in the G-NatlStmt, the participant must consent if the participant has the capacity, or the participant’s legal representative/guardian must consent on behalf of the participant. Where a legal representative/guardian has given consent, the researchers still must explain to the participant what the research is about and what participation involves. If the participant recovers the capacity to consent, the researcher should offer the opportunity to continue participation or withdraw. Refusal or reluctance to participate in a research project should be respected.

The G-NatlStmt states that if the participant’s impairment, disability, or illness is temporary or episodic, researchers should seek consent when the condition does not interfere with the capacity to give consent. This consent should occur in the presence of a witness who is familiar with the participant, is independent from the research, and understands the research’s merits, risks, and procedures.

Research Involving Unconscious Persons

The G-NatlStmt states when prior consent is not possible for research involving unconscious persons, consent should be provided by the participant’s legal representative/guardian. However, relevant jurisdictional laws must be taken into account. Because of their extreme vulnerability, unconscious persons should be excluded from all but minimally invasive research, or in research designed both to be therapeutic for them and to improve treatment for the condition from which they suffer.

The G-TrialsSOP notes that as per the Declaration of Helsinki (AUS-52), for research involving participants who are physically or mentally incapable of giving consent (e.g., unconscious patients/participants), the study must be relevant to the physical or mental condition of the participant(s) that prevents them from being able to consent to participate in the study.

SOP 09

Section 4 (Chapters 4.4 and 4.5)

Last content review/update: May 16, 2024

As per the MHCTR and GBR-9, a recognized ethics committee (EC) within the Health Research Authority (HRA), must approve the participation of adult research participants who are incapable by reason of physical and mental capacity to give consent, and must obtain advice from professionals with expertise in handling this population.

The MHCTR and the G-ConsentPIS, specify that when a study involves adult participants with mental incapacities, informed consent should be obtained from the legal representative/guardian. This consent should only be provided once the legal representative/guardian has had an interview with the investigator(s) to understand the trial objectives and risks, been provided with a point of contact for further information, and been informed of the right to withdraw the participant from the trial at any time. The G-ConsentPIS provides additional country-specific information on legal representative requirements.

As delineated in the MHCTR, a clinical trial of an investigational product may involve participants with mental incapacities under the following conditions:

The participant has received information according to the participant’s capacity of understanding regarding the trial, its risks, and its benefits
No incentives or financial inducements are given to the participant or legal representative/guardian except in the event of trial-related injury or loss
The trial relates directly to a condition from which the participant suffers, or is of such a nature that it can only be carried out on participants with mental incapacities
The participant(s) will derive some direct benefit from their participation in the trial, or produce no risk at all
The trial is necessary to validate data obtained in other trials involving persons able to give informed consent, or by other research methods
The trial has been designed to minimize pain, discomfort, fear, and any other foreseeable risk in relation to the disease and the participant’s stage of development

See the MHCTR, G-ConsentPIS, and GBR-3 for detailed requirements.

2.51-2.58

Principles of Consent - Adults Who Are Not Able to Consent for Themselves

Part 1 (15), Schedule 1 (Parts 1 and 5)

Definition of Investigational Product

Last content review/update: May 2, 2024

According to the AU-ICH-GCPs and the G-TrialsSOP, an investigational product (IP) is defined as a pharmaceutical form of an active ingredient or placebo being tested or used as a reference in a clinical trial. This includes a product with a marketing authorization when used or assembled (formulated or packaged) in a different way from the approved form; when used for an unapproved indication; or when used to gain further information about an approved use.

In Australia, IPs are also referred to as unapproved therapeutic goods. As per the G-CTHandbook and AUS-47, an unapproved therapeutic good includes:

Any medicine, biological, or medical device not entered on the Australian Register of Therapeutic Goods (ARTG) (AUS-22), including any new formulation, strength or size, dose, name, indications, directions for use or type of container of a medicine already in the ARTG
Any therapeutic good already in the ARTG to be used in a manner not covered by the existing ARTG entry

Determine if the product is ‘unapproved’

1

Terms

Last content review/update: May 16, 2024

As delineated in the MHCTR, the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (GBR-113), and GBR-9, an investigational product (IP), referred to as an investigational medicinal product (IMP) in the United Kingdom (UK), is defined as a pharmaceutical form of an active substance or placebo being tested or used as a reference in a clinical trial. This includes a product with a marketing authorization when it is used or assembled (formulated or packaged) in a different way from the approved form; when used for an unapproved indication; or when used to gain further information about an approved use.

Terminology (Statutory Definitions Relating to CTIMPs)

1.3

Part 1 (2)

Manufacturing & Import

Last content review/update: May 2, 2024

Manufacturing

As specified in the TGAct, the TGR, and the G-CTHandbook, the Therapeutic Goods Administration (TGA) authorizes the manufacture of investigational products (IPs) in Australia. As per AUS-47 and AUS-49, the sponsor provides manufacturer and/or active ingredient information to the TGA in the clinical trial application under one (1) of the two (2) regulatory schemes—the Clinical Trial Notification (CTN) scheme or the Clinical Trial Approval (CTA) scheme. Pursuant to TGManuf, Australia adopted the Pharmaceutical Inspection Co-operation Scheme (PIC/S) Guide to Good Manufacturing Practice for Medicinal Products (AU-PIC-S-GMP-Guide) regarding the manufacture of therapeutic goods.

Per the AU-PIC-S-GMP-Guide, the holder of a manufacturing authorization must manufacture IPs to ensure that they are fit for their intended use, comply with the requirements of the clinical trial authorization, and do not place participants at risk due to inadequate safety, quality, or efficacy. The production of IPs involves added complexity in comparison to marketed products and therefore requires personnel with a thorough understanding of, and training in, the application of good manufacturing practice (GMP) to IPs. Cooperation with trial sponsors, who undertake the ultimate responsibility for all aspects of the clinical trial, is also required.

See the AU-PIC-S-GMP-Guide for detailed manufacturing requirements.

Import

The G-CTHandbook and AUS-47 indicate that IPs may be imported and held under the direct control of the sponsor (importer) until the IPs are the subject of a notification to the TGA under the CTN scheme or an approval under the CTA scheme. The IPs must be kept in a warehouse or other properly secured area. There is no requirement for the CTN or CTA process to have been completed prior to importation of the clinical trial goods.

Per AUS-47, importers are advised to contact other relevant agencies, as there may be further restrictions on importation imposed through other legislation.

Other Considerations

AUS-47 states that Australian clinical trial product importers/manufacturers are not required to provide the TGA with six (6) monthly reports under regulation 47B of the TGR. However, the TGA can require information or documents relating to the supply (including quantity) of therapeutic goods that are exempt under the CTN scheme or approved under the CTA scheme.

Creating a New CTN Form

CTA Scheme and FAQs

The CTN and CTA schemes, Manufacturing, and Importing

Chapter 1 (Principle) and Annex 13

Part 1 (Section 4) and Schedule 1 (Part 1)

Chapter 3 (Part 3-2 (19) and Part 3-3 (34-38))

Parts 3 (12AB) and 8 (47B)

Last content review/update: May 16, 2024

According to the MHCTR, the MHCTR2006, the G-CTApp, and the G-GMP-GDP, the Medicines and Healthcare Products Regulatory Agency (MHRA) is responsible for authorizing the manufacture of investigational products (IPs) (known as investigational medicinal products (IMPs) in the United Kingdom (UK)) to be used in a trial. A Manufacturer’s Authorization for Investigational Medicinal Products (MIA(IMP)) must be obtained by the person responsible for the manufacture of any IP to be used in the trial. The sponsor or the designated representative must include a copy of the MIA(IMP) in the clinical trial application submission to the MHRA. The applicant must complete the form listed in GBR-28 to obtain an MIA(IMP) from the MHRA. The MHCTR defines “manufacturing authorization” to include importing and assembly authorizations, as applicable. The G-CTApp states that if an IP is manufactured outside the European Union (EU), the clinical trial application should include an MIA(IMP), importer authorization, and qualified person (QP) declaration on good manufacturing practice (GMP) for each site. The MHRA will approve the manufacture or import of an IP after the clinical trial application has been approved.

Per G-ATMP, a manufacturer’s license from MHRA is needed to manufacture unlicensed advanced therapy medicinal products (ATMPs) in the UK. See G-ATMP for guidance on the two (2) ATMP manufacturer license pathways: the hospital exemption or the “specials” scheme.

As per the MHCTR, the MHCTR2006, the G-GMP-GDP, and GBR-15, and the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (GBR-113), the MIA(IMP) holder must also comply with the GMP guidelines and provide an IMP Certificate of Analysis. In addition, the MHCTR and the MHCTR2006 specify that the holder of an MIA(IMP) must always have the services of at least one (1) QP at their disposal. The QP must satisfy the qualification and experience requirements delineated in the aforementioned sources. The QP’s primary legal responsibility is to certify batches of IPs prior to use in a clinical trial, or prior to release for sale and placement in the market. See Part 6 and Schedule 6 of the MHCTR for detailed applicant requirements.

In accordance with the G-ImportIMPs, IPs that have been QP-certified in countries on the list of approved countries (initially, EU and European Economic Area (EEA) countries per G-CTApprovedCountries) do not need to be re-certified when importing to the UK. However, the sponsor must require the MIA(IMP) holder to put in place an assurance system to check these IMPs have been certified by a QP in a listed country before release to the trial. A sponsor may perform verification of QP certification in a listed country themselves if they are the holder of a UK MIA(IMP). Alternatively, they may outsource this verification to a third party who holds a UK MIA(IMP). IPs coming to Great Britain from Northern Ireland do not require this additional oversight. IPs coming directly to the UK from third-party countries that are not on the list of approved countries will continue to require import and QP certification in the UK by the MIA(IMP) holder as per the existing requirements. See the G-ImportIMPsAuth, for additional details on the authorizations and procedures. For additional details on what is new from Brexit, see the Scope of Assessment section.

The G-IPsNIreland delineates that the supply and use of IPs in Northern Ireland must follow EU laws as per the Northern Ireland Protocol. For policy papers and details on the Northern Ireland Protocol, see GBR-119.

Per the G-SubtlAmndmt, for any change to IP manufacturing, importation, or certification relevant to the supply of IPs in an ongoing UK trial, a substantial amendment must be submitted to the MHRA. However, if the sponsor chooses to retain an existing UK release site for the ongoing UK trial but includes an additional EU/EEA site for trials in the EU/EEA only, then no substantial amendment to the MHRA will be required.

Please note: The UK is party to the Nagoya Protocol on Access and Benefit-sharing (GBR-5), which may have implications for studies of IPs developed using certain non-human genetic resources (e.g., plants, animals, and microbes). For more information, see GBR-48.

Application for New Manufacturer’s Authorization for Investigational Medicinal Products MIA (IMP) (Human Use)

Annex 2

Manufacture of unlicensed ATMPs in the UK

Documents to send with your application

Overview

Amendment of Regulation 13 of the Principal Regulations; Amendment of Regulation 42 of the Principal Regulations; Amendment of Regulation 44 of the Principal Regulations; and Part 2 (Principles based on Articles 2 to 5 of the GCP Directive, Conditions Based on Article 3 of the Directive and Amendment of Schedule 6 to the Principal Regulations)

Part 1 (2), Part 3 (13), Part 6, Schedule 1 (Part 2), Schedule 3 (Part 2), Schedule 6, and Schedule 7

Quality Requirements

Last content review/update: May 2, 2024

Investigator’s Brochure

According to the AU-ICH-GCPs, the sponsor is responsible for providing the investigators with an investigator’s brochure (IB). The IB must contain all of the relevant information on the investigational product(s) (IPs), including significant physical, chemical, pharmaceutical, pharmacological, toxicological, pharmacokinetic, metabolic, and clinical information. The sponsor must ensure that an up-to-date IB is made available to the investigator(s), and the investigator(s) must provide an up-to-date IB to the ethics committee.

According to the G-TrialsSOP, where the investigator contributes to the content and development of the IB, the investigator must ensure the IB follows the outline in the AU-ICH-GCPs. The AU-ICH-GCPs requires the IB to cover the following areas:

Physical, chemical, and pharmaceutical properties and formulation parameters

Non-clinical studies (pharmacology, pharmacokinetics, toxicology, and metabolism profiles)

Effects of IP in humans (pharmacokinetics, metabolism, and pharmacodynamics; safety and efficacy; and regulatory and post-marketing experiences)

Summary of data and guidance for the investigator(s)

See Section 7 of the AU-ICH-GCPs for detailed content guidelines.

Quality Management

As specified in the AU-ICH-GCPs, the sponsor must ensure that the products are manufactured in accordance with Good Manufacturing Practice (GMP). Furthermore, the sponsor must maintain a Certificate of Analysis to document the identity, purity, and strength of the IP(s) to be used in the clinical trial.

Per the AU-PIC-S-GMP-Guide, GMP ensures that products are consistently produced and controlled to the quality standards appropriate to their intended use and as required by the clinical trial authorization. A quality system designed, set up, and verified by the manufacturer or importer should be described in written procedures available to the sponsor, taking into account the GMP principles and guidelines applicable to IPs. Manufacturers should maintain documentation including specifications and instructions; the IP order; the product specification file; manufacturing formulae and processing instructions; packaging instructions; and processing, testing, and packaging batch records. The product specifications and manufacturing instructions may be changed during development, but full control and traceability of the changes should also be maintained.

See the AU-PIC-S-GMP-Guide for more details on quality documentation requirements.

5, 7, and 8

Chapter 1 (1.8) and Annex 13 (Quality Management)

SOP 04

Last content review/update: May 16, 2024

Investigator’s Brochure

In accordance with the MHCTR, the MHCTR2006, and GBR-92, the sponsor or the designated representative is responsible for providing investigators with an Investigator’s Brochure (IB), which must contain all of the relevant information on the investigational product(s) (IPs) (known as investigational medicinal products (IMPs) in the United Kingdom (UK)) obtained through the earlier research phases, including preclinical, toxicological, safety, efficacy, and adverse events data. The sponsor or the designated representative should also update the IB as significant new information becomes available.

As specified in the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (GBR-113), the IB must provide coverage of the following areas:

Physical, chemical, and pharmaceutical properties and formulation parameters
Non-clinical studies (pharmacology, pharmacokinetics, toxicology, and metabolism profiles)
Effects of IPs in humans (pharmacology, pharmacokinetics, metabolism, and pharmacodynamics; safety and efficacy; regulatory and post marketing experiences)
Summary of data and guidance for the investigator(s)
Bibliography

See Section 7 of GBR-113 for detailed content guidelines.

Quality Management

Per GBR-113, the sponsor must maintain a Certificate of Analysis to document the identity, purity, and strength of the IP(s) to be used in the clinical trial.

5.12 and 7

Overview

Insertion of Regulation 3A of the Principal Regulations; Amendment of Regulation 13 of the Principal Regulations; Amendment of Regulation 15 of the Principal Regulations; Amendment of Regulation 42 of the Principal Regulations, Amendment of Regulation 44 of the Principal Regulations; and Part 2 Principles based on Articles 2 to 5 of the GCP Directive

Part 1 (2), Part 3 (13), Part 6, Schedule 6, and Schedule 7

Labeling

Last content review/update: May 2, 2024

Investigational product (IP) labeling in Australia must comply with the requirements set forth in the G-CTHandbook, the AU-ICH-GCPs, and the AU-PIC-S-GMP-Guide. Per the AU-PIC-S-GMP-Guide, as annotated by the G-CTHandbook, the following information must be included on the IP label:

Sponsor’s name, address, and phone number. The main contact details for information on the product, clinical trial, and emergency unblinding must be an Australian contact.
Pharmaceutical dosage form, route of administration, and quantity of dosage units. For closed blinded trials, the labeling should include a statement indicating “placebo or [name/identifier] + [strength/potency]”.
The batch and/or code number to identify the contents and packaging operation
A trial reference code, which should identify the particular trial site, unless provided elsewhere or its absence can be justified. The trial reference code used should also identify the Australian trial sponsor, unless provided as the main contact or its absence can be justified.
The trial participant identification number/treatment number
Investigator’s name. The name of the principal investigator should appear on the label unless already included in a trial reference code or unless its absence can be justified.
Directions for use
“For clinical trial use only” or similar wording
The storage conditions
The period of use (use-by date, expiry date, or re-test date as applicable) in month/year format and in a manner that avoids any ambiguity
“Keep out of reach of children” except when the product is not taken home by participants

The G-CTHandbook recognizes that in exceptional circumstances, it may not be possible to meet the requirements of Annex 13 of the AU-PIC-S-GMP-Guide for labeling IPs. In this case, the sponsor must contact the Therapeutic Goods Administration (TGA) (see AUS-23) if they wish to request a departure from the requirements of Annex 13.

In addition, the AU-ICH-GCPs states that the IP must be coded and labeled in a manner that protects the blinding, if applicable.

Per the G-CTHandbook, labeling is a manufacturing step under the TGAct. However, an exemption from the requirement to hold a manufacturing license may apply to certain persons identified within the TGR, to allow relabeling of the IP with name and address of the new sponsor. If there is a change of Australian trial sponsor, the clinical trial medication should be relabeled appropriately with the details of the new trial sponsor at the time of transfer. See the G-CTHandbook for more details on these manufacturing exemptions.

Additional details on IP labeling are provided in the G-CTHandbook and the AU-PIC-S-GMP-Guide.

Manufacturing

5.13

Annex 13 (Labelling)

Chapter 3 (Part 3)

Schedule 8

Last content review/update: May 16, 2024

Labeling for investigational products (IPs) (known as investigational medicinal products (IMPs) in the United Kingdom (UK)) must comply with the requirements set forth in the MHCTR, the MHCTR2006, GBR-15, the EU Good Manufacturing Practice Directive (GBR-12), and the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (GBR-113). Per GBR-12, labeling for IPs must ensure protection of the participant and traceability, to enable identification of the product and trial, and to facilitate proper use of the IP. As specified in GBR-15, for an IP to be used in a clinical trial, it must be properly labeled in the official language of the country where the trial is being conducted.

As set forth in GBR-15, the following labeling information must be included on the primary package label (or any intermediate packaging), and the outer packaging:

Name, address, and telephone number of the sponsor, contract research organization (CRO), or investigator
Pharmaceutical dosage form, route of administration, quantity of dosage units, and in the case of open trials, the name/identifier and strength/concentration
Batch and/or code number to identify the contents and packaging operation
Trial reference code allowing identification of the trial, site, investigator, and sponsor (if not given elsewhere)
Trial participant identification number/treatment number and where relevant, the visit number
Investigator name (if not already included above)
Instructions for use (reference may be made to a leaflet or other explanatory document intended for the trial participant or person administering the product)
“For clinical trial use only” or similar wording indicating the IP is clinical trial material
Storage conditions
Expiration date (use by date, expiration date, or re-test date as applicable), in month/year format and in a manner that avoids any ambiguity
“Keep Out of Reach of Children” except when the product is not going to be taken home by participants

As per the MHCTR, a sample of the labeling is required as part of the clinical trial application submission. (See the Submission Content section for detailed clinical trial application submission requirements). Furthermore, according to GBR-15, the IP must also be suitably packaged in a manner that will prevent contamination and unacceptable deterioration during transport and storage.

Article 15

Annex 1-3 - Investigational Medicinal Products - Packaging, Labelling, and Table 1

5.13

Amendment of Regulation 46 of the Principal Regulations

Part 1 (2) and Part 7, and Schedule 3, Part 2 (12)

Product Management

Last content review/update: May 2, 2024

Supply, Storage, and Handling Requirements

As defined in the AU-ICH-GCPs and the AU-PIC-S-GMP-Guide, the sponsor must supply the investigator(s) with the investigational product(s) (IPs)), including the comparator and placebo, if applicable. The G-CTHandbook and AUS-47 indicate that Therapeutic Goods Administration (TGA) approval through the Clinical Trial Approval (CTA) scheme or notification through the Clinical Trial Notification (CTN) scheme must occur prior to supplying the IP(s) to the trial site(s).

The AU-ICH-GCPs specifies that the sponsor must ensure the following:

Timely delivery of the IP(s)

Records maintained for IP document shipment, receipt, disposition, return, and destruction

A system for retrieving or disposing of IP(s) and documenting this retrieval or disposal

Written procedures including instructions for IP handling and storage, adequate and safe receipt of the IP(s), dispensing of the IP(s), retrieval of unused IP(s), return of unused IP(s) to the sponsor, and disposal of unused IP(s) by the sponsor
IP product quality and stability over the period of use
IP manufactured according to any application of the Good Manufacturing Practices (GMPs)
Proper coding packaging, and labeling of the IP(s)
Acceptable IP handling and storage conditions and shelf-life

In addition, the AU-ICH-GCPs states that the IPs must also be suitably packaged in a manner that will prevent contamination and unacceptable deterioration during transport and storage. Refer to the AU-ICH-GCPs for detailed sponsor-related IP requirements.

As per the G-TrialsSOP, responsibility for IP management and accountability at the trial site rests with the principal investigator (PI). However, the PI may delegate responsibility for IP management to the site pharmacist or, where a pharmacist is not available or involved, to an appropriately qualified person. The site pharmacist or the appropriately qualified person will undertake IP management at the primary site and/or the satellite site in a teletrial. The investigator, pharmacist, or appropriately qualified non-pharmacist must ensure the IP is used only in accordance with the approved protocol and confirm IP certification and all relevant trial approvals/notifications are in place before releasing the IP for dispensing to participants. Refer to the G-TrialsSOP for detailed investigator-related IP requirements.

Record Requirements

According to the G-TrialsSOP, the investigator, pharmacist, or appropriately qualified non-pharmacist must maintain records of all IP management aspects. These records at a minimum should include: shipping documents; date of each transaction; quantities; batch/serial numbers; expiration dates/retest dates (if applicable); temperature logs showing the storage conditions of the IP throughout the trial period; the set of unique code numbers assigned to the IP and to the trial participant; and record of destruction/return.

As set forth in the AU-ICH-GCPs, the sponsor must retain essential documents for 15 years following completion of the trial. The sponsor should inform the investigator(s) and institution(s) in writing when record retention is needed and when the trial-related records are no longer needed.

FAQs

Importing

5 and 7

Annex 13

SOP 11

Last content review/update: May 16, 2024

Supply, Storage, and Handling Requirements

As defined in the MHCTR and the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (GBR-113), the sponsor must supply the investigator(s)/institution(s) with the investigational product(s) (IPs) (known as investigational medicinal products (IMPs) in the United Kingdom (UK)), including the comparator(s) and placebo, if applicable. The sponsor should not supply either party with the IP(s) until obtaining Medicines and Healthcare Products Regulatory Agency (MHRA) approval and a favorable opinion from a recognized ethics committee (EC).

Per the MHCTR and GBR-113, the sponsor must ensure the following (Note: Each of the items listed below will not necessarily be found in both sources, which provide overlapping and unique elements):

IP product quality and stability over the period of use
IP manufactured according to good manufacturing practice guidance (G-GMP-GDP and GBR-15)
Proper coding, packaging, and labeling of the IP(s)
IP use record including information on the quantity, loading, shipment, receipt, dispensing, handling, reclamation, and destruction of the unused IP
Acceptable storage temperatures, conditions, and times for the IP
Written procedures including instructions for handling and storage of the IP, adequate and safe receipt, dispensing, retrieval of unused IP(s), and return of unused IP(s) to the sponsor
Timely delivery of the IP(s)
Establishment of management and filing systems for the IPs
Sufficient quantities of the IP for the trial

As delineated in GBR-15, IPs should remain under the control of the sponsor until after completion of a two-step procedure: certification by the Qualified Person (QP) and release by the sponsor for use in a clinical trial. Both steps should be recorded and retained in the relevant trial files held by or on behalf of the sponsor. Shipping of IPs should be conducted according to instructions given by or on behalf of the sponsor in the shipping order. De-coding arrangements should be available to the appropriate responsible personnel before IPs are shipped to the investigator site. A detailed inventory of the shipments made by the manufacturer or importer should be maintained and include the addressees’ identification.

Refer to the MHCTR and GBR-113 for detailed, sponsor-related IP requirements.

To help ensure the continuity of supply of medicines for clinical trials from January 1, 2021, the BrexitLtr-IPs indicates that the UK will unilaterally recognize certain European Union (EU) regulatory processes for a time-limited period. This recognition is known as “standstill.”

Record Requirements

As per GBR-113, the sponsor should inform the investigator(s) and institution(s) in writing of the need for record retention and should notify the investigator(s) and institution(s) in writing when the trial-related pharmacy records are no longer needed. Additionally, the sponsor must ensure sufficient quantities of the IP(s) used in the trial to reconfirm specifications, should this become necessary, and should maintain records of batch sample analyses and characteristics.

As set forth in GBR-113, sponsor-specific essential documents should be retained until at least two (2) years after the last approval of a marketing application, until there are no pending or contemplated marketing applications, or at least two (2) years have elapsed since the formal discontinuation of the IP’s clinical development. The sponsor should inform the investigator(s) and the institution(s) in writing when trial-related records are no longer needed.

However, per the MHCTR2006, the sponsor and the chief investigator must ensure that the documents contained in the trial master file are retained for at least five (5) years following the trial’s completion. The documents must be readily available to the MHRA upon request and be complete and legible. The sponsor should ensure that trial participant medical files are also retained for at least five (5) years after the trial’s conclusion.

Annex 13 – Investigational Medicinal Products – Packaging, Labelling

5.12-5.15, 5.5, and 7

Insertion of Regulation 3A of the Principal Regulations; Amendment of Regulation 15 of the Principal Regulations; and Amendment of Regulation 31 of the Principal Regulations

Part 3 (13 and 15), Part 4 (28), Part 6 (36 and 38), and Schedule 7 (Parts 2 and 3)

Definition of Specimen

Last content review/update: May 2, 2024

In Australia, a specimen is referred to as a “biological” or a “human biospecimen.” According to the TGAct, a biological is made from, or contains, human cells or human tissues that are likely to be taken to:

Treat or prevent disease, ailment, defect, or injury
Diagnose the condition of a person
Alter the physiological processes of a person
Test the susceptibility of a person to disease
Replace or modify a person’s anatomy

The G-NatlStmt defines human biospecimen as any biological material obtained from a person, including tissue, blood, urine, sputum, and any derivative from these including cell lines.

Legislation in Australian states and territories do not use standard terminology, but generally refer to human biospecimens as “human tissue.”

Section 3 (Chapter 3.2)

Chapter 3 (Part 3-2A)

Last content review/update: May 16, 2024

The term “specimen” is not referenced within the United Kingdom (UK). However, the following terms are used relating to specimens:

Relevant material: As per the UK-HTA, Code-E, GBR-73, and GBR-76, “relevant material” or “human tissue” is any material from a human body, other than gametes, that consists of, or includes, cells. This also includes blood (except where held for transplantation). Hair and nails from living persons are specifically excluded from this definition, as are gametes and embryos outside the body.
Bodily material: UK-HTA and GBR-64 defines “bodily material” as material from a human body that consists of, or includes, human cells. Unlike relevant material, this includes gametes, embryos outside the human body, and hair and nails from the body.
Tissue: GBR-64 defines “tissue” as any human material (e.g., blood, biopsies, urine) and includes relevant and bodily material.

Bodily Material and Tissues

Definition of Relevant Material

Glossary

Part 3 (45 and 53)

Specimen Import & Export

Last content review/update: May 2, 2024

Import

Per the G-NatlStmt, if a human biospecimen will be, or has been, imported for research, researchers must establish whether the human biospecimen was obtained in a manner consistent with the requirements of the G-NatlStmt and relevant Australian legislation. If this cannot be established, then the human biospecimen should not be used for research in Australia.

Per the G-CTHandbook, other legislation and requirements may impose restrictions on the import of therapeutic goods for clinical trials involving materials of biological origin (human, animal, plant, or microbial), genetically modified organisms, and other substances. See the G-CTHandbook for a non-exhaustive list.

Export

The G-NatlStmt states that a human biospecimen obtained in Australia may be sent overseas for research if its exportation is consistent with the original consent, and if ethics committee (EC) (known as a Human Research Ethics Committee in Australia) approval is obtained.

Per the G-SpecExport, a permit to export human body fluids, organs, and other tissue must be obtained from the Therapeutic Goods Administration (TGA) when the volume of a container exceeds 50 mL. If exporting substances derived from human blood, a TGA permit is required regardless of the volume. The application form requires the reason for the request, which can include research purposes. See the G-SpecExport for more details on when export permits are required, and AUS-24 for the application forms.

Other Considerations

The G-TrialsSOP indicates that to ensure the integrity of biological samples has been maintained, there should be evidence of the chain of custody from their point of collection through processing, storage, transport, through to disposal, with evidence of appropriate storage and transit conditions. Equipment used for processing and storage of samples (e.g., centrifuges, fridges, and freezers) should be maintained by suitably qualified persons and periodically inspected, cleaned, and calibrated to the relevant International Organization for Standardization (ISO) standard according to local policy and manufacturer’s manuals. Additionally, the investigator must ensure all study staff, who have cause to handle or ship biological substances, hold a current certificate in the International Air Transport Association (IATA) Approved, Civil Aviation Safety Authority (CASA) Certified Dangerous Goods Packaging Course. The investigator must also ensure that documentation (e.g., receipts, shipping records, order forms, and proformas) related to handling and shipment of biological specimens is maintained and filed in the respective site file.

Additional details on import and export requirements are provided in the G-CTHandbook, the G-TrialsSOP, the G-SpecExport, and AUS-24.

Importing and exporting

About this Guidance, Determining if You Need a TGA Export Permit, and Applying for a TGA Export Permit

SOP 10

Section 3 (Chapter 3.2)

Last content review/update: May 16, 2024

Import/Export

As specified in the UK-HTA, the Human Tissue Authority (HTA) has jurisdiction regarding the import and export of specimens (known as “relevant materials” or “human tissue” in the United Kingdom (UK)) and complies with the Code of Practice on import and export set forth in Code-E. According to the UK-HTA, Code-E, GBR-56, GBR-73, and GBR-52, the import and export of relevant material/human tissue is not in itself a licensable activity under the UK-HTA. However, once the material is imported, storage of this material may be licensable unless it is for a specific research project with ethical approval from an ethics committee (EC). GBR-73 explains that it is preferable for imported human tissue to be stored in a licensed establishment where possible, and if so, there is no requirement for EC approval to undertake research. However, if the premises where the human tissue will be held are not covered by a HTA license, each research project using the human tissue will require EC approval.

If relevant material/human tissue is being imported or exported for an application, the HTRegs specify that this must be carried out under the authority of a license or third-party agreement with an establishment licensed by the HTA to store material for human application. See G-Tissues-Brexit for guidance on Brexit-related regulatory changes that apply to the movement of human tissues and cells between Great Britain, Northern Ireland, and Europe. Establishments importing or exporting human tissues and cells intended for human application may require an HTA license covering these activities. For additional help, clinical trial staff should contact the HTA at enquiries@hta.gov.uk. For more information about Brexit, see the Scope of Assessment section.

Code-E requires imported and exported material to be procured, used, handled, stored, transported, and disposed of in accordance with the donor’s consent. In addition, due regard should be given to safety considerations, and with the dignity and respect accorded to human bodies, body parts, and tissue as delineated in Code-E. Any individual or organization wishing to import human bodies, body parts, and tissue into England, Wales, or Northern Ireland must comply with the guidelines set forth in Code-E. For exports, donors should be provided with adequate information upon providing consent, that their samples may be transported as exported samples for use abroad. It is the responsibility of the recipient country to ensure that, prior to export, the material is handled appropriately and that the required country standards have been met.

In addition, the G-QualityBlood lists the quality and safety standards when importing or exporting blood into or from the EU/European Economic Area (EEA). The UK maintains the existing quality and safety standards for the collection, testing, processing, storage, and distribution of human blood and blood components. The Medicines and Healthcare Products Regulatory Agency (MHRA) should be consulted before importing or exporting blood or blood components. See the G-QualityBlood for relevant EU quality and safety directives.

Human Tissues, Cells, and Blood as Starting Material

Per G-ATMP, if tissues and cells are being used as starting materials in a medicinal product, the donation, procurement, and testing of the cells are covered by the HTRegs under the authority of the Human Fertilisation and Embryology Authority (HFEA) for the use of gametes and embryos, which may be used in the derivation (development) of cells in the manufacture of advanced therapy medicinal products (ATMPs), and under HTA for the licensing and inspection for all other tissues and cells. Once the starting materials have been made available, medicines legislation applies to and is regulated by the MHRA.

Per G-ATMP, the HTA and the MHRA have agreed that the collection of blood as a starting material for an ATMP can be carried out under either a tissues and cells license or a blood establishment license.

Other Considerations

As set forth in the UK-HTA, the HTRegs, and GBR-9, the HTA also regulates the storage and use of specimens from the living, and the removal, storage, use, and licensing of relevant materials/human tissue from the deceased for specified health-related purposes in the UK. The UK-HTA refers to specified purposes as “scheduled purposes.” Per GBR-9, the HTA and the Health Research Authority (HRA) have agreed to collaborative arrangements in a Memorandum of Understanding.

Note that per GBR-9 and GBR-105, an HTA license is not needed for the storage of specimens for certain research projects that have been approved by an ethics committee (EC). The HTA and the UK Health Departments’ Research Ethics Service (RES) (GBR-62) have agreed that an EC can give generic ethical approval for a research tissue bank’s arrangements for collection, storage, and release of specimens, provided the specimens in the bank are stored on HTA-licensed premises. This approval can extend to specific projects receiving non-identifiable tissue from the bank. The specimens do not then need to be stored on HTA-licensed premises, nor do they need project-specific ethical approval. However, a license is required for specimens stored for which there is no ethical approval (e.g., in large biobanks).

Per the UK-HTA, the G-QAHumTissue, and Code-E, the scope of the UK-HTA provisions specifically cover England, Northern Ireland, and Wales. The UK-HTA licensing requirements do not apply in Scotland, with the exception of those provisions relating to the use of DNA. Scotland complies with the Scotland-AnatAct and the Scotland-HTA for the removal, retention, use, licensing, and import of human organs, tissue, and tissue samples specifically removed post mortem, and subsequently used for research. Per GBR-52, the Scotland-HTA does not regulate the use of tissue from the living for research.

Section 12 and Annex H

1 and 3

Import and Export of Tissue

Human tissues and cells in ATMPs and Blood and blood components in medicinal products

Introduction to the Human Tissue Authority Codes of Practice, Licensing – Import and Export, Licensing – HTA Licensing Standards, and Annex A

Glossary/Definitions, Import and Export

Part 5 (53 (6))

Section 3 - Licenses and Section 7 - Licenses - general provisions

Part 2 (13, 14, 16, 26, and 41)

Part 1 (6), and Part 2 (7), and Part 3

Consent for Specimen