Therapeutic Goods Administration

As per the TGAct, the TGR, and the G-CTHandbook, the Therapeutic Goods Administration (TGA) is the regulatory authority responsible for clinical trial approvals, oversight, and inspections in Australia at the national level. The TGA allows for the supply of unapproved therapeutic goods to be used in clinical trials for experimental purposes in humans in accordance with the provisions in the TGAct and the TGR. There are two (2) regulatory schemes for supplying unapproved therapeutic goods in clinical investigations, which are more fully examined in the Scope of Assessment section.

As per AUS-28, the TGA is part of the Health Products Regulation Group (HPRG) within the Australian Department of Health, Disability and Ageing. The TGA’s Pharmacovigilance Branch is responsible for evaluating and authorizing certain clinical trials for all types of therapeutic products. According to the G-TrialsSOP the TGA also regulates the supply, import, export, manufacturing, and advertising of therapeutic goods. Per AUS-32, therapeutic goods include prescription medicines, non-prescription medicines, vaccines, sunscreens, vitamins, medical devices, blood and blood products, and software and artificial intelligence-based medical devices. See AUS-31 for more information on the different types of therapeutic goods that the TGA regulates.

AUS-32 indicates that the TGA maintains the Australian Register of Therapeutic Goods (ARTG) (AUS-22), a public database of therapeutic goods that can be legally supplied in Australia. According to the TGAct, the TGA grants exemptions from inclusion in the ARTG for unapproved therapeutic goods to be supplied in clinical trials.

Other Considerations

According to AUS-74, the TGA closely aligns its regulatory approaches to therapeutic products with those of comparable international regulatory counterparts, including the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH), the European Medicines Agency (EMA), and the United States Food & Drug Administration (FDA), wherever possible. For more information on the international scientific guidelines adopted in Australia, see AUS-74.

Contact Information

Per AUS-23, the contact information for the TGA is as follows:

Postal Address:
P.O. Box 100
Woden ACT 2606
Australia

For general questions:

Phone: 1 800 020 653 (free call within Australia) or +61 2 6289 4124 (international calls)
Fax: 02 6203 1605
E-mail: use online form (see AUS-11)

For clinical trial questions:
E-mail: clinical.trials@health.gov.au

AUS-47 notes that the TGA info team (see AUS-23) should be contacted if the question is not specifically about clinical trials conducted within the Clinical Trial Notification (CTN) or the Clinical Trial Approval (CTA) schemes. Users who are deaf or have a hearing or speech impairment can call through the National Relay Service. See AUS-47 for more information.

Medicines and Healthcare Products Regulatory Agency

As per the MHCTR, the “licensing authority” is responsible for clinical trial authorization. Pursuant to the MMDAct, the Secretary of State for the Department of Health and Social Care (DHSC) is authorized to make clinical trials regulations and amend or supplement the law relating to human medicines, taking into consideration the safety of human medicines and the availability of human medicines. As indicated in GBR-71 and GBR-90, the Medicines and Healthcare Products Regulatory Agency (MHRA) is an executive agency, sponsored by the DHSC, and is responsible for regulating medicines and medical devices in the United Kingdom (UK) (i.e., it is the licensing authority).

MHRA-More states that the MHRA regulates medicines, including vaccines, supplied in the UK, spanning the whole of a medicine’s lifecycle. The MHRA decides whether medicines should be granted licenses (i.e., marketing authorizations) and whether licenses can be varied. These decisions are based on safety, quality, and effectiveness data submitted. Further, the MHRA conducts several regulatory activities including the following:

• Inspecting facilities that manufacture and carry out safety tests on medicines to ensure they comply with Good Manufacturing Practice and Good Laboratory Practice standards
• Approving UK-based clinical trials and inspecting them to ensure they comply with Good Clinical Practice standards
• Carrying out vital research to support the development of new biological medicines and vaccines
• Developing reference materials for biological medicines to ensure their quality can be assessed in a standard way
• Monitoring the safety of the medicine while on the market, for example by actively assessing post-market safety reports
• Reclassifying existing medicines, if there is evidence to safely support doing so
• Regulating the importation of licensed medicines to the UK from European Union countries
• Carrying out inspections to ensure that medicines are developed, manufactured, distributed, and monitored to internationally recognized standards
• Helping set and enforce the legal advertising regulations for medicines in the UK
• Independent quality testing of batches of biological medicines before they go onto the market to make sure that it is consistent with batches previously shown to be safe and effective
• Regulating the supply of unlicensed medicines into the UK
• Carrying out enforcement activities to prevent the illegal supply of unlicensed medicines, to or within the UK

In addition, according to GBR-57, the MHRA’s responsibilities are to:

• Ensure that medicines, medical devices, and blood components for transfusion meet applicable standards of safety, quality, and efficacy
• Ensure that the supply chain for medicines, medical devices, and blood components is safe and secure
• Promote international standardization and harmonization to assure the effectiveness and safety of biological medicines
• Help to educate the public and healthcare professionals about the risks and benefits of medicines, medical devices, and blood components
• Enable innovation and research and development that is beneficial to public health
• Collaborate with partners in the UK and internationally to enable the earliest access to safe medicines and medical devices and to protect public health

For a listing of MHRA services and information, see GBR-36.

G-ATMP states that the MHRA is also the competent authority for advanced therapy medicinal products (ATMPs) and for UK manufacturers or importers of ATMPs. An ATMP is a medicinal product which is either a gene therapy medicinal product, a somatic cell therapy medicinal product, or a tissue engineered product.

Changes to the UK Clinical Trials Regulations

As summarized in the CT-Hub and the MHCTR-Chgs, the amended MHCTR updates the UK framework for clinical trials involving investigational medicinal products (CTIMPs), including changes relating to definitions and terminology, the approvals process, ethics committee review, simplified consent arrangements, pharmacovigilance, risk proportionality, and transparency requirements. The MHCTR-Chgs also provides an overview of the changes to policies and standards. The amended regulations apply across all four (4) nations of the UK. The CT-Transtn lays out the transitional provisions because some requirements depend on whether the application for trial approval was submitted before or on/after April 28, 2026, and certain amended requirements will also apply to older trials from that date. (Note: Transitional details are described in the relevant sections of this profile.)

International Alignment

Per GBR-44, the MHRA is a member of the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). The MHCTR requires that all clinical trials must be conducted in accordance with the conditions and principles of good clinical practice (GCP), including the ICH GCP, as amended from time to time. The UK-ICHE6-Comply explains that this legal requirement applies to the ICH E6 GCP conditions and principles rather than the entirety of the guideline. ICH-UKimp indicates that the UK is implementing the ICH’s Guideline for Good Clinical Practice E6(R3) (GBR-91) and the ICH General Considerations for Clinical Studies E8(R1) (GBR-104), among others. As explained in the UKannot-ICH, the MHRA has issued UK-specific annotations—UKannot-E6R3 and UKannot-E8—to support compliance with the ICH efficacy guidelines by clarifying how the ICH provisions should be read alongside applicable UK legal requirements and by directing users to relevant UK requirements. (Note: As these applicable requirements are addressed throughout the profile, the annotations are cited only where they provide additional UK-specific clarification, exceptions, or requirements.) See ICH-UKimp for all the current ICH guidelines that have been implemented by the MHRA.

In addition, the MHCTR requires that clinical trials must be conducted in accordance with the principles of the Declaration of Helsinki (GBR-81) except where it would be a contravention of the MHCTR. The Hlsnki-Align explains that reference to specific versions of GBR-81 have been removed as compliance is expected with the principles of GBR-81 rather than with a specific version.

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.

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

Contact Information

Per GBR-58, the following is the MHRA’s contact information:

Medicines and Healthcare Products Regulatory Agency
10 South Colonnade
Canary Wharf
London E14 4PU
United Kingdom

Main Phone: +44 020 3080 6000
General Email: info@mhra.gov.uk
Clinical Trials of Medicines:
Email: clintrialhelpline@mhra.gov.uk
Telephone: +44 020 3080 6456

Pharmacovigilance: vigilanceservice@mhra.gov.uk and gpvpinspectors@mhra.gov.uk
Data Protection Email: DataProtection@mhra.gov.uk
Importing or Exporting Investigational Medical Products Email: for queries, complete the GMP contact form and email it to gmpinspectorate@mhra.gov.uk
Scotland-related regulatory matters: Scotland-support@mhra.gov.uk
Wales-related regulatory matters: Wales-support@mhra.gov.uk
Northern Ireland-related regulatory matters: NI-support@mhra.gov.uk

See GBR-58 for additional MHRA contact information.

For help with setting up and conducting research in the National Health Service (NHS) across multiple UK nations, the UKwide-Rsrch provides the following emails for queries:

• England: queries@hra.nhs.uk
• Northern Ireland: Research.Approvals@hscni.net
• Wales: healthandcareresearch@wales.nhs.uk
• Scotland: enquiries@nrs.org.uk

Overview

In accordance with the G-CTHandbook, the G-TrialsSOP, and AUS-86, 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-86, 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. See AUS-91 for TGA summaries of recent clinical trial reforms.

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.

However, as noted in AUS-88, the CTA scheme is mandatory for certain Class 4 biologicals. See AUS-86 for more general information on choosing a clinical trial scheme.

CTN Scheme

As per the G-CTHandbook, the G-TrialsSOP, and AUS-87, 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 notification. AUS-87 further notes that some ECs and institutions may need the TGA’s acknowledgement before beginning their own approval processes. In these cases, the TGA will accept a CTN submission while the sponsor gets the required approvals from the EC and institution. 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 and AUS-87 indicate 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/variations to the trial details notified to the TGA, the sponsor must update the relevant fields on the online CTN form. AUS-87 notes that some changes/variations (such as the addition of a new site to a trial, a change to the notified therapeutic good that creates a separate and distinct good, or the addition of a new therapeutic good to a previously notified trial) will incur a fee.

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

AUS-88 indicates that the CTA scheme involves an application to the TGA for approval to supply an unapproved therapeutic good(s) in a clinical trial, where the TGA will evaluate scientific data about the therapeutic good(s) (quality, preclinical, and early clinical safety data) prior to the start of a trial. The sponsor can, either following TGA approval or in parallel with the TGA’s evaluation, contact their chosen EC to initiate the EC’s review of the scientific and ethical details of the trial proposal. However, trials can only commence once both TGA and EC approvals have been received.

According to AUS-88, the TGA is in the process of reviewing the CTA scheme. Stakeholders seeking more information on the CTA process are encouraged to contact the TGA at clinical.trials@health.gov.au. Sponsors planning to submit a CTA application are also encouraged to request a pre-submission meeting with the TGA. See the Submission Process section for more information on pre-submission meetings.

AUS-88 states that after the sponsor submits the CTA application form and supporting data, the TGA generally conducts a preliminary assessment to ensure that the data is sufficient to begin evaluation. If there is critical data missing, the TGA will request further information. Once it is satisfied that there is sufficient data/information to commence evaluation, the TGA will send an invoice. The TGA’s evaluation begins after the sponsor pays the fee. During its review, the TGA generally evaluates the quality of the therapeutic good, the safety of the therapeutic good, compliance with applicable Therapeutic Goods Orders (TGOs) (see AUS-93), compliance with international guidelines, and labelling (including traceability). The evaluation process usually consists of two (2) rounds of evaluation and one (1) round of request for information from the sponsor. Additional rounds may be required if there is outstanding information required to support the evaluation process or decision.

As delineated in AUS-88, evaluation reports with recommendations are then submitted to the decision maker, a TGA senior medical officer, for consideration. The decision maker considers the overall risk-benefit profile of the trial, which may include TGA evaluation reports; the trial’s usage guidelines (such as the trial protocol, investigator’s brochure, literature references, and pharmacy guidelines); and plans for shipment and storage at trial sites. The decision maker may seek expert advice from TGA statutory advisory committees. The TGA will inform the sponsor in a letter of the decision whether to approve the trial or not.

AUS-88 further states that if a sponsor wishes to change the therapeutic good(s) or any aspect of the clinical trial that was evaluated in the original CTA submission, a variation requiring additional evaluation by the TGA may be required. These changes are assessed to ensure that the quality and safety of the good(s), or the overall risk-benefit profile of the trial, will not be inadvertently altered by the variation. Examples may include significant changes to the manufacturing process, intended patient group, route of administration, and/or container. CTA variations incur a fee. Any changes that were not evaluated in the original submission or are predicted to have no effect on the therapeutic good or safety of the trial will not be assessed by the TGA. However, all changes should be communicated to and approved by the EC before commencement. Sponsors are encouraged to contact the TGA at clinical.trials@health.gov.au for specific advice on what constitutes a variation to a previously approved CTA application.

As indicated in the G-CTHandbook, 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. The TGA can conduct a GCP inspection, which typically occurs over one (1) to three (3) consecutive days, at any stage of the clinical trial lifecycle from the early phase of participant recruitment to completed trials. Additionally, the TGA can request certain information or documents about therapeutic goods exempt under the CTN scheme or approved under the CTA scheme. This can include the investigator’s brochure and protocol, further information about safety reports, clarification about the safety profile of a specific therapeutic good, and/or details of problems or complaints. The TGA will normally give advance notice of its intention to conduct a GCP inspection but has the right to perform an inspection at any time. In exceptional circumstances, the TGA can perform an inspection without notice.

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. See AUS-90 for more information on the TGA’s GCP inspection program.

Overview

In accordance with the MHCTR and as described in GBR-71, the Medicines and Healthcare Products Regulatory Agency (MHRA) is the licensing authority responsible for reviewing, evaluating, and approving applications for clinical trials of investigational medicinal products (CTIMPs). Per the MHCTR and the CTApp-Appvl, a person must not start or conduct a clinical trial without prior MHRA authorization and a favorable ethics committee (EC) opinion. The CTApp-Appvl calls it a joint ‘clinical trial approval’. The MHCTR-Chgs states that a clinical trial application is submitted to the MHRA and the EC using the combined review part (GBR-125) of the Integrated Research Application System (IRAS) (GBR-78). As explained in GBR-72, 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 the MHRA and the EC (and study-wide review, which is discussed below) leading to a single United Kingdom (UK) decision for clinical trials. See GBR-72 for additional updates and information on combined review.

Per the G-Biosimilars, the MHRA also regulates the licensing of biosimilars (i.e., similar biological medicinal products).

See Schedule 14 of the MHCTR, and the CT-Transtn for background information on transitional arrangements from the ‘old rules clinical trial’ to the ‘new rules clinical trial’.

Clinical Trial Review Process

Per the MHCTR, the MHRA and the EC — collectively, “the authorities” — must confirm whether a request for approval is valid within seven (7) days beginning with the date of submission and must notify the sponsor. Once the request for approval is deemed valid, the MHRA must assess the request for authorization, and the EC must assess the application for an EC opinion. The MHCTR-Chgs indicates that the authorities will aim to notify sponsors of the outcome of the validation check within one (1) working day. As indicated in the CTApp-Appvl, the outcome of these checks will be communicated by email and through IRAS within seven (7) calendar days of submission. As soon as possible during this 7-day period, and no later than on the fifth calendar day, the MHRA may notify the applicant by email of any deficiencies identified during the validation checks and allow them to be addressed. If these deficiencies remain unresolved by the end of this 7-day period, the application will be invalidated, and the applicant will need to resubmit the application with the deficiencies corrected. The MHRA’s CTApp-Appvl and the Health Research Authority (HRA)’s MHCTR-Chgs provide operational guidance on the joint review and approval process laid out in the MHCTR.

The CT-Transtn provide that the “new rules” under MHCTR apply to the whole process of requesting approval for a clinical trial that is submitted on or after April 28, 2026. If an application to approve a clinical trial is submitted before April 28, 2026:

• The “old rules” apply to the whole process of requesting approval (even after April 28, 2026, if the MHRA and the EC have not issued a decision or opinion by then)
• If the MHRA issues a notice of grounds for non-acceptance after April 28, 2026, the old rules still apply following the applicant’s response to the grounds for non-acceptance
• The provision that a clinical trial approval will lapse two (2) years from the date on which the trial was approved if no participants have been recruited to take part does not apply

As part of its assessment, MHCTR states that the MHRA must consider the safety of the clinical trial and the safeguarding of clinical trial participants. The MHRA may consider whether the sponsor has failed to comply with clinical trial transparency requirements in relation to another clinical trial and, if so, whether the failure has been rectified (e.g., registering a previous clinical trial and/or publishing a summary of final results). Where the request for authorization contains a statement that the trial is a notifiable trial (i.e., eligible low-risk trials), the MHRA may, if it considers appropriate and without undertaking further assessment, rely on that statement to provide an automatic authorization of the clinical trial (more details below). The MHRA may consult a relevant committee and/or a specialist group or committee if it considers it appropriate (more details on this below). The authorities must not authorize a clinical trial involving products for gene therapy if the use of those products in that trial would result in modifications to any participant’s germ line genetic identity. Also see the CTApp-Appvl, and the MHCTR-Chgs for additional details.

After completing the initial review, MHCTR stipulates that the MHRA must provide its decision on the request for authorization, and the EC must give its opinion on the clinical trial. The authorities must notify the sponsor in writing of the joint outcome, which is one (1) of the following:

• Approve the request for approval
• Approve the request for approval, subject to conditions specified in the notice
• Not approve the request for approval, setting out the grounds for the decision and requesting the further information (RFI) required for the application to be reconsidered

Per the MHCTR, subject to applicable extensions and special circumstances, the authorities must take all reasonable steps to ensure that the joint notice is given within 30 days beginning with the date on which the authorities notified the sponsor that the request for approval was valid. Where approval is subject to conditions, the notice must specify whether the conditions relate to the MHRA’s decision, the EC opinion, or both. The clinical trial is treated as approved only if the conditions specified in the notice are satisfied. Following an RFI, the amended request for approval must be reviewed by the appropriate authority. The MHRA reviews the amended request where the RFI relates to the MHRA’s authorization decision; the EC reviews it where the RFI relates to the EC opinion; and both authorities review it where the request relates to both.

Next, the MHCTR states that applicants have 60 calendar days from the date on which the decision letter was issued to provide the requested information for the application to be reconsidered. The CTApp-Appvl indicates that the applicant’s submittal can be either a written response or an amended application for approval. The application is treated as rejected if this deadline is not met. However, extensions to this deadline can be requested by contacting the MHRA at clintrialhelpline@mhra.gov.uk (or by contacting the EC directly, if the information requested relates only to its opinion), explaining why the extension is needed and proposing an alternative submission date. The MHCTR-Chgs explains that the applicant must wait for the full RFI (issued in GBR-125) before responding to any points received individually from the MHRA or EC. The full RFI will have the final consolidated feedback, including any queries or issues, from both the MHRA and EC. See G-IRASCombRev and IRAS-User for additional details on using GBR-125 during the review process.

Next, MHCTR provides that after reviewing the amended request, the appropriate authority must notify the sponsor in writing of the outcome, which is one (1) of the following:

• Approve the amended request
• Approve the amended request, subject to conditions specified in the notice
• Not approve the amended request, setting out the grounds for the decision

As per the MHCTR, subject to applicable extensions and special circumstances, the appropriate authority must take all reasonable steps to ensure that notice is given within 10 days beginning with the date of receipt of the amended request. The CTApp-Appvl further provides that for approvals with conditions, it is not necessary to inform the authorities that the conditions have been met before starting the trial, unless otherwise specified in the approval letter. In some cases, the MHRA and/or the EC may allow a condition of approval to be fulfilled at a specific timepoint after the trial begins. In these cases, the trial may begin before meeting the condition, but failure to meet the condition by the specified timepoint will mean that the approval is not valid and the trial must be stopped until the condition is discharged. A substantial modification can then be submitted requesting approval to restart the trial.

For the initial review, the MHCTR provides that the 30-day period is extended by 90 days where the MHRA or the EC consults a relevant committee and/or specialist group or committee. For review of an amended request, the 10-day period is extended by 30 days where the MHRA or the EC consults a relevant committee and/or specialist group or committee, or by 60 days where the investigational medicinal product (IP) is an advanced therapy medicinal product (ATMP) and such consultation occurs. If the clinical trial involves a medicinal product for xenogenic cell therapy, the usual time periods do not apply. See below and the Submission Process section for more details on consultations.

Per the MHCTR, in exceptional circumstances (for example, in an urgent situation where it would be beneficial to progress one (1) request or application while preparing the other), and if agreed in advance by the MHRA or the EC, a request for authorization and an application for an EC opinion may be made separately outside of combined review. Where an agreement has been reached, the MHRA or the EC must confirm which of the particulars and documents specified in Part A1 of Schedule 3 must accompany the request for authorization and the application for an EC opinion; and the arrangements for the payment of the fee.

The MHCTR-Chgs states that the sponsor can appeal an MHRA non-approval or an EC unfavorable opinion by contacting appeals@hra.nhs.uk within 28 calendar days of receiving the outcome. In their appeal, the sponsor must explain why they disagree with the outcome. See the CTApp-Appvl for additional details on the appeals process and requirements.

See GBR-82 for a flowchart summarizing the process of applying for clinical trial approval. In addition, see MHCTR-Chgs for more descriptions of the approval process to the MHCTR.

Per the MHCTR, if a clinical trial is to be conducted in another country as well as the UK, the MHRA may require the sponsor, and/or the owner or occupier of any premises in that country, to permit those premises to be inspected by or on behalf of the MHRA for the purpose of establishing whether the conditions and principles of good clinical practice (GCP) are satisfied or adhered to in relation to that trial.

The MHCTR and the EndingCT state that a clinical trial approval will lapse two (2) years from the date on which the trial was approved if no participants have been recruited. The EndingCT indicates that the MHRA will monitor the status of the trial’s approval. If the approval lapses, the sponsor will be contacted via email to confirm this. The sponsor will then need to submit an end of trial notification. To enable the MHRA to monitor approval status, all sponsors will need to notify the MHRA and the EC of the date on which the first participant was recruited to a clinical trial through the modification of an important detail process. Sponsors can apply to the authorities for an extension of this period by emailing clintrialhelpline@mhra.gov.uk, explaining both why the extension is needed and the length of the proposed extension. The authorities can grant an initial extension of up to 36 months beyond the lapse date and a further extension of up to 24 months, which must be requested (through the same process) before the previous extensions end. The MHRA and the EC will respond to extension requests via email within 30 calendar days or, if the trial is awaiting approval, at the same time as the outcome of the application for clinical trial approval is issued.

Per the MHCTR, the MHRA may, by notice, require that a clinical trial, or the conduct of a trial at a particular trial location, be suspended or terminated where it has objective grounds for considering that an applicable condition, restriction, or limitation is no longer satisfied, has information raising doubts about the safety or scientific validity of the trial, or where the trial has lapsed and the sponsor has not notified the MHRA that the trial has ended. The notice must specify whether it applies generally or to specific trial locations, whether it requires suspension or termination in whole or in part, and when it takes effect; for a suspension, whether it continues until further notice or for a specified period and any conditions for recommencement. The notice must be served to the sponsor or the investigator(s) at the relevant trial location(s). Additionally, the MHRA must inform the relevant EC and the sponsor (if the notice was not served to the sponsor). Unless the MHRA believes there is an imminent risk to the health or safety of any participants, the MHRA must inform the sponsor or investigator in writing of its intent to issue the notice at least one (1) week before issuance, and provide an opportunity for written representations within one (1) week as to whether the trial should be suspended or terminated. A person served with the notice of suspension or termination may, within 28 days or an extended period as allowed, give notice of a wish to make written or oral representations to the appropriate committee, and any referred suspension or termination remains in force unless revoked in accordance with Schedule 5.

To support compliance with the International Council for Harmonisation’s Guideline for Good Clinical Practice E6(R3) (GBR-91), the GCP-Inspct states that the MHRA:

• Requires organizations sponsoring clinical trials to notify them of serious breaches
• May conduct triggered inspections of organizations where serious breaches are suspected
• May conduct routine risk-based inspections of organizations that sponsor or conduct clinical trials
• May conduct inspections of clinical trials, and associated activities, submitted in support of a marketing authorization application

The G-GMP-GDP specifies that the MHRA follows a risk-based approach to inspections. Once an inspection has been completed, a formal report outlining the findings will be sent to the inspected organization.

Consultations for Expert Advice

Regarding consultations, the CT-Experts explains that the MHRA or the EC may consult a relevant committee or specialist group before issuing a clinical trial decision, including for certain scientifically complex or higher-risk trials. In deciding whether to seek expert advice, the authorities may consider factors such as the IP’s mode of action, the nature of the target, and the relevance of animal species and models; examples include novel compounds and certain first-in-human trials. See the CT-Experts for additional details and a process flowchart. (See Submission Process section for more details.)

Modifications to a CTIMP Approval

Per the MHCTR and the CTMod, a clinical trial approval may be modified by the trial’s sponsor, the MHRA, or the EC. Modifications to a clinical trial approval can be categorized into substantial modifications (Route A or Route B), modifications of an important detail, and minor modifications. Approval to make substantial modifications must be received from the MHRA and EC before implementation. The exception to this is for substantial modifications that relate to urgent safety measures. When considering implementing substantial modifications, sponsors should assess whether such modifications alter the original clinical trial approval to the extent that it should be considered a new clinical trial. If this is the case, a new application for clinical trial approval should be submitted. As described in the CTMod, the sponsor is responsible for using a risk-based approach to determine which of the following modification categories applies:

• Minor modifications: A sponsor may make a minor modification to a clinical trial approval at any time and without submitting a modification request or informing the MHRA and the EC at the point of implementation; the sponsor must keep records and provide them if requested.
• Modifications of an important detail: These do not significantly impact the safety or rights of the participants, but the authorities need to be aware of them for administrative or oversight purposes. Instructions for notifying the authorities about a modification of an important detail are provided on completion of the Modification Tool in GBR-125. See the CTMod for examples of modifications of an important detail.
• Route A substantial modification: This modification to a clinical trial approval is likely to have a substantial impact on the safety or rights of the participants or on the reliability or robustness of the data generated in the trial. If the sponsor proposes to make a substantial modification of this kind, the sponsor must submit a modification request to the authorities before implementation.
• Route B substantial modification: This modification poses no new significant safety concerns with any IP and the modification meets Condition A, B, or C. Condition A applies where the trial does not involve an IP used for the first time in humans and the modification has already been reviewed and approved by the clinical trials authority in the European Union (EU), an European Economic Area (EEA) State, or the United States, based on the same particulars and documents submitted in the UK, excluding UK-specific particulars. Condition B applies where the modification is limited to certain protocol changes. Condition C applies where the modification is limited to certain changes to the investigator’s brochure or summary of product characteristics. These modifications are eligible for automatic approval by the MHRA, with EC approval issued within 35 days of validation if needed.

Per GBR-83, the MHRA and the EC will manage submitted modifications in the Modification Tool of GBR-125. See GBR-106 for help using the Tool. For additional resources on clinical trial modifications, see the following:

• GBR-84: A decision tree for determining the correct category for a modification
• GBR-88: A flowchart for applying for approval of Route A substantial modifications
• GBR-85: Table of Route B substantial modifications
• GBR-134: Notification form for a substantial modification when the Modification Tool is not appropriate (for example for bulk modification (See CTMod, for more information on this))
• MHCTR-Chgs: Background on amendment/modification terminology updates, modification process overview, and examples
• GBR-98: Examples of modification types

With regard to transitional arrangements (i.e., old rules clinical trials vs. new rules clinical trials) relating to approval for modifications, CT-Transtn explains that the applicable regulations are determined by the date on which the application to approve the substantial modification was submitted. Therefore, if the sponsor submits an application to approve a substantial modification (or receives notice of a proposed modification by the MHRA or EC) prior to April 28, 2026, the old rules clinical trials apply to the whole process of requesting approval (even after April 28, 2026, if the authorities have not issued a decision by then). If an application to approve a substantial modification is submitted on or after April 28, 2026, the new rules (i.e., the MHCTR) apply to the approval process even if the clinical trial approval to be modified is for an old rules clinical trial.

Per the CTMod, to request approval for a Route A or Route B substantial modification, applicants must submit a single application, including all documentation, through IRAS (GBR-125) for trials approved through the combined review process. Applications undergo validation checks, with the outcome communicated within seven (7) calendar days. Any deficiencies must be resolved within that period or the application will be invalidated and must be resubmitted. A joint decision on a valid Route A application will be issued within 35 calendar days of validation. For an eligible Route B modification, automatic approval from the MHRA will be issued within 14 calendar days; however, the modification cannot be implemented until a combined decision approving it, or approving it with conditions, is received. If the MHRA or EC do not approve the applicant’s proposed substantial modification, the applicant will be given one (1) opportunity to provide further information and have the application reconsidered. The additional information needed will be specified in the notice stating that the application has not been approved, and it will be made clear whether the additional information requested relates to the MHRA’s decision, the EC’s opinion, or both.

Next, the CTMod states that applicants have 60 calendar days from the date on which the decision letter was issued to submit the RFI, either as a written response or an amended application for approval, in order for the application to be reconsidered. The application will be treated as rejected if this deadline is not met. Note that it is not currently possible to submit a response to an RFI about a substantial modification through IRAS (GBR-125). The response must be submitted to the MHRA through MHRA Submissions (GBR-13) and to the relevant EC via email. The MHRA cannot accept responses to RFIs that are submitted via email to an assessor or via the Clinical Trial Helpline unless this has been agreed to in advance. Extensions to the 60-day deadline can be requested by contacting the MHRA at clintrialhelpline@mhra.gov.uk or by contacting the EC directly, and the applicant should explain why the extension is needed and propose an alternative submission date. A decision will be issued by email within 10 calendar days of the response being submitted, stating that the application is either approved, approved with conditions, or not approved. If the application is still not approved, the reasons will be outlined and the application will be treated as rejected.

As per MHCTR and the CTMod, either or both the MHRA or EC may require the sponsor to make modifications to a clinical trial to ensure the trial’s safety or scientific validity or to ensure adherence to the principles of GCP. Sponsors will receive a notification of the proposed modification, and the reasoning behind the proposal via email at least seven (7) calendar days before the modification is set to take effect. The sponsor may accept the proposal, or otherwise has seven (7) calendar days to submit representations against the proposal in writing to the relevant authority. The appropriate authority will issue a final decision on whether the modification must be implemented after considering the sponsor’s representations. The date on which the proposed modification is to take effect may be delayed so that the MHRA and/or the EC has sufficient time to consider these proposals. The CTMod states that where the appropriate authority makes a final decision to modify a clinical trial approval, the sponsor has 28 calendar days from the date on which the decision letter was issued to provide written notice to the authorities of their intention to appeal. This notice should be sent to appeals@hra.nhs.uk, after which the authorities will contact the applicant to discuss the appeals process.

Notifiable Trials

The MHCTR includes a notifiable trial pathway under which certain eligible low-risk trials may receive automatic authorization from the MHRA (but an EC review is still mandatory). A notifiable trial is a trial in which, as far as the sponsor is aware having made reasonable inquiries, there are no significant safety concerns with any IP; the trial meets Condition A, Condition B, or Condition C; and the trial does not involve participants who are under 18 years of age, pregnant, or breastfeeding, or an IP that is an advanced therapy medicinal product or is used for the first time in humans. Following are the requirements for each Condition:

• Condition A: The IP/s is/are authorized for use in the UK and is used either in accordance with that authorization or in a manner supported by established clinical practice
• Condition B: A trial relating to the IP/s has/have been approved in the UK within the preceding two (2) years of the request for approval, and in that approved trial, the IP was investigated at the same or higher dose, same or higher frequency, and same or longer duration; the same manufacturing process was used; and the product was administered by the same route of administration and investigated for the same indication
• Condition C: The trial has undergone assessment and been approved by the authority responsible for licensing clinical trials in the EU, an EEA State, or the United States

Per the MHCTR, where the request for approval contains a statement confirming that the trial is a notifiable trial, the MHRA may, if it considers appropriate and without undertaking further assessment, rely on that statement to provide an authorization of the clinical trial.

The CT-Ntfble states that notifiable trial applications undergo the same validation checks as non-notifiable trial applications. After validation, the MHRA assesses whether the application meets the eligibility criteria for automatic authorization. If the criteria are met, the MHRA will issue confirmation of automatic authorization within 14 calendar days of validation. Next, a combined decision is issued, following EC review, within 30 calendar days of validation. If the MHRA finds that the application does not meet the eligibility criteria, or otherwise decides that a full review is needed, it will notify the applicant, and the application will automatically proceed through the non-notifiable review pathway. The MHRA also reserves the right to undertake a full review before issuing a decision, even where the trial is otherwise eligible for notification. See the CT-Ntfble for more details and a process flowchart.

UK-wide Research

The UKwide-Rsrch indicates that the UK’s four (4) nations—England, Northern Ireland, Scotland, and Wales—work together and with a range of organizations to support and regulate different aspects of health research. Study-wide review is the process by which all research in the UK is reviewed and approved, bringing together the assessment of governance and legal compliance of research in healthcare. The UK nations take a consistent approach to study-wide reviews, so sponsors only need to submit one (1) application in GBR-125 (combined review section of IRAS) or GBR-78 (non-combined section of IRAS). GBR-78 explains that the system 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. If a project is led from Northern Ireland or Scotland and involves NHS sites, then applications should be made through the appropriate permission process for that lead nation. Studies with sites in Northern Ireland or Scotland are supported through existing UK-wide compatibility systems where each country accepts relevant centralized assurances from national coordinating functions to avoid duplication.

The UKwide-Rsrch specifies that each UK nation will take assurances from the study-wide review conducted by the lead nation (the nation conducting the initial review). The following outlines key differences in approvals from UK nations:

• England and Wales – For any research taking place in England and/or Wales, the sponsor will receive an HRA and HCRW approval letter, which will detail any further requirements before beginning the research
• Northern Ireland – Each participating Northern Ireland Health and Social Care (HSC) R&D Approvals Service body will confirm their capacity and capability after the relevant study-wide reviews and participating site assessments and arrangements are complete
• Scotland – For any research taking place in Scotland, the sponsor will receive Research & Development permission after the relevant study-wide reviews and site assessments and arrangements are complete

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:

• $464 Australian dollars for unapproved medicines CTN, and for each notification of one (1) or more additional trial sites
• $2,212 Australia dollars for unapproved medicines CTA (30-day evaluation)
• $608 Australian dollars for unapproved medicines CTA – variation (30-day evaluation)
• $27,500 Australian dollars for unapproved medicines CTA (50-day evaluation)
• $7,506 Australian dollars for unapproved medicines CTA – variation (50-day evaluation)
• $464 Australian dollars for unapproved biologicals CTN, and for each notification of one (1) or more additional trial sites
• $33,489 Australian dollars for unapproved biologicals CTA
• $9,136 Australian dollars for unapproved biologicals CTA – variation

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 on TGA fees and payments. Also see AUS-49 for additional guidance and system screenshots related to paying CTN fees.

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

Medicines and Healthcare Products Regulatory Agency

As per MHCTR and CTApp-Appvl, an application for a clinical trial approval must be accompanied by a fee to the Medicines and Healthcare Products Regulatory Agency (MHRA) as specified in the G-MHRAFees. 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 indicated in the CTMod, the applicable fees for submission of an application to modify a clinical trial approval are in G-MHRAFees. If the MHRA determines that a Route B substantial modification does not meet the eligibility criteria, the applicant may withdraw the application before it undergoes Route A review and receive a refund of the application fee. If an applicant withdraws a substantial modification application before a decision or request for further information is issued, part of the application fee may be refunded depending on how much of the review has been completed. There are no fees for a modification of an important detail.

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

• 4,656 British Pounds – Applications with an Investigational Medicinal Product (IMP) dossier (higher fee for phase 1, full and simplified IMP dossier)
• 343 British Pounds – Applications without an IMP dossier (lower fee for phase IV, cross referral, additional protocol)
• 343 British Pounds – Clinical trial variation/amendment
• 343 British Pounds – Assessment of annual safety reports (which are in the form of a development safety update report (DSUR) per the CT-Sfty)

Note per the G-MHRAFees, there is no annual clinical trials fee. 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.

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, 2nd 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. The 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.

Per the CT-Sfty, fees applicable to submission of a DSUR must be paid through the MHRA payment center on the dedicated DSUR payments page (GBR-43). Following payment, a receipt will be sent by email to the payee, which must be included in the submission in its original format as a standalone document that serves as proof of payment. Failure to provide this evidence of payment will result in the submission being invalidated.

Overview

As indicated in the TGAct, the TGR, the G-CTHandbook, the G-NatlStmt, and AUS-86, 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-86, 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.

Overview

Per MHCTR, research ethics committees (ECs) in the United Kingdom (UK) are established, recognized, and monitored by the UK Ethics Committee Authority (UKECA). As explained in the REC-Policy, UKECA is responsible for recognizing ECs that can review clinical trials of investigational medicinal products (CTIMPs) in the UK and ensuring compliance with MHCTR. Per the REC-Policy and GBR-62, ECs are part of an accountable and independent Research Ethics Service (RES) (GBR-62). The REC-Policy indicates that the Health Research Authority (HRA) and Devolved Administrations (i.e., Governments of Scotland, Wales, and Northern Ireland responsible for health and social care services in their nations) work together to deliver the RES through the UKECA. For ECs that review CTIMPs, Appointing Authorities in each UK nation operate and work on behalf of UKECA to enable the discharge of its functions. Outside of CTIMP reviews, REC-Policy explains that ECs also review a broad range of proposed research in health and care settings in the UK, and certain functions may be carried out under nation-specific arrangements or bilateral agreements.

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 the REC-Policy, the RES encompasses England’s HRA under the Department of Health and Social Care (DHSC), Northern Ireland’s Department of Health, the Scottish Government Health and Social Care Finance Directorate, and the Welsh Government’s Health, Social Care and Early Years Group. In addition to its functions as the Appointing Authority for the RES for England, by agreement and through consultation with the Devolved Administrations (i.e., Scotland, Wales, and Northern Ireland), the HRA performs national coordinating functions for the RES. Per GBR-90, HRA is “an arm’s length body” of England’s DHSC, which means the government has devolved some of its responsibilities to HRA.

GBR-9 establishes an EC allocation framework for CTIMP ethics review, under which CTIMP applications must be reviewed by an EC recognized by UKECA to review the appropriate type of CTIMP as well as flagged ECs (e.g., for gene therapy or research on children). See GBR-9 for more guidance and the EC allocation categories.

See GBR-111 for an overview of ECs and GBR-112 to search listings, contact information, and meeting dates for ECs.

Ethics Committee Composition

As delineated in the MHCTR, an EC must be constituted of five (5) or more members, appointed by the Appointing Authority, who collectively have the qualifications and experience to review and evaluate the science, medical aspects, and ethics of the proposed trial; and include one (1) member appointed to be a chairperson. The REC-Policy additionally provides that each EC should comprise a range of people with individual expertise and experience, including registered health and social care professionals, research professionals, and members of the public who have experience using health and social care services and no professional knowledge. EC members are appointed to provide a broad range of perspectives on the committees, which scrutinize the rationale, aims, and objectives of the proposed research to reconcile this effectively with protecting the dignity, rights, safety, and well-being of potential participants. They are appointed independently of their employing organization and are expected to reflect their own experience and ethical judgement on an individual basis, bringing sound judgement and personal experience, underpinned and supported by relevant training and RES standard operating procedures (SOPs) (GBR-9).

Per the REC-Policy, each EC will be established and membership maintained by the Appointing Authority to ensure that the EC collectively has the qualifications and experience to review the ethics of proposed research. Where an EC member has an interest in a research proposal or affiliation with a research organization where impartiality and independence cannot be maintained, the declaration of interest process is followed. Each EC must have a chair and a vice-chair and the option to appoint an alternate vice-chair, which are appointed by the relevant Appointing Authority. Chairs, vice chairs, and alternate vice chairs are appointed for a specified period not exceeding five (5) years, but can resign anytime. An acting chair’s appointment ceases when the chair, vice chair, and alternate vice chair of that EC becomes available again or when their term as a member expires, whichever is sooner. EC members are appointed for up to five (5) years, but can resign at any time. Members may stay on for another term of five (5) years, subject to agreement with the Appointing Authority. After this time, they will be required to join a different EC if their membership extends for longer than a 10-year period. The Appointing Authority may extend a member’s term while new members are appointed, to ensure continuity of service. Former members may be reappointed to the same EC no sooner than one (1) year after the end of their last term, or to another EC without interval.

See the REC-Policy and GBR-9 for additional details.

Terms of Reference, Review Procedures, and Meeting Schedule

Per the MHCTR, an EC must make standing orders and adopt SOPs for its proceedings and business. The meetings and proceedings of an EC and its sub-committees must be conducted in accordance with the standing orders made, and the SOPs adopted. All applications for an EC opinion must be considered by a full meeting of an EC. REC-Policy states that a volunteer agreement outlining the expectations of appointment for EC members is required and includes: duration of appointment, renewal policy, process for resignation, process to be followed if a member who is a registered professional becomes disqualified, and the policy relating to declaration of interests. Also see REC-Policy for additional guidance.

As delineated the MHCTR and GBR-9, the quorum for EC meetings is five (5) members. However, GBR-9 states that ECs should always aim to have seven (7) members at a meeting where possible. The EC meeting will include at least the following: a chairperson (this can be a chair, vice chair, or alternate vice chair); at least one (1) lay member; and at least one (1) member with a healthcare designation. The EC membership will collectively reflect the qualifications and experience to review the science, medical aspects, and ethics of the research applications. For applications relating to research with funding support from the U.S. Department of Health and Human Services or one of its agencies, the quorum is a majority of the EC membership. Where the EC has an even number of members, a majority means 50% of the members plus one (1). A co-opted member should also be counted for the purpose of the quorum. An EC may co-opt additional members at any EC meeting only if they are a member of another EC within the RES or a member of Ministry of Defense Research Ethics Committee. A CTIMP review meeting may not co-opt more than two (2) members. Where a quorum is not present, the EC may not give an ethics opinion on any new application for ethics review.

REC-Policy states that members are expected to attend as many full meetings as possible, as well as participate in proportionate review and sub-committee meetings. Expenses incurred during an EC members’ duties are reimbursed, which may cover travel, subsistence, and care arrangements, but not loss of earnings. EC members are required to complete specific training modules to ensure that the approach to reviewing research is consistent across the RES and that members have the right information to support their reviews. EC members have a duty to maintain confidentiality regarding applications, meeting deliberations and any other information about research applications that they have access to. Each Appointing Authority provides indemnity cover for their EC members.

GBR-9 specifies that ECs should normally hold at least 10 scheduled full meetings each year for ethics review of applications, at 1-month intervals, with schedules staggered to ensure valid applications can be reviewed within the relevant time limit. The annual schedule should be agreed to by December 1 for the financial year beginning April 1 and should include meeting dates, times, and application closing dates. Closing dates for full applications should normally be 14 calendar days before the EC meeting, with later closing dates permitted for Phase 1 healthy volunteer trials in certain circumstances. A standard agenda should be prepared for each EC meeting and should include quoracy, declarations of interest, previous minutes, previous matters to discuss, applications for ethics review, lead reviewers, and the EC Report. Agendas may also include general ethics issues, EC establishment or membership matters, procedures, training issues, quality control (QC)/quality assurance (QA) reports, and workload or decision-making data. ECs should review around 3–4 new applications per meeting on average. The EC Report should notify members in writing of business undertaken outside EC meetings, including delegated decisions or actions, sub-committee decisions, conclusions or early termination of research, minor modifications, and final study reports. ECs are strongly recommended to appoint one (1) or more lead reviewers for each full application, and a lead reviewer must be appointed for each application reviewed by a proportionate review sub-committee. Documents for meetings should be made available as soon as possible after the agenda is finalized and applications are validated, and in any case no later than 10 calendar days before the meeting, except for expedited, proportionate review, and Phase 1 applications where agreed.

In accordance with GBR-9, the chief investigator (CI) or delegated representative should be invited to attend the meeting, and the sponsor’s representative and other research team members may attend alongside the CI. Attendance is intended to allow the EC to request further information, clarification, or reassurance directly, but it is not compulsory and the application should not be prejudiced if the CI is unable or unwilling to attend. The CI should not make a formal presentation at the meeting. EC members who cannot attend may submit written comments which should be recorded in the minutes. An EC may seek referee advice on aspects of an application relevant to forming an ethics opinion where the issue lies beyond members’ expertise or where the EC is unable to agree. Referees may provide written advice before or after the meeting or may attend the meeting to discuss the application, but they are not voting members and should not question the CI or take part in EC business beyond the application for which advice is sought. The application clock does not stop while referee advice is sought, only once a written request for further information is made to the CI. EC meetings should be held in private so members can discuss applications freely, and members are required to keep EC business confidential. EC members should delete any saved electronic copies of documents after a final ethics opinion has been issued. Internal and external observers may attend meetings subject to applicable requirements, including confidentiality arrangements for external observers, but observers should take no part in EC deliberations or ethics decisions. The Chair is responsible for the conduct of business and for ensuring that the EC reaches clearly agreed decisions. The meeting should reach unanimous decisions by consensus wherever possible; where consensus is not achievable, a formal vote should be taken by show of hands, with the decision determined by a simple majority of members present and entitled to vote. Where the vote is tied, the Chair may give a casting vote but should first consider other options to reach a more consensual decision.

Next, GBR-9 provides that EC meeting minutes should be prepared by the relevant staff and should contain an accurate record of what was discussed during the meeting. For each study, the minutes should record:

• The members, co-opted members, referees, and observers present for the review
• Any material interests declared and the EC’s decision on the member’s participation
• Any written comments submitted by members or deputy members
• The substance of any referee advice
• The EC’s decision on the application
• A summary of the main ethics issues considered
• For a favorable opinion, any conditions to be met before the study starts or any additional non-binding advice
• For an unfavorable opinion, the predominant reasons for the decision, clearly distinguished from other comments or advice
• For a provisional opinion, the further information requested and the arrangements for considering the information and issuing the final opinion
• The outcome of any vote taken
• Any formal dissent by a named member, with reasons
• Whether the application was reviewed voluntarily rather than as a requirement of policy or legislation

GBR-9 further indicates that minutes should be presented as the outcome of collective discussion, written in the third person, and should not attribute statements to individual members or include verbatim comments. A draft version should be provided to the Chair, and in England and Wales the Approvals Specialist, within two (2) working days of the meeting, and checked within three (3) working days. Draft minutes should be uploaded to the HRA Assessment and Review Portal (HARP) (GBR-139), with a watermark “management in confidence”; once ratified, the final signed minutes must be uploaded to HARP, and the draft version should be deleted. Signed final copies of the minutes of full EC meetings and sub-committee business, where relevant, should be retained electronically for at least 20 years and then transferred to the place of deposit, as per the records management policy in the relevant UK nation. See GBR-9 for a list of other EC documents that should be retained and their associated retention dates.

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-86, 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. AUS-87 notes that some ECs and institutions may need the TGA’s acknowledgement before beginning their own approval processes. In these cases, the TGA will accept a CTN submission while the sponsor gets the required approvals from the EC and institution. 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. AUS-88 indicates that the sponsor can, either following TGA approval or in parallel with the TGA’s evaluation, contact their chosen EC to initiate ethics review of the CTA scheme trial proposal. However, trials can only commence once both TGA and EC approvals have been received.

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-GCP
• 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-GCP, if requirements specified in the G-NatlStmt appear to differ from those specified in the AU-ICH-GCP, 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.

Overview

The REC-Policy states that the role of the ethics committee (EC) is to help ensure that proposed research conforms to recognized ethical standards, which includes respecting the dignity, rights, safety, and well-being of the people who will take part. In addition, per GBR-46, the ethical review process should evaluate how the study involves the public in research, especially at the design stage (e.g., the participant information sheets).

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; or research involving prisoners or prisons.

Role in Clinical Trial Approval Process

In accordance with the MHCTR, the EC is responsible for giving an opinion on applications for clinical trials using investigational medicinal products (CTIMPs). As explained in the REC-Policy, ECs recognized by the UK Ethics Committee Authority (UKECA) can review CTIMPs. Per the MHCTR and the CTApp-Appvl, a person must not start or conduct a clinical trial without a favorable EC opinion and prior Medicines and Healthcare Products Regulatory Agency (MHRA) authorization. The CTApp-Appvl calls it a joint ‘clinical trial approval’. The MHCTR-Chgs states that a clinical trial application is submitted to and managed by the EC and MHRA using the combined review part (GBR-125) of the Integrated Research Application System (IRAS) (GBR-78). As explained in GBR-72, the combined review process offers a single application route and parallel/coordinated review from the EC and MHRA leading to a single UK decision for clinical trials. See GBR-72 for additional updates and information on combined review.

Per the MHCTR, the EC and the MHRA — collectively, “the authorities” — must confirm whether a request for approval is valid within seven (7) days beginning with the date of submission and must notify the sponsor. Once the request for approval is deemed valid, the EC must assess the application for an EC opinion and the MHRA must assess the request for authorization. The MHCTR-Chgs indicates that the authorities will aim to notify sponsors of the outcome of the validation check within one (1) working day. As indicated in the CTApp-Appvl, the outcome of these checks will be communicated by email and through IRAS (GBR-78) within seven (7) calendar days of submission. As soon as possible during this 7-day period, and no later than on the fifth calendar day, the MHRA may notify the applicant by email of any deficiencies identified during the validation checks and allow them to be addressed. If these deficiencies remain unresolved by the end of this 7-day period, the application will be invalidated, and the applicant will need to resubmit the application with the deficiencies corrected. The MHRA’s CTApp-Appvl and the Health Research Authority (HRA)’s MHCTR-Chgs provide operational guidance on the joint review and approval process laid out in the MHCTR.

As part of its review, MHCTR and the REC-Policy require the EC to consider whether the anticipated benefits to participants and other individuals or groups affected by the medical condition under investigation outweigh the anticipated risks and inconveniences. In doing so, the EC must take into account the risks to participants’ health posed by the condition under investigation and the nature of the intervention compared to normal clinical care. The EC must also consider the measures used to seek and obtain informed consent and to protect and promote the interests of participants and the general public, including by promoting transparency in research. The EC may also consider and give an opinion on any other issue relating to the clinical trial if the sponsor has asked the EC to consider the issue and, in the EC’s opinion, the issue is relevant to the other matters the EC must consider. Before giving its opinion, the EC may obtain expert advice on any field relating to the clinical trial. The MHCTR-Chgs, explains that the EC conducts its initial review of the application at a full meeting of the EC.

After completing the initial review, MHCTR stipulates that the EC must give its opinion on the clinical trial, and the MHRA must provide its decision on the request for authorization. The authorities must notify the sponsor in writing of the joint outcome, which is one (1) of the following:

• Approve the request for approval
• Approve the request for approval, subject to conditions specified in the notice
• Not approve the request for approval, setting out the grounds for the decision and requesting the further information (RFI) required for the application to be reconsidered

Per the MHCTR, subject to applicable extensions and special circumstances, the authorities must take all reasonable steps to ensure that the joint notice is given within 30 days beginning with the date on which the authorities notified the sponsor that the request for approval was valid. Where approval is subject to conditions, the notice must specify whether the conditions relate to the EC opinion, the MHRA’s decision, or both. The clinical trial is treated as approved only if the conditions specified in the notice are satisfied. Following an RFI, the amended request for approval must be reviewed by the appropriate authority. The EC reviews the amended request where the RFI relates to the EC opinion, and the MHRA reviews it where the RFI relates to the MHRA’s authorization decision; both authorities review it where the request relates to both.

The MHCTR states that applicants will have 60 calendar days from the date on which the decision letter was issued to provide the requested information for the application to be reconsidered. The CTApp-Appvl indicates that the applicant’s submittal can be either a written response or an amended application for approval. The application will be treated as rejected if this deadline is not met. However, extensions to this deadline can be requested by contacting the MHRA at clintrialhelpline@mhra.gov.uk (or contacting the EC directly, if the information requested relates only to its opinion), explaining why the extension is needed and proposing an alternative submission date. The MHCTR-Chgs explains that the applicant must wait for the full RFI (issued in GBR-125) before responding to any points received individually from the EC or the MHRA. The full RFI will have the final consolidated feedback, including any queries or issues, from both the MHRA and EC. See G-IRASCombRev and IRAS-User for additional details on using GBR-125 during the review process.

The MHCTR specifies that after reviewing the amended request, the appropriate authority must notify the sponsor in writing of the outcome, which is one (1) of the following:

• Approve the amended request
• Approve the amended request, subject to conditions specified in the notice
• Not approve the amended request, setting out the grounds for the decision

As per the MHCTR, subject to applicable extensions and special circumstances, the appropriate authority must take all reasonable steps to ensure that notice is given within 10 days beginning with the date of receipt of the amended request. The CTApp-Appvl further provides that for approvals with conditions, it is not necessary to inform the authorities that the conditions have been met before starting the trial, unless otherwise specified in the approval letter. In some cases, the EC and/or the MHRA may allow a condition of approval to be fulfilled at a specific timepoint after the trial begins. In these cases, the trial may begin before meeting the condition, but failure to meet the condition by the specified timepoint will mean that the approval is not valid and the trial must be stopped until the condition is discharged. A substantial modification can then be submitted requesting approval to restart the trial.

For the initial review, the MHCTR specifies that the 30-day period is extended by 90 days where the EC or the MHRA consults a relevant committee and/or specialist group or committee. For review of an amended request, the 10-day period is extended by 30 days where the EC or the MHRA consults a relevant committee and/or specialist group or committee, or by 60 days where the investigational medicinal product (IP) is an advanced therapy medicinal product (ATMP) and such consultation occurs. If the clinical trial involves a medicinal product for xenogenic cell therapy, the usual time periods do not apply. See the Regulatory Authority and Submission Process sections for more details on consultations.

Per the MHCTR, in exceptional circumstances (for example, in an urgent situation where it would be beneficial to proceed with one (1) request or application while preparing the other), and if agreed in advance by the EC or the MHRA, an application for an EC opinion and a request for authorization may be made separately outside of combined review. Where an agreement has been reached, the MHRA or the EC must confirm which of the particulars and documents specified in Part A1 of Schedule 3 must accompany the request for authorization and the application for an EC opinion; and the arrangements for the payment of the fee.

The MHCTR-Chgs states that the sponsor can appeal an MHRA non-approval or an EC unfavorable opinion by contacting appeals@hra.nhs.uk within 28 calendar days of receiving the outcome. In their appeal, the sponsor must explain why they disagree with the outcome. See the CTApp-Appvl for additional details on the appeals process and requirements. Also see GBR-9 for standard operating procedures for ECs giving an ethics opinion.

Per GBR-9, the EC’s favorable ethics opinion for a specific research study applies for the duration of the study, except where action is taken to suspend or terminate the opinion. Where the duration of the study is to be extended beyond the period specified in the application form, the EC should be notified. For additional information on the duration of the EC opinion, see the CTIMP-Condtns.

Per the UKannot-E6R3, there is no legal requirement in the UK for the EC to undertake periodic reviews of a clinical trial once approved. However, the EC will review documentation relating to an ongoing trial under specific circumstances, such as in the event of an urgent safety measure or serious breach, or as part of its review of an application to make a substantial modification. GBR-9 indicates that the EC should continue to assess whether its favorable ethics opinion remains appropriate if significant developments arise during the research, but it is not responsible for proactive monitoring of the study. Rather the sponsor is responsible for EC notification of urgent safety measures; pharmacovigilance and safety reporting; and EC notification of the conclusion or early termination of the trial. The EC may request that the CI and representatives of the sponsor attend a meeting of the EC or sub-committee at any time to discuss any ethical or safety concerns about the research. For additional information on the EC’s right to review an opinion, see the CTIMP-Condtns. In addition, GBR-9 lays out circumstances when the EC should notify the MHRA of CTIMP compliance issues.

See GBR-68 for an overview of the EC review process.

(Because the MHRA and EC review processes are integrated under the UK’s joint/combined review framework, this section does not repeat the identical process information for modifications, notifiable trials, ending a clinical trial, and lapses where no participants are recruited. Refer to the Scope of Assessment section for those joint EC/MHRA review requirements.)

Fast Track Ethics Review

Per GBR-116, 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 U.S. Department of Health and Human Services, and any other type of clinical trial or research study. Also see GBR-9 for more information on the fast-track ethics review.

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.

As set forth REC-Policy, ethics committees (ECs) may not charge an application fee or seek any other financial contribution or donation to consider a research proposal for which their review is required. Members receive no payment for contributing to the review of applications at scheduled meetings or for attending such meetings. EC members are volunteers and are not paid for their role as part of the Research Ethics Service.

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 project monitoring
• 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.

Overview

Per MHCTR, research ethics committees (ECs) in the United Kingdom (UK) are established, recognized, and monitored by the UK Ethics Committee Authority (UKECA). As explained in the REC-Policy, the UKECA is responsible for recognizing ECs that can review clinical trials of investigational medicinal products (CTIMPs) in the UK and ensuring compliance with MHCTR.

As stated in REC-Policy, for ECs that review CTIMPs, Appointing Authorities in each UK nation operate and work on behalf of the UKECA to enable the discharge of its functions. Appointing Authorities are responsible for setting up ECs, appointing members, and overseeing delivery of the Research Ethics Service (RES) (GBR-62) for the ECs within their remit. Their functions include establishing ECs to act for the whole or part of their geographical area, establishing ECs to review particular descriptions or classes of research, appointing EC members and chairs, approving EC standard operating procedures (SOPs), and monitoring the extent to which their ECs adequately perform their functions. Where an EC will review CTIMPs, the Appointing Authority must seek UKECA recognition of the EC. The UKECA may also adjust the extent to which an EC is authorized to act and/or abolish or revoke recognition of an EC.

Per the REC-Policy, in addition to its functions as England’s Appointing Authority for the RES, by agreement and through consultation with the Devolved Administrations (i.e., Scotland, Wales, and Northern Ireland), the Health Research Authority (HRA) performs national coordinating functions for the RES. Following are some of the HRA’s functions relating to management of GBR-62 outside of England in consultation with the UKECA:

• Develops and manages a national training program for EC members and EC operational lead staff and provides resources to support this training
• Develops, implements, and maintains SOPs (see GBR-9) for ECs and provides advice and support to ECs on procedural issues
• Develops a quality assurance program, including accreditation of ECs
• Provides and supports information systems for all nations
• Provides guidance and advice to assist ECs in their work and encourages consistency of approach to common issues in research ethics
• Provides advice on the practical implications of implementing legislation, policy, and guidance across the UK
• Acts for the UKECA to provide a national mechanism for operational advice and assistance to ECs recognized for the purposes of clinical trials regulations and to receive, on the UKECA’s behalf, the EC’s annual report
• Acts for the UKECA to handle appeals against the unfavorable opinions of ECs in respect of clinical trials of investigational products
• Acts for the UKECA to transfer an EC’s functions to a successor EC if the original EC has ceased to operate, has been varied or abolished, or had its recognition revoked

Registration, Auditing, and Accreditation

Per the REC-Policy, the HRA, acting for the 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 the HRA implements a rolling accreditation program to audit UK ECs against standards as detailed in the REC-Policy 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, the 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.

Overview

In accordance with the G-CTHandbook, the G-TrialsSOP, and AUS-86, 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-86, 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-87 notes that some ECs and institutions may need the TGA’s acknowledgement before beginning their own approval processes. In these cases, the TGA will accept a CTN submission while the sponsor gets the required approvals from the EC and institution. However, it is the sponsor’s responsibility to ensure that all relevant approvals and authorizations are in place before commencement of the trial. Additionally, AUS-88 indicates that the sponsor can, either following TGA approval or in parallel with the TGA’s evaluation, contact their chosen EC to initiate ethics review of the CTA scheme trial proposal. However, trials can only commence once both TGA and EC approvals have been received.

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-92, sponsors may request pre-submission meetings with the TGA. A pre-submission meeting can help both the applicant and the TGA to obtain a common understanding of the therapeutic good and what supporting documentation is needed to evaluate the application, as well as any issues to resolve before submitting applications. A meeting can also help the applicant and the TGA plan for the submission and manage both timeframes and resources.

AUS-88 indicates that all sponsors considering a CTA application submission are encouraged to request a pre-submission meeting. In the meeting, the TGA can clarify any questions the applicant has about existing studies or the proposed data package for a CTA application and give specialized advice on the CTA application process (including the best ways to submit the application and dossier).

See AUS-92 for more information on pre-submission meetings and AUS-17 for the applicable forms.

CTN Scheme

According to AUS-87 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.

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-88 and AUS-89, the sponsor must submit the application form (AUS-56) and supporting data to the TGA as part of a CTA application, followed by a trial commencement notification form (AUS-57). Per AUS-89, all CTA forms should be submitted to the TGA via email at clinical.trials@health.gov.au (PDFs or Word files). If sending the forms by email (the recommended method), the sponsor is not required to send physical copies to the mailing addresses detailed in each form. Electronic/digital signatures can be used.

AUS-89 indicates that the sponsor should submit the supporting data in an electronic dossier (searchable PDFs). This should be sent via email to clinical.trials@health.gov.au. The sponsor is encouraged to contact the TGA for advice if the file is too large. See AUS-94 for more information on electronic dossiers and submissions.

As stated in AUS-89, the sponsor must send the notification form (AUS-57) to the TGA within 28 days of commencing supply of the unapproved therapeutic goods at each site.

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.

Overview

In accordance with the MHCTR, the sponsor must request Medicines and Healthcare Products Regulatory Agency (MHRA) authorization and apply for an ethics committee (EC) opinion to conduct a clinical trial by submitting a single application dossier, referred to as “request for approval.” GBR-72 explains that in this combined review framework, the regulatory and ethics reviews are done in parallel and any requests for further information (RFIs) are raised jointly. A single response to these requests leads to a single decision from both reviews. See CTApp-Appvl and the MHCTR-Chgs for operational guidance.

Per the MHCTR, in exceptional circumstances (for example, in an urgent situation where it would be beneficial to progress one (1) request or application while preparing the other), and if agreed in advance by the MHRA or the EC, a request for authorization and an application for an EC opinion may be made separately outside of combined review.

See the Scope of Review section for details on the transitional arrangements for applying for clinical trial approval or modifications.

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

In accordance with the MHCTR, the combined request for approval application (i.e., the request for authorization and the application for EC opinion) must be submitted via the online portal and include any required notifiable trial statement, required documentation, and applicable fee. Per the CTApp-Appvl, the MHCTR-Chgs, and GBR-72, the combined request for approval for clinical trials of investigational medicinal products (CTIMPs) are submitted through the Integrated Research Application System (IRAS) (GBR-125). The G-ATMP states that all advanced therapy medicinal products must submit clinical trial applications using the same processes as all other medicines. As described in GBR-78, IRAS is a single system for applying for the permissions and approvals for health and social care/community care research in the United Kingdom (UK). The system generates the IRAS ID, which has been adopted by stakeholders across the UK as the common study identifier, and enables the applicant to enter required information once. The filters collect and collate the data appropriate to the type of study, and consequently the permissions and approvals required. Further, IRAS helps the applicant submit information needed for other relevant review bodies (e.g., the Administration of Radioactive Substances Advisory Committee, the Confidentiality Advisory Group, or the Gene Therapy Advisory Committee (GTAC)).

The 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
• Submit application

IRAS-User indicates that the sponsor/sponsor delegate and chief investigator (CI) “authorize” an application in the system; the application cannot be submitted until the CI has accepted the project, and the sponsor or sponsor delegate has reviewed the completed dataset and confirmed the submission. Once the sponsor or sponsor delegate has confirmed the submission, the applicant must complete the EC booking. The task 'Complete REC booking' is assigned to the individual who sent the request to the sponsor or sponsor delegate for review. To book using the online booking service (GBR-95), applicants should select 'Create booking' on the EC booking page. The EC booking page also provides instructions on what to do if the booking was made directly with the EC, via telephone (or email). When the EC booking page shows the confirmed booking details, the applicant can select “Submit to the regulators” to submit the application.

Per IRAS-User, fast-track EC review is also available for global clinical trials and Phase 1 trials. The Phs1CTs provides that applicants undertaking Phase 1 clinical trials may reserve an EC meeting slot before submission, and most ECs recognized to review Phase 1 healthy volunteer trials accept applications submitted up to seven (7) days before the meeting date. To make a request for 7-day submission for an application, applicants should contact their preferred EC which is flagged to review Phase 1 clinical trials. Per GBR-116, applicants seeking fast-track ethics review of clinical trial applications must also apply via combined review on GBR-125.

GBR-9 reiterates that an application for ethics review via the combined review service is submitted jointly by the CI and the sponsor. Only one (1) application for ethics review should be submitted for any research protocol to be conducted in the UK; however, for research projects with separate protocols governing one (1) or more sub-studies in addition to the main study, a full application should be submitted for each protocol. The MHCTR delineates that the CTIMP application must be made to one (1) EC only, regardless of the number of trial locations at which the trial is to be conducted. The application must be made to a UKECA-recognized EC for the entire UK and in relation to a description or class of clinical trial into which the proposed trial falls. However, an exception is when an application must be made to an EC constituted by regulations made by the Scottish Ministers under the Adults with Incapacity (Scotland) Act 2000 (AIA2000) when a clinical trial is conducted at one (1) or more trial locations in Scotland; the trial involves adults unable by virtue of physical or mental incapacity to give informed consent; and the CI is professionally based at a hospital, health center, surgery, or other establishment or facility in Scotland.

As detailed in GBR-9, when the application is ready to submit, the applicant should book an agenda slot at the next meeting of an appropriate EC. For full meetings, the applicant may decline the first available slot in the UK if they have a preference for a particular EC (for example, it has reviewed an earlier phase of the trial). Once the booking has been accepted, the application form and supporting documentation must be submitted the same day the booking is made. An email confirmation of the booking will be sent to the applicant and the EC to which the application has been allocated. If the applicant is not ready to submit the application including all required authorizations and supporting documentation on the same day, the booking should not be completed. Applications received up to 16:00 hours are considered to be received that working day. Applications received after 16:00 are considered to have been received the following working day.

In accordance with the MHCTR, the CT-Ntfble explains that applications for approval of a notifiable trial must be submitted through the same combined review process as applications for non-notifiable clinical trials. See Scope of Assessment section for details on criteria, eligibility, and other requirements for notifiable clinical trials; and refer to the CT-Ntfble for additional guidance and a process flowchart.

Regarding the exceptional circumstances in which a CTIMP application may be submitted outside of combined review, the MHCTR requires this approach to be agreed in advance by the MHRA or the EC. Per the CTApp-Appvl, applicants must obtain written approval/agreement in advance by contacting the MHRA at clintrialhelpline@mhra.gov.uk. Once this approach has been agreed to, the process for submitting separate applications to the MHRA and the EC will be communicated to the applicant.

The CTapp-Issues offers guidance on common issues identified during clinical trial applications to help applicants avoid requests for further information or grounds for non-acceptance. See the CTApp-Appvl, the MHCTR-Chgs, the G-IRASCombRev, the IRAS-User, and GBR-72 for additional guidance on submitting via GBR-125.

The UKwide-Rsrch provides guidance and requirements for research in more than one (1) UK nation, and specifies that the four (4) nations of the UK take a consistent approach to study-wide reviews so that sponsors only need to submit one (1) application on GBR-125 in most circumstances. Each UK nation will take assurances from the site-wide review conducted by the lead nation (the nation conducting the initial review).

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

See IRAS-User and G-IRASCombRev for detailed help on submitting CTIMP applications.

As indicated in the MHRA-advice, applicants can seek scientific advice from the MHRA at any stage of a product’s development or regulatory lifecycle. The MHRA encourages applicants to seek advice on clinical trial topics, including first-in-human studies and design of pivotal clinical trials. See MHRA-advice for details on how to request advice.

Consultation

Per the CT-Experts, prior to submitting an application for clinical trial approval, the applicant should use the criteria in CT-Experts to assess whether their trial may need to be reviewed by a specialist group or relevant committee. If unsure, applicants should contact the MHRA for advice by emailing clintrialhelpline@mhra.gov.uk with a summary of the nature of the compound, its target and mechanism of action, and the relevance of the animal models. If the applicant believes that expert review is required, they should email the MHRA at clintrialhelpline@mhra.gov.uk at least 28 calendar days before submitting the application, stating their intention to submit an application for clinical trial approval that may require review by the Clinical Trials Biologicals and Vaccines Expert Advisory Group (CTBVEAG) of the Commission on Human Medicines (CHM) and specifying their preferred CTBVEAG meeting date. The MHRA will confirm by email that the review has been scheduled. Note that where expert advice from any specialist group or relevant committee other than CTBVEAG is required, the MHRA will discuss this with the applicant. The application should be submitted to IRAS (GBR-125) (using the same process as for trials not identified as requiring expert advice) at least four (4) weeks in advance of the CTBVEAG meeting at which the trial will be discussed. See the CT-Experts for additional details and a process flowchart.

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. An Australian contact number is required to be listed with either the primary sponsor contact or the alternate sponsor contact
• Protocol number
• Expected trial start and completion dates
• Potential use of restricted goods
• Study title and description, which must be a minimum of 250 characters (spaces included) and up to a maximum of 2,500 characters
• “This Trial” check boxes indicating whether the trial involves the use of a medicine, a medical device, and/or a biological. For a medicine or biological, additional information must be provided, such as dosage form, route of administration, indication, and the good manufacturing practice (GMP) license/clearance number of a relevant exemption
• 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-89 states that the CTA scheme includes two (2) forms – Part 1: the CTA application (AUS-56), which is submitted along with supporting data, and Part 2: Notification of the conduct of a trial under the CTA scheme (AUS-57).

Part 1: the CTA application (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.

Part 2: Notification of the conduct of a trial under the CTA scheme (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-GCP. 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-GCP 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

Combined Submission Requirements

As required by the MHCTR, the request for approval (application) in the single application dossier to the Medicines and Healthcare Products Regulatory Agency (MHRA) and the ethics committee (EC) must include the following material:

• A completed application
• A statement or cover letter drawing attention to any features which are particular to the clinical trial, if required
• The protocol for the proposed trial describing the objective, design, methodology, statistical considerations, purpose, and organization of the clinical trial
• The investigator’s brochure (IB) or equivalent document
• Documentation relating to compliance with the principles and guidelines of good manufacturing practice, where applicable
• A dossier providing information on the quality of any investigational medicinal product (IP), the manufacture and control of the IP, and data from non-clinical studies and from clinical use of the IP
• A copy of the scientific advice of the licensing authority, or of any third country, with regard to the clinical trial
• A description of the content of the labelling
• All information given to the participants, or their legal representatives, before their decision to participate or abstain from participation in the clinical trial
• Proof of insurance, a guarantee, or any other similar arrangement, where applicable
• Responses to areas for discussion raised by the Commission on Human Medicines (CHM), where applicable

See the CTApp-Appvl for additional detailed requirements and guidance for each item listed above. In addition, the DocMgt-Apps lists the document types for combined review applications, identifies which are mandatory, and shows which review body each document is sent to upon submission.

Per the MHCTR, where separate applications are permitted in exceptional circumstances, the MHRA or EC must confirm with the applicant which documents must accompany each submission.

In accordance with the MHCTR, the CT-Ntfble indicates that applications for approval of a notifiable trial must include the same documents as applications for non-notifiable clinical trials. In addition, the applicant must also submit the confirmation of notifiable trial criteria form (GBR-135). The cover letter must include a statement that the application is for approval of a notifiable clinical trial.

Per the MHCTR, a request for modification must include the following material:

• The identifying details of the trial, including the title of the trial and any number allocated to the trial by the authorities
• A description of the proposed modification
• A statement of the reasons for proposing that modification, and if more than one (1) modification, a statement for each modification
• A copy of the proposed changes to the clinical trial protocol or any other particulars or documents accompanying the request for approval
• Summaries of any data submitted in support of the proposed modification or modifications, and any change to the summary assessment of the potential risks and benefits of using the product in the proposed trial

Clinical Protocol

Per the CTApp-Appvl, the clinical trial protocol describes the objectives, design, methodology, statistical considerations, and organization of a clinical trial and should include (where applicable):

• A descriptive title, a sponsor-created identification number, the version number, and the date of the last update
• Discussion of the trial’s relevance, design, anticipated risks and benefits, and participant recruitment and informed consent procedures (setting out any particular considerations with respect to inclusion of participants unable to provide informed consent or belonging to other special populations); for a multi-part trial where the submission does not include full details to enable the conduct of all the trial parts, outline any adaptive elements and plans for future substantial modifications
• Justification for the use of placebos, standard of care arms, or real-world data comparators
• An unambiguous definition of the end of the trial; this should usually be the date of the last visit of the last participant, and a justification should be given for any exceptions (e.g., for trials involving human tissue, analysis of samples should be undertaken as part of the data collection before the end of trial is declared)
• A description of any additional care for trial participants once their participation has ended
• A description of any sub-studies conducted at any trial locations
• A discussion of safety events and recording and reporting procedures
• Procedures for unblinding of the IP in the case of an adverse reaction
• A synopsis of the protocol
• A signature from the sponsor and the chief investigator (for single-location trials) or overall coordinating investigator (for multi-center trials) (electronic signatures are acceptable)

For more detailed guidance on the content and format of the protocol, see the International Council for Harmonisation’s Guideline for Good Clinical Practice E6(R3) (GBR-91) which the UK is implementing.

Overview

In accordance with the G-CTHandbook, the G-TrialsSOP, and AUS-86, 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-86, 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-87 notes that some ECs and institutions may need the TGA’s acknowledgement before beginning their own approval processes. In these cases, the TGA will accept a CTN submission while the sponsor gets the required approvals from the EC and institution. However, it is the sponsor’s responsibility to ensure that all relevant approvals and authorizations are in place before commencement of the trial. Additionally, AUS-88 indicates that the sponsor can, either following TGA approval or in parallel with the TGA’s evaluation, contact their chosen EC to initiate ethics review of the CTA scheme trial proposal. However, trials can only commence once both TGA and EC approvals have been received.

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

No timeline information is available for applications under the CTN or CTA schemes.

For information on how to check the status of a CTN, see AUS-49. Per AUS-88, stakeholders seeking more information on the CTA process are encouraged to contact the TGA at clinical.trials@health.gov.au.

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.

Overview

Per the MHCTR, all new applications for clinical trials of investigational medicinal 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 MHCTR, the MHRA and the EC must confirm whether a CTIMP request for approval is valid within seven (7) days beginning with the date of submission and must notify the sponsor. The MHCTR-Chgs indicates that the authorities will aim to notify sponsors of the outcome of the validation check within one (1) working day. As indicated in the CTApp-Appvl, the outcome of these checks will be communicated within seven (7) calendar days of submission. As soon as possible during this 7-day period, and no later than on the fifth calendar day, the MHRA may notify the applicant by email of any deficiencies identified during the validation checks and allow them to be addressed. If these deficiencies remain unresolved by the end of this 7-day period, the application will be invalidated and the applicant will need to resubmit the application with the deficiencies corrected.

Once the request for approval is deemed valid, the MHCTR states that the authorities must take all reasonable steps to issue the joint outcome within 30 days from the date the sponsor is notified that the request is valid. The joint outcome may approve the request, approve it subject to conditions, or not approve it and request further information for reconsideration. If further information is requested, applicants will have 60 calendar days from the date of the decision letter to submit a written response or amended application; otherwise, the application will be treated as rejected. Extensions to this 60-day deadline may be requested.

As per the MHCTR, after the applicant submits the amended request, the appropriate authority — the MHRA, the EC, or both, depending on the nature of the request for information — must take all reasonable steps to notify the sponsor of the outcome within 10 days beginning with the date of receipt of the amended request. The amended request may be approved, approved subject to conditions, or not approved.

For the initial review, MHCTR provides that the 30-day period is extended by 90 days where the MHRA or the EC consults a relevant committee and/or specialist group or committee. For review of an amended request, the 10-day period is extended by 30 days where the MHRA or the EC consults a relevant committee and/or specialist group or committee, or by 60 days where the investigational medicinal product (IP) is an advanced therapy medicinal product (ATMP) and such consultation occurs. If the clinical trial involves a medicinal product for xenogenic cell therapy, the usual time periods do not apply.

The MHCTR-Chgs states that the sponsor can appeal an MHRA non-approval or an EC unfavorable opinion by contacting appeals@hra.nhs.uk within 28 calendar days of receiving the outcome. In their appeal, the sponsor must explain why they disagree with the outcome.

See GBR-82 for a flowchart summarizing the timelines and the process of applying for clinical trial approval.

Governance

Per the UKwide-Rsrch, centralized, study-wide review (for a study involving sites across one (1) or more UK nations) coordinates the assessment of governance and legal compliance for healthcare research. GBR-72 indicates that study-wide review is usually issued at the same time as the MHRA and EC decision but may come later if there are still issues to discuss with the applicant. GBR-18 further explains that, during the trial approvals phase, local research and development site review occurs in parallel with the MHRA and EC submissions so that organizations can assess and confirm their capacity and capability to deliver the study at the sites. See Site/Investigator Selection section, GBR-63, and GBR-106 for more information on the UK Local Information Pack (LIP) to support study setup and delivery.

Overview

In accordance with the G-TrialsSOP, the G-CTHandbook, and AUS-86, 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.

AUS-87 notes that for trials conducted under the CTN scheme, it is the sponsor’s responsibility to have all relevant approvals in place. All approvals must be obtained before supplying the unapproved therapeutic good(s) in the clinical trial. After submission of the online CTN form with payment of the relevant fee is made to the TGA, the clinical trial is deemed to have been notified. Once this notification occurs, the sponsor may lawfully supply the unapproved therapeutic good(s) for the purposes of the trial. A CTN acknowledgement from the TGA is not required before the trial can begin recruiting.

AUS-89 indicates that the sponsor must send a trial commencement notification form (AUS-57) to the TGA within 28 days of commencing supply of the good(s) at each site for each new trial conducted under the CTA scheme, as well as additional sites in ongoing CTA trials.

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 an 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-GCP, 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
• Comply with procedures for data recording and reporting
• Permit monitoring, auditing, and inspection
• 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.

Overview

Per the MHCTR, the REC-Policy, and the CTApp-Appvl, a person must not start or conduct a clinical trial of investigational medicinal products (CTIMPs) without prior Medicines and Healthcare Products Regulatory Agency (MHRA) authorization and a favorable ethics committee (EC) opinion. In addition per GBR-9, some health and social care research projects require regulatory approvals under a range of legislation applicable to the United Kingdom (UK) as a whole or to particular countries. It is the responsibility of the sponsor to ensure where necessary that a research study has appropriate regulatory approval. GBR-18 states that contracts and agreements should be in place before the start of a trial and should be subject to periodic review to ensure they remain up to date and relevant.

The MHCTR and the UKannot-E6R3 state that all CTIMPs must be conducted in accordance with the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Guideline for Good Clinical Practice (GCP) conditions and principles, as amended from time to time. The UK-ICHE6-Comply explains that this legal requirement applies to the ICH GCP conditions and principles rather than the entirety of the guideline. ICH-UKimp indicates that the UK is implementing the ICH’s Guideline for Good Clinical Practice E6(R3) (GBR-91). Per the UKannot-E6R3, unlike the stated scope of GBR-91, the UK GCP requirement applies to all UK CTIMPs, whether or not the trial is intended to support a marketing authorization application.

Per the CTIMP-Condtns, if a CTIMP does not recruit within 24 months of the date of the favorable ethical opinion, the approvals are deemed to have lapsed but can be extended upon request. In addition, the trial should not commence at any location until management permission has been obtained from the organization responsible for the care of the participants at the location. For information related to participant recruitment and communication during clinical trial setup, see DigiTrials (GBR-40).

See GBR-55 for an overview of research transparency requirements.

Clinical Trial Agreement

According to GBR-107 and GBR-18, contracts and agreements should be in place prior to the initiation of a trial. GBR-107 provides model templates that apply UK-wide (unless otherwise indicated) and should be used unmodified to avoid delays, including:

• Model Clinical Trial Agreement (mCTA) and Clinical Research Organization mCTA (CRO-mCTA)
• Commercial mCTA for Investigational Advanced Therapy Medicinal Products (ATMP-mCTA and CRO-ATMP-mCTA)
• Commercial Primary Care mCTA
• Model Clinical Investigation Agreement (mCIA) and CRO-mCIA
• Model Non-Interventional Study Agreement (mNISA) and CRO mNISA (CRO-mNISA)
• Model non-commercial agreement (mNCA)
• UK template Hub and Spoke Agreements
• Model agreements for Participant Identification Centres (mC-PICA and mNC-PICA)
• Model Material Transfer Agreement
• Model Confidentiality Disclosure Agreements (mCDA and mMCDA)
• Model Commercial Chief Investigator Agreement (mCCIA) and clinical research organization mCCIA (CRO-mCCIA)
• Model Non-commercial Research Grant Collaboration Agreement
• Other model agreements

The UKwide-Rsrch states that contracting expectations and arrangements across the four (4) UK nations are broadly similar. For all four (4) nations:

• In commercially sponsored research, it is mandatory to use the unmodified contract templates appropriate to the study type
• In non-commercially sponsored research, it is expected that the unmodified contract appropriate to the study type is used; use of bespoke or modified agreements, where an appropriate template exists, is likely to result in significant delay and costly review; any modifications must be highlighted in the application

The UKwide-Rsrch also highlights national differences relating to the way contractual agreements are reviewed and agreed to. Additional details and templates are available in GBR-107.

Clinical Trial Registration

As delineated in the MHCTR and the CTApp-Appvl, the sponsor must register a clinical trial in a public registry by the earliest of the following: the date the first participant is recruited or 90 days after the clinical trial is approved. MHCTR-Chgs explains that this registration requirement applies to CTIMP applications submitted from April 28, 2026; for trials submitted before that date, the requirement depends on whether the trial ended before April 28, 2026, whether it was already registered, and whether the first participant has already been recruited. (See CT-Transtn for additional details on transitional arrangements.) Per the MHCTR and the MHCTR-Chgs, the sponsor may request a deferral or waiver of the registration requirement, including at the time of the request for approval or before the registration deadline. Where appropriate, the MHRA may defer registration for up to 30 months after the trial concludes, including to protect commercially confidential information, or waive the requirement in exceptional circumstances, such as national defense or security reasons. Phase I clinical trials may be eligible for an automatic deferral of up to 30 months from the conclusion of the trial, provided that the required minimum information is registered in a public registry before the aforementioned clinical trial registration deadline.

Per the MHCTR-Chgs, the public registry must be a primary or partner registry of, or data provider to, the World Health Organization International Clinical Trials Registry Platform (GBR-93), which allows public access to UK trial information. The International Standard Randomised Controlled Trial Number (ISRCTN) Registry (GBR-47) and ClinicalTrials.gov (GBR-49) satisfy the public registry requirement, although sponsors should generally register with ISRCTN unless there is a U.S. Food and Drug Administration requirement to register with GBR-49. Registration with the European Union’s Clinical Trials Information System (CTIS) (GBR-39) or previous registration with EudraCT does not satisfy the MHCTR registration requirement because these systems do not facilitate public access to information about trials taking place in the UK.

Further, per the MHCTR-Chgs, if a clinical trial application is submitted in the Integrated Research Application System (IRAS) (GBR-125), the system will share basic trial information with GBR-47 to support registration, but this does not mean that the trial is registered; GBR-47 will contact the sponsor for additional details to complete registration. If the sponsor intends to register with GBR-49 instead, this may be indicated in the IRAS application. Sponsors must also confirm the date the first UK participant was recruited by using the Modification Tool in IRAS to submit a modification of an important detail confirming that first recruitment has occurred.

As indicated in the Phs1CTs, if a sponsor submits a Phase 1 CTIMP application only involving healthy volunteers, it will automatically be deferred for all transparency requirements until 30 months after the end of the trial. However, the sponsor must still publish a minimal record on a publicly accessible registry, which can be done with ISRCTN.

See GBR-102, GBR-18, and CTIMP-Condtns for additional information on clinical trial registration.

Governance

Study-wide Review

The UKwide-Rsrch indicates that the UK’s four (4) nations—England, Northern Ireland, Scotland, and Wales—work together and with a range of organizations to support and regulate different aspects of health research. Study-wide review is the process by which all research in the UK is reviewed and approved, bringing together the assessment of governance and legal compliance of research in healthcare. The UK nations take a consistent approach to study-wide reviews, so sponsors only need to submit one (1) application in the combined review section of IRAS (GBR-125). As described in GBR-67, Health Research Authority (HRA) and Health and Care Research Wales (HCRW) approval applies to all project-based research taking place in the National Health Service (NHS) in England and Wales and brings together the assessment of governance and legal compliance with the EC opinion. Projects led from Northern Ireland or Scotland that involve NHS research sites should follow the appropriate permission process for that lead nation. Studies with research sites in Northern Ireland or Scotland are supported through existing UK-wide compatibility systems, where each country accepts relevant centralized assurances from national coordinating functions to avoid duplication. Also see the Stdy-wide for information on study-wide governance criteria.

The UKwide-Rsrch specifies that each UK nation will take assurances from the study-wide review conducted by the lead nation (the nation conducting the initial review). The following outlines key differences in approvals from UK nations:

• England and Wales – For any research taking place in England and/or Wales, the sponsor will receive an HRA and HCRW approval letter, which will detail any further requirements before beginning the research
• Northern Ireland – Each participating Northern Ireland Health and Social Care (HSC) R&D Approvals Service body will confirm their capacity and capability after the relevant study-wide reviews and participating site assessments and arrangements are complete
• Scotland – For any research taking place in Scotland, the sponsor will receive research and development (R&D) permission (see below) after the relevant study-wide reviews and site assessments and arrangements are complete

Research & Development Review

As explained in GBR-18, CTIMPs within the NHS need permission from the local NHS R&D office. The review process varies across the UK, depending on the lead NHS R&D office, typically where the Chief Investigator is based. In England and Wales, HRA and HCRW provide an integrated governance and legal compliance review through the combined review process, submitted via GBR-125 alongside ethics and MHRA applications. Each NHS organization then assesses their capacity and capability before confirming participation. In Scotland, the NHS Research Scotland Permissions Coordinating Centre has a national system that provides a single point for the governance and legal compliance review. The combined review process covers MHRA and ethics approvals. Each NHS Board completes a local capacity and capability assessment before confirming participation. In Northern Ireland, the HSC R&D Approvals Service coordinates governance reviews in secondary care studies. Each HSC Trust completes a local capacity and capability assessment before confirming participation.

Per GBR-106, the UK Local Information Pack is the UK-wide mechanism for setting up participating NHS/HSC organizations. It is used for all studies with participating NHS/HSC organizations. See Site/Investigator Selection section, GBR-63, and GBR-106 for more information on the UK Local Information Pack to support study setup and delivery.

GBR-18 indicates that researchers without contractual arrangements with NHS organizations, but whose research involves direct patient contact or access to NHS premises, may need an Honorary Research Contract (HRC) or Letter of Access (LoA). HRA will determine if an HRC or LoA is required during the governance review. Where a study does not involve the NHS (i.e., patients, their data, tissues, or NHS resources), NHS permission is not required. Investigators should follow their own organization’s governance processes.

GBR-9 states that ECs do not undertake location-specific assessments. A standard condition of a favorable EC opinion is obtaining applicable organization-level capacity, capability, or management approvals before any research project activity begins at an investigator location within the NHS or Northern Ireland Health and Social Care. For non-NHS locations, it is expected that sponsors have arrangements in place to ensure selection of suitable locations and investigators. For CTIMPs, these arrangements need to be submitted to the EC for review with the initial application, and significant changes to these arrangements treated as a substantial modification.

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@health.gov.au or mailed to Pharmacovigilance and Special Access Branch, PO Box 100, Woden ACT 2606. More information about reporting to the TGA may be found on the Adverse Event Management System (AEMS) (AUS-7).

See AUS-37 for the SSI/USM reporting form, which should be submitted to clinical.trials@health.gov.au.

Safety Reporting Definitions

Per the MHCTR and the CT-Sfty, the following definitions provide a basis for a common understanding of the United Kingdom (UK)’s safety reporting requirements:

• Adverse event (AE) – Any untoward medical occurrence in a participant to whom a medicinal product has been administered, including occurrences which are not necessarily caused by or related to that product
• Adverse reaction – Any untoward and unintended response in a participant to an investigational medicinal product (IP) which is related to any dose administered to that participant
• Serious adverse event (SAE), serious adverse reaction (SAR), or unexpected serious adverse reaction (SUSAR) – Any AE, adverse reaction, or unexpected adverse reaction, respectively, that (a) results in death, (b) is life-threatening, (c) requires hospitalization or prolongation of existing hospitalization, (d) results in persistent or significant disability or incapacity, or (e) consists of a congenital anomaly or birth defect
• Unexpected adverse reaction – An adverse reaction the nature and severity of which is not consistent with the information about the medicinal product in question set out in (a) the case of a product with a marketing authorization, the summary of product characteristics, or equivalent document, for that product, and (b) in the case of any other IP, in the investigator’s brochure (IB) relating to the trial in question

See the CT-Sfty and GBR-30 for guidance on reference safety information, including its role in expectedness assessments for SUSARs and annual safety reporting.

See the CT-Transtn for transitional arrangements for pharmacovigilance. See GBR-18 and GBR-9 for additional summaries of safety reporting.

The MHCTR requires that clinical trials must be conducted in accordance with the conditions and principles of good clinical practice (GCP), including the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) GCP, as amended from time to time. ICH-UKimp indicates that the UK is implementing the ICH’s Guideline for Good Clinical Practice E6(R3) (GBR-91) and the ICH’s General Considerations for Clinical Studies E8(R1) (GBR-104), among others. In addition, see CT-Sfty for additional ICH guidance that are relevant to safety reporting, including the Development Safety Update Report (E2F) (GBR-61).

Safety Reporting Requirements

Urgent Safety Measure

Per the MHCTR and the CT-Sfty, an urgent safety measure (USM) is an action that the sponsor and investigator may take to protect the participants of a trial against any immediate hazard to their health or safety. As stated in the CT-Sfty, once trial participants have been recruited, appropriate USMs may be taken at any time to protect the participants from any immediate hazard to their health or safety. USMs may be implemented without first notifying the Medicines and Healthcare Products Regulatory Agency (MHRA) and ethics committee (EC). No later than three (3) days after the measures are taken (but ideally within 24 hours), the sponsor must contact the MHRA through an initial telephone conversation or email. Failure to notify the MHRA of the implementation of an USM for safety reasons may be considered a serious breach.

Per the MHCTR and the CT-Sfty, following the initial telephone conversation or email with the MHRA, the sponsor must provide a written notice to the MHRA and the relevant EC, describing the events requiring action to be taken, and the measures taken in response to those events, including any additional actions requested by the MHRA. The written notification must be done within seven (7) calendar days from the date the measures are taken, or as soon as possible during any period where a disease is pandemic and is a serious or potentially serious risk to human health. The CT-Sfty states that the MHRA will review the written notification and may request additional information. Once the MHRA has sufficient information, it will decide whether the measure taken is a USM and communicate the outcome to the sponsor by email (and through Integrated Research Application System (IRAS) (GBR-125), if this route of submission was used). If the MHRA agrees that the measure is a USM, the sponsor should submit a substantial modification that covers the USM (with no additional changes) within two (2) weeks of the date on which the MHRA was first informed (via telephone) of the USM. If the MHRA does not agree that the measure is a USM, it will confirm with the sponsor whether any further actions are needed. See the CT-Sfty for process flowcharts and GBR-18 and GBR-9 for an overview of USMs.

Investigator Responsibilities

Per MHCTR, and the CT-Sfty, the investigator’s responsibilities include reporting of SAEs to the sponsor and reporting of certain non-serious AEs and/or laboratory abnormalities to the sponsor. The CT-Sfty indicates that an investigator must report any SAE that occurs to a participant at a trial site immediately to the sponsor, and no later than 24 hours following knowledge of the SAE. The MHCTR clarifies that the immediate report may be made orally or in writing, but the investigator must follow it with a detailed written report. These immediate reporting requirements do not apply to SAEs specified in the protocol or IB as not requiring immediate reporting. AEs other than immediately reportable SAEs that are identified in the protocol as critical to safety evaluations must be reported to the sponsor in accordance with the reporting requirements specified in the protocol. Reports must identify each participant by the number assigned to that participant in accordance with the protocol. Where the reported event consists of, or results in, the death of a participant, the investigator must provide any additional information requested by the sponsor or EC (if the death has been reported to that EC).

After the immediate report, the CT-Sfty states that the investigator must send a detailed, written follow-up report to allow the sponsor to determine whether the SAE requires a reassessment of the benefit-risk balance of the clinical trial, if the relevant information was not already available and provided in the initial report. In cases where an initial/immediate report is not required, the investigator should report within the appropriate timeframe, taking account of the specificities of the trial and of the SAE, as well as possible guidance in the protocol or the IB. The investigator does not need to actively monitor participants for AEs once the trial has ended, unless provided otherwise in the protocol. SAEs considered related to the IP occurring to a participant after the treatment of that participant has ended should be reported to the sponsor if the investigator becomes aware of them. Clinically significant abnormal laboratory findings are considered AEs; however, abnormal laboratory findings may not be considered as AEs if there is no change compared to baseline values. Certain abnormal laboratory parameters should also be specified in the protocol as requiring reporting within the same timeframes as SAEs, depending on the IP safety profile. These must be clearly stated in the protocol and made clear to the concerned laboratory to ensure that these alert values are reported immediately to the investigator for onward reporting to the sponsor.

See GBR-18 for an overview including a safety reporting flowchart.

Sponsor Responsibilities

Per the MHCTR, the sponsor must keep detailed records of all SAEs and SARs, including SUSARs, that occur during a UK clinical trial. The sponsor must evaluate these events and reactions with a view to minimizing and preventing risks presented by use of the IP and must take appropriate measures as soon as reasonably practicable to investigate the risks and implement actions for minimizing and preventing them. In addition, the sponsor must keep detailed records of all AEs relating to a clinical trial that are reported by the investigators. The MHRA may require the sponsor, by written notice, to send those records, or copies of those records. The sponsor must ensure that all relevant information about a SUSAR that occurs during a UK clinical trial and is fatal or life-threatening is reported to the MHRA as soon as possible, and no later than seven (7) days after the sponsor is first aware of the reaction. The sponsor must send any additional relevant information to the MHRA within eight (8) days of that report. SUSARs that are not fatal or life-threatening must be reported as soon as possible, and no later than 15 days after the sponsor is first aware of the reaction. These SUSAR reporting timelines do not apply where the protocol specifies that certain SUSARs do not require immediate reporting; in those cases, the SUSARs must be reported to the MHRA in accordance with the protocol.

As specified in the CT-Sfty, there is no mandatory requirement for the sponsor to inform the EC or investigators of SUSARs. However, to comply with the ICH’s Guideline for Good Clinical Practice E6(R3) (GBR-91), notification of safety information to investigators (which includes SUSARs) may be appropriate. The sponsor may wish to notify investigators of an occurrence through a letter to the investigator or an updated IB. Where urgent action is required because of a SUSAR, the sponsor should also consider whether a USM is required. See the CT-Sfty for additional guidance on sponsor’s causality, seriousness, and expectedness analyses. The UKannot-E6R3 clarifies, with respect to GBR-91, that individual SUSARs are not required to be reported to investigators or the EC under UK law and must instead be reported to the MHRA.

Under the MHCTR, if a clinical trial is being conducted at a trial site in another country in addition to UK sites, the sponsor must ensure that all SUSARs occurring at the non-UK site are reported to the MHRA as soon as possible. Fatal or life-threatening reactions must be reported within seven (7) days beginning with the day after the sponsor is first aware of the reaction, and all other SUSARs must be reported within 15 days beginning with the day after the sponsor is first aware of the reaction.

Per MHCTR, within 60 days beginning with the day after the reporting year ends, the sponsor must provide the MHRA with a report on the safety of the participants of those trials for each IP tested in a clinical trial. The annual safety report must include records and evaluations of SARs and SAEs that occurred during the reporting year, including SUSARs; the record of measures taken to investigate, minimize, and prevent risks; a description of how safety concerns in the clinical trial have been assessed and managed; and a description of the overall safety profile of each IP, along with a summary description of the sponsor’s processes to monitor the overall safety profile. The MHRA may request that the sponsor provide a list of SARs and SAEs, including SUSARs, that occurred at any time during the reporting year where necessary to investigate specific safety issues. The sponsor must provide the requested list within 30 days of receiving the request, or within any shorter period specified by the MHRA. The CT-Sfty states that the annual safety report should be submitted in the form of a Development Safety Update Report (DSUR). This includes clinical trials approved via automatic authorization under the notifiable trials pathway, as well as DSURs covering a combination of notified and non-notified trials. A single DSUR may cover multiple trials as it relates to a single IP and not a specific trial. See CT-Sfty for details on the required contents of the DSUR.

See the CT-Sfty and GBR-18 for additional guidance on safety reporting.

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 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.

Form Completion & Delivery Requirements

Transitional Arrangements

Per GBR-99, for clinical trials of investigational medicinal products (CTIMPs), the submission of some of the reports may differ depending on whether the study was submitted through combined review or not. From April 28, 2026, the safety reporting requirements for CTIMPs change in line with the amended MHCTR. The new requirements apply to all CTIMPs whether they were submitted before or from this date. For example, SUSARs and annual safety reports for CTIMPs are only to be reported to the MHRA (not the EC). If any ethical issues are identified by the MHRA when they receive these reports, they will liaise with the EC directly. See CT-Transtn for additional details on transitional arrangements.

Urgent Safety Measures

As stated in the CT-Sfty, USMs must be reported to the MHRA through an initial telephone conversation or email no later than three (3) days after the measures are taken (but ideally within 24 hours). The sponsor should contact the MHRA through the Clinical Trial Helpline (020 3080 6456) to discuss the USM. If the sponsor is unable to report the USM by telephone, they should email clintrialhelpline@mhra.gov.uk with contact details, the trial’s ID, a description of the USM, and an explanation as to why it was not reported via phone. The MHRA will then contact the sponsor with further actions. The follow-up written report should be submitted to the MHRA and the EC no later than seven (7) days from the date the measures are taken via IRAS (GBR-125). Guidance on submitting an USM through IRAS can be found in the G-IRASCombRev, GBR-9, and GBR-99. If the clinical trials affected were approved through separate applications to the MHRA and the EC, email the report to clintrialhelpline@mhra.gov.uk.

SUSARs

Per the CT-Sfty, SUSARs should be reported to the MHRA in one (1) of the following ways using the format in the ICH E2B(R3) Individual Case Safety Report (ICSR) Specification and Related Files (GBR-94):

• ICSR Submissions (GBR-126) – The ICSR submissions route is used to submit single reports
• MHRA 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

The CT-Sfty further explains that following submission of a SUSAR, the sponsor should expect to receive acknowledgement of the submission within 48 hours. If an acknowledgement is not received, then the sponsor should contact the E2B support team (E2B.support@mhra.gov.uk) to determine next steps, including whether resubmission is required. See the CT-Sfty for SUSAR submission content.

Annual Safety Report

For the annual safety report, CT-Sfty states that the fee for the MHRA to review a DSUR must be paid online (GBR-43) at the point of submission, not in advance. If at least one (1) of the clinical trials covered by the DSUR was approved through the combined review process, the report should be submitted through the combined review section of the IRAS (GBR-125). If all the clinical trials covered by the DSUR were approved through separate applications to the MHRA and the EC, the report should be submitted through MHRA Submissions (GBR-13). As explained in GBR-96, following payment, the emailed receipt must be included with the DSUR submission in its original format as a standalone document serving as proof of payment; failure to provide this evidence will result in the submission being invalidated. The payment reference number must follow the required format: “DSUR-[5 digit MHRA company number]-[Investigational Medicinal Product name]-[Payment date DD/MM/YYYY]”. The company number should be the first five (5) digits of either the product license number or the clinical trial application number from a trial the organization has previously submitted. The format must be adhered to so the MHRA can match the payment to the DSUR submission and allocate monies correctly. The reference number must not be duplicated for future DSUR submissions. Submissions reflecting a fee waiver will be considered valid. DSUR submissions that do not provide proof of payment indicate a failure to submit annual safety reports. Fee-related inquiries should be sent to DSURfees@mhra.gov.uk.

Per the CT-Sfty, ICH DSUR (E2F) (GBR-61) is relevant to the report format.

The CT-Sfty states that after submission, the DSUR undergoes validation checks. The person that submitted the DSUR will receive acknowledgement of their submission by email. If the submission is invalidated, the person that submitted the DSUR will be informed by email and will need to resubmit the DSUR with the deficiencies corrected. Valid DSURs are reviewed and requests for additional information may be made by email (and through IRAS (GBR-125), if this route of submission was used), with a timeline for response set by the MHRA. Once the MHRA has sufficient information, the person that submitted the DSUR will be informed by email (and through IRAS (GBR-125), if this route of submission was used) that the DSUR has been accepted.

Interim and Annual Progress Reports

As per the AU-ICH-GCP, 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-GCP 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-88 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) after the trial has been completed at all sites. There is no fee for this notification. 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. AUS-87 further notes that there is no fee to submit a CTN completion. See AUS-49 for additional information on the completion advice.

The AU-ICH-GCP 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.

Additionally, the TGA has adopted the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH)’s Topic E 3: Structure and Content of Clinical Study Reports (AUS-81). For more information, see AUS-81.

Interim and Annual Progress Reports

In accordance with GBR-18 and GBR-65, it is not a requirement to submit annual progress reports to the ethics committee (EC) for all studies receiving a final EC opinion in England, Wales, Scotland, and Northern Ireland. However, the MHCTR and CT-Sfty indicate that an annual safety report must be submitted to the Medicines and Healthcare Products Regulatory Agency (MHRA) in the form of a Development Safety Update Report (DSUR). See the Safety Reporting section for more details on this annual report.

As a best practice, GBR-18 points out that sponsors should ensure that arrangements are in place for reporting trial progress to stakeholders throughout the life of the study. These stakeholders commonly include Trial Steering Committees, Data Monitoring Committees, funders, sponsors, and governance bodies at each participating site. For research funded by the National Institute for Health and Care Research (NIHR), regular progress reports are required in line with funding agreements.

Final Report

As per the MHCTR and the EndingCT, within the period of 12 months beginning with the day after the conclusion of the clinical trial, the sponsor must:

• Publish a summary of the results of the clinical trial in the same public registry or registries (if more than one (1)) as the trial was registered in
• Offer to all relevant persons a summary of the results written in a manner that is understandable to laypersons

The MHCTR and the EndingCT state that at any point before the 12-month deadline, sponsors may apply for a deferral or waiver to one (1) or both requirements, explaining why this is needed. Phase I clinical trials may be eligible for an automatic deferral of up to 30 months from the conclusion of the trial, which may be further extended on request.

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 the Integrated Research Application System (IRAS) (GBR-125).

As per GBR-9, for all project-based research that have received a favorable ethics opinion from an EC, a final report on the research should be submitted to the UK Health Departments’ Research Ethics Service (RES) (GBR-62) within one (1) year of the trial’s conclusion. In the case of early termination, the provision of a final report is at the discretion of the sponsor. All final reports will be acknowledged within 30 days. The EC should be notified of receipt of the report, and the EC can ask to see a copy of the final report on request. In addition, 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 RES (GBR-62). The information contained in this final report helps the RES 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.

Other Reporting Requirements

Per the MHCTR-Chgs, the sponsor must publish a summary of the trial results in all registries the trial is registered in. It is not acceptable for a sponsor to publish the summary of results in another location (for example the sponsor's website) and insert a link to that in the registry.

The MHCTR and the EndingCT specify that within 90 days of the conclusion of a clinical trial, the sponsor must notify the MHRA and the relevant EC in writing that the trial has ended. If a trial is terminated prior to the date or event specified in the protocol, the sponsor must notify the MHRA and the relevant EC in writing of the termination of the trial within 15 days of the date of termination. According to the EndingCT, if the clinical trial that has ended was approved through the combined review process, the end of trial declaration form should be submitted through Integrated Research Application System (IRAS) (GBR-125). Guidance on using IRAS to submit an end of trial declaration form can be found in G-IRASCombRev and IRAS-User. If the clinical trial was approved through separate applications to the MHRA and the EC, the end of trial declaration form should be submitted to the MHRA via MHRA Submissions (GBR-13) and to the EC via email. The steps for gaining access to MHRA Submissions are contained within the G-MHRASubmiss and GBR-11. After submission, an acknowledgement will be issued by email (and through IRAS for combined review trials). No acknowledgement will be issued if the submission was related to the local end of trial. Details of where the results have been published should be provided to the MHRA and the EC within 12 months of trial completion (except for some pediatric trials involving the use of authorized medicinal products).

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.

As per the AU-ICH-GCP 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.

In accordance with the AU-ICH-GCP, 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 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 and the G-TrialsSOP, a sponsor must be an Australian entity.

As per the MHCTR, a sponsor of a clinical trial is the person who takes responsibility for the initiation, management, and financing (or arranging the financing) of that trial. If two (2) or more persons take responsibility for these matters, they may either take joint responsibility for carrying out the functions of the sponsor or allocate responsibility for carrying out the sponsor’s functions. Where two (2) or more persons take joint responsibility, any reference to the sponsor in the regulations is construed as a reference to those persons. If responsibility is allocated instead, one (1) person must be responsible for carrying out the sponsor’s functions related to the clinical trial approval process and for making the request for authorization to the Medicines and Healthcare Products Regulatory Agency (MHRA) and an ethics committee (EC) opinion. The request for approval must specify who is responsible for carrying out the sponsor’s functions related to the approval process, good clinical practice (GCP) and conduct of the clinical trial, and pharmacovigilance. After the clinical trial has been approved, a different person may be specified as responsible for carrying out the sponsor’s functions by making a modification of an important detail to the terms of the clinical trial approval.

As delineated in the MHCTR, a sponsor must be established in the United Kingdom (UK) or in a country included in a list published by the MHRA, or have a legal representative who is so established. The MHRA’s list is published at G-CTApprovedCountries and initially includes European Union (EU) and European Economic Area (EEA) countries.

Further per the MHCTR, a sponsor may delegate any or all of its functions to any person, but such delegation does not affect the responsibility of the sponsor. The functions of the sponsor include the development and maintenance of trial-specific computerized systems, and the selection and oversight of a laboratory in relation to the analysis or evaluation of human samples collected as part of the clinical trial.

GBR-101 provides that 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. All health and social care research has a sponsor. The sponsor is normally expected to be the employer of the chief investigator in the case of non-commercial research or the funder in the case of commercial research. The sponsor has overall responsibility for the research, including:

• Identifying and addressing poorly designed or planned research and poor-quality research proposals, protocols or applications and ensuring that research proposals and protocols take into account systematic reviews of relevant existing research evidence and other relevant research in progress; make appropriate use of patient, service user, and public involvement; and are scientifically sound, safe, ethical, legal, and feasible and remain so for the duration of the research, taking account of developments while the research is ongoing
• Satisfying itself that the investigators, research team, and research sites are suitable
• Ensuring that roles and responsibilities of the parties involved in the research and any delegation by the sponsor of its tasks are agreed and documented
• Ensuring adequate provision is made for insurance or indemnity to cover liabilities which may arise in relation to the design, management, and conduct of the research project
• Ensuring appropriate arrangements are made for making information about the research publicly available before it starts (unless a waiver or deferral is agreed by or on behalf of the EC); agreeing appropriate arrangements for making data and tissue accessible, with adequate consent and privacy safeguards, in a timely manner after it has finished; and ensuring arrangements for information about the findings of the research to be made available, including, where appropriate, to participants
• Ensuring that, where expected or required, the research has approval from an EC and any other relevant approval bodies before it begins
• Verifying that regulatory and practical arrangements are in place, before permitting the research to begin in a safe and timely manner
• Putting and keeping in place arrangements for adequate finance and management of the research project, including its competent risk management and data management
• Ensuring that effective procedures and arrangements are kept in place and adhered to for reporting (e.g., safety reports) and for monitoring the research, including its conduct and the ongoing suitability of the approved proposal or protocol in light of adverse events or other developments

Per GBR-103, sponsors of clinical trials of investigational medicinal products (CTIMPs) have particular legal duties. The sponsor of a CTIMP is responsible for ensuring that a clinical trial complies with the MHCTR and GCP. Regarding GCP compliance, the MHCTR requires that clinical trials must be conducted in accordance with the conditions and principles of GCP, including the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) GCP, as amended from time to time. ICH-UKimp indicates that the UK is implementing the ICH’s Guideline for Good Clinical Practice E6(R3) (GBR-91) and the ICH’s General Considerations for Clinical Studies E8(R1) (GBR-104), among others.

GBR-103 states that where it is necessary to appoint a legal representative based in the UK or a country on the MHRA’s list, the details of the legal representative should be entered into Integrated Research Application System (IRAS) (GBR-125). 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 and contactable 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
• May in some cases enter 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

As explained in GBR-103, in all cases, evidence should be provided with the CTIMP application that the legal representative is willing to take on the role of legal representative and is established at an address in the UK or a country on the approved country list. For example, a copy of correspondence between the sponsor and legal representative on appropriate headed paper could be supplied, or a copy of a contract. Where the legal representative is also a co-sponsor, this should be separately recorded on the application form and details given of the allocation of sponsorship responsibilities.

See GBR-103, GBR-9, GBR-18, and GBR-2 for additional guidance on sponsors.

Overview

As set forth in the AU-ICH-GCP, 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 and the G-TrialsSOP, 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) (also referred to as Data Monitoring Committees (DMCs)) 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-GCP, 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

Additionally, the Therapeutic Goods Administration (TGA) has adopted the European Medicines Agency (EMA)’s Guideline on Data Monitoring Committees (AUS-78), which discusses the key issues involved when sponsors include DSMBs as part of their trial management. For more information, see AUS-78.

Multicenter Studies

As delineated in the AU-ICH-GCP, 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 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.

Overview

Per the MHCTR, the investigator for a clinical trial must be a health care professional who is appropriately trained to undertake that role in a clinical trial. Health care professional means a doctor, dentist, registered nurse, pharmacist, optometrist, relevant Health and Care Professions Council registrant, registered osteopath, registered chiropractor, anaesthesia associate or physician associate, or registered midwife. The investigator is responsible for the conduct of the trial at its trial location(s). The CT-Roles states that the appointment of an investigator is the responsibility of a sponsor, and this person must be qualified by education and experience, having the scientific background and experience in participant care required for the clinical trial. Organizations conducting clinical trials should consider what training and support is required for investigators. Consideration should be given to participation in suitable training and provision of mentoring support, for example. The type and level of training for an investigator should facilitate knowledge and understanding of the relevant regulations and guidance, and expectations associated with the role, while being proportionate to the type of trial being conducted. Sponsors should also note that a qualified doctor (or, where appropriate, a qualified dentist) who is an investigator for the trial should have the overall responsibility for trial-related medical care and decisions on behalf of participants.

GBR-18 lists examples of factors that should influence investigator/site selection:

• Interest in the research question
• Experience and qualifications of the investigator
• Sufficient staff to conduct the study and their experience and qualifications
• Availability of suitable patient population, including anticipated rate of patient recruitment (determined through feasibility assessments) and conflicting studies
• Adequate time to conduct and oversee the trial
• Adequate facilities such as the availability of any specialized diagnostic, therapeutic equipment required by the protocol, adequate space and storage conditions (including archive), and available resources in support departments
• Previous track record with similar trials
• Geographic location
• Contractual and budgetary negotiations and arrangements

Regarding investigator training, CT-Roles explains that both the Health Research Authority (HRA) and the Medicines and Healthcare Products Regulatory Agency (MHRA) advocate a proportionate approach to the application of good clinical practice (GCP) to the conduct of clinical trials and the appropriate training of staff involved. Training needs may range from detailed knowledge to just awareness of GCP principles and the MHCTR, and training can be tailored accordingly. For certain trials it may be necessary for staff involved in trial activities to be aware of other regulatory requirements outside those of GCP. For example, healthcare professionals retaining tissue samples should be aware of relevant human tissue and blood safety legislation and regulations. Per the CT-Roles, It is expected that organizations involved in the conduct of clinical trials have considered staff training needs in regard to the MHCTR and GBR-91 (and GBR-104 where relevant).

Regarding GCP compliance, the MHCTR requires that clinical trials must be conducted in accordance with the conditions and principles of GCP, including the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) GCP, as amended from time to time. ICH-UKimp indicates that the UK is implementing the ICH’s Guideline for Good Clinical Practice E6(R3) (GBR-91) and the ICH’s General Considerations for Clinical Studies E8(R1) (GBR-104), among others.

GBR-106 provides a site-selected email template, which should be used as the formal notification from the commercial sponsor (or delegated agent) confirming that the organization has been selected to participate as a site in a commercial-contract clinical trial or clinical investigation. Also see GBR-18 additional resources to support investigator and site selection.

The UKannot-E6R3 states that unlike in the GBR-91, there is no regulatory requirement for an investigator to inform the authorities that they are withdrawing from a trial. However, depending on the circumstances of the investigator’s withdrawal, the sponsor may need to temporarily halt the trial or report a serious breach to the MHRA in accordance with the MHCTR. In addition, if the investigator that has withdrawn from the trial is the chief investigator (CI), then the sponsor will need to submit a substantial modification to the authorities with the details of the new CI.

As described in GBR-18, for clinical trials of investigational medicinal products (CTIMPs), adding a new trial location not listed with the original application is considered a modification of an important detail. In addition, if a trial location is added in a UK nation that was not previously involved in the project, the sponsor should ensure that:

• The change is correctly categorized using the Modification Tool and submitted through the combined review process of Integrated Research Application System (IRAS) (GBR-125)
• The appropriate nation-specific study set-up processes are followed for the new trial location(s)

UK Local Information Pack

Per GBR-63 and GBR-106, the HRA's UK Local Information Pack (LIP) provides a consistent set of documents to support study setup and delivery across National Health Service (NHS) organizations in England, Northern Ireland, Scotland, and Wales. While the core contents are standardized, country-specific processes govern how the LIP is distributed and used:

• England and Wales: the sponsor should send the LIP directly to the site's R&D office, delivery team, and local network (if applicable, the National Institute for Health and Care Research's Research Delivery Network Portfolio)
• Scotland: the NHS Research Scotland Permissions Coordinating Centre distributes the LIP to R&D offices and relevant portfolio managers, while sponsors provide it to research teams using a Scotland-specific email template.
• Northern Ireland: the sponsor may send the LIP to participating sites after receiving instruction from the Northern Ireland Health and Social Care (HSC) R&D Approvals Service.

For templates, detailed instructions, and contact information by country, refer to UKwide-Rsrch, GBR-106, and GBR-63.

Foreign Sponsor Responsibilities

GBR-103 provides that if a sponsor(s) is not established in the UK or on an approved country list, 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. See the G-CTApprovedCountries for 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 European Union (EU)/European Economic Area (EEA).

Data Safety and Monitoring Board

Per GBR-18, the CI should plan oversight structures as appropriate including a data safety and monitoring board (known as a data monitoring committee (DMC) in the UK).

Multicenter Studies

Per the G-Ovrsight, for multi-country trials, global documentation for the trial is acceptable, but it may be necessary to include specific procedures to mitigate any country-specific risks that were identified from the risk assessment – for example, differences in clinical practice or local regulations. It may be necessary to include some site-specific actions such as additional monitoring checks at the CI’s site (for example, if the sponsor has delegated numerous functions) or the site may be responsible for undertaking a specific trial activity or where a site-specific risk may have been identified.

As described in GBR-18, for CTIMPs, change of a principal investigator (PI) (other than a CI) in a multicenter trial is considered a modification of an important detail.

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.

Insurance

The AU-ICH-GCP 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-GCP 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-GCP, 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.

Insurance

As set forth in the MHCTR, all clinical trials must make provisions for insurance or indemnity to cover all liabilities of the investigator and sponsor. Proof of insurance, a guarantee, or any other similar arrangement, must accompany a request for approval, a modification request, and a notification of the conclusion of a trial; or an explanation of why the proof is not being provided. Per GBR-103, if a sponsor of a clinical trial of an investigative medicinal product (CTIMP) is a commercial body, a copy of an insurance or indemnity certificate should normally be included with the ethics committee (EC) application as evidence of the cover in place for the potential liability of the sponsor. This may be a certificate for a trial-specific policy or a block policy covering a number of trials conducted by the sponsor. If the certificate is not yet available, the EC will require as a condition of its favorable opinion that a copy of the certificate is provided prior to the start of the trial. See UKannot-E6R3, GBR-2, GBR-9, GBR-103, GBR-101, and GBR-18 for additional guidance.

The MHCTR requires that clinical trials are conducted in accordance with the principles of good clinical practice (GCP) set out in the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) GCP, as amended from time to time. ICH-UKimp indicates that the United Kingdom (UK) is implementing the ICH’s Guideline for Good Clinical Practice E6(R3) (GBR-91) and the ICH’s General Considerations for Clinical Studies E8(R1) (GBR-104), among others.

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.

Compensation

Injury or Death

According to GBR-33, before the start of a Phase I study, 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.

Trial Participation

Per Compstn, where payment is proposed for trial participation, the payment should be proportionate to the burden imposed by the research. Such burdens may often be significant without involving excessive risk (e.g., number of hospital visits, tissue samples taken, lifestyle restrictions, diaries, questionnaires, use of technology such as electronic patient reported outcomes, interaction with apps, etc.). Where the risk and burdens of the research are considered by an EC to be justified by the potential benefits, then it will normally be acceptable for competent adults to participate in the research study without being paid (including reimbursement of expenses). Where it is considered ethically acceptable for individuals to take part in a study for no payment, it would also be acceptable to pay individuals for participation in that study proportionate to the level of burdens and/or risk. Financial or other incentives, of themselves, are not considered coercive nor do they present an undue inducement to a potential participant where the risks and burdens involved are those that a competent, adult participant might reasonably accept for no payment. Regarding payment to participants who use drugs to take part in research, where payment is deemed to be acceptable for taking part in research, it is acceptable for that payment to be made in cash or vouchers.

As delineated in the MHCTR, incentives and financial inducements must not be given to a minor or a legal representative/guardian, except provision for compensation in the event of injury or loss. Similarly, incentives and financial inducements must not be given to a participant who is an incapacitated adult or their legal representative, except provision for compensation in the event of injury or loss.

Post-Trial Access

As explained in the Hlsnki-Align, the Declaration of Helsinki (GBR-81) requires arrangements for post-trial access to beneficial interventions, whereas the MHCTR does not impose this as a statutory obligation. In practice, GBR-81 and the MHCTR are aligned regarding expectations. Sponsors should aim to comply with both, but where strict adherence to GBR-81 would undermine UK statutory safeguards or operational feasibility, the Medicines and Healthcare Products Regulatory Agency (MHRA) expects sponsors to prioritize compliance with UK law while documenting the rationale for deviations.

The UKannot-E6R3 clarifies, with respect to GBR-91, that there is no specific regulatory requirement for the sponsor to provide the investigator with information about the treatment taken by participants for blinded trials. However, clinical trials should be designed and conducted in ways that ensure the rights, safety, and well-being of participants, which includes the post-trial transition back to standard of care, and to support this, it may be necessary to know which treatment the participant received. The sponsor should act in accordance with the approved clinical trial protocol.

Quality Assurance/Quality Control

As per the AU-ICH-GCP, 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. 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 communicating 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 summarizing 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-GCP 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-GCP, 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.

As per AUS-74, the Therapeutic Goods Administration (TGA) has adopted certain guidelines released by the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH), the European Medicines Agency (EMA), and the United States Food & Drug Administration (FDA) regarding quality management and technical aspects of clinical trials. See each of these documents for additional details:

• ICH Guideline E8 (R1) on General Considerations for Clinical Studies (AUS-76)
• Guideline on Strategies to Identify and Mitigate Risks for First-in-Human Clinical Trials with Investigational Medicinal Products (AUS-77)
• Guideline on Clinical Trials in Small Populations (AUS-79)
• ICH E11(R1) Guideline on Clinical Investigation of Medicinal Products in the Pediatric Population (AUS-80)
• Use of Electronic Health Record Data in Clinical Investigations - Guidance for Industry (AUS-82)
• Considerations for the Use of Real-World Data and Real-World Evidence to Support Regulatory Decision-Making for Drug and Biological Products - Guidance for Industry (AUS-83)
• ICH Topic E 10 Choice of Control Group in Clinical Trials (AUS-84)
• ICH Topic E 9 - Statistical Principles for Clinical Trials (AUS-85)

See AUS-74 for more information on, as well as a list of, the international scientific guidelines adopted by the TGA.

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-GCP 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-GCP, 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 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. According to the G-GCP-Inspect, clinical trial sites that have been notified of a GCP inspection should prepare for the inspection by:

• Ensuring their authorizing institution, trial sponsor, and clinical team are advised of the inspection (the G-GCP-Inspect notes that although the TGA does not require that the sponsor be informed, there is generally a requirement in the contract between the site and the sponsor to share this type of information)
• Ensuring access for the inspectors to clinical trial records and source documents is arranged for the time of the inspection
• Ensuring their IT processes allow them to grant view-only access to the inspectors

The G-GCP-Inspect adds that ECs and trial sponsors are not included in the scope of the TGA’s GCP inspection program. The site PI can invite other personnel, including the sponsor and institution/EC representative(s), to attend the inspection opening and closing meeting. See the Scope of Assessment section, the G-GCP-Inspect, and AUS-90 for more information on TGA inspections.

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-GCP 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 the 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.

Quality Assurance/Quality Control

As stated in the MHCTR, a person must not conduct a clinical trial or perform the functions of the sponsor of a clinical trial unless it is in accordance with the conditions and principles of good clinical practice (GCP). The GCP conditions and principles include those in the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) GCP, as amended from time to time. ICH-UKimp indicates that the United Kingdom (UK) is implementing the ICH’s Guideline for Good Clinical Practice E6(R3) (GBR-91) and the ICH’s General Considerations for Clinical Studies E8(R1) (GBR-104), among others. As explained in the UKannot-ICH, the Medicines and Healthcare Products Regulatory Agency (MHRA) has issued UK-specific annotations—UKannot-E6R3 and UKannot-E8—to support compliance with the ICH efficacy guidelines by clarifying how the ICH provisions should be read alongside applicable UK legal requirements and by directing users to relevant UK requirements. Regarding GCP, the CT-Transtn states that from April 28, 2026, the new GCP rules under MHCTR apply to all clinical trials, whether the application was submitted before or after April 28, 2026. The only exception relates to retention of the trial master file for trials where the application was submitted before April 28, 2026.

Per the MHCTR, the sponsor of a clinical trial must put and keep in place arrangements for the purpose of ensuring that the conditions and principles of GCP are satisfied or adhered to. This includes developing and maintaining trial-specific computerized systems, selecting and overseeing a laboratory for human samples, and analyzing and evaluating human samples collected as part of the clinical trial. Further, the sponsor must ensure that the investigational medicinal products (IPs) used in the trial are made available to the participants free of charge.

The Qlty-Risk provides an explanation of the interconnected quality concepts embedded within GBR-91, such as quality by design, risk-based quality management, and risk proportionality, and outlines the practical implications for trial conduct, oversight, and compliance. In addition, the Qlty-Risk should be read in conjunction with GBR-104, which establishes the overarching scientific and quality principles for clinical study design and conduct, including the application of quality by design approaches. See the Qlty-Risk and GBR-18 for additional details on implementing proportionate, risk-based systems for clinical trials.

The MHCTR and the SrsBreachNotif state that the sponsor of a clinical trial must notify the MHRA in writing of any serious breach of the conditions and principles of GCP in connection with that trial or the protocol within seven (7) days of becoming aware of that breach. A serious breach is a breach which 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.

To make the MHRA notification, the SrsBreachNotif emphasizes that the serious breach notification should be carried out by the sponsor or a person legally authorized by the sponsor to perform this function (for example, a legal representative or service provider), if delegated by the sponsor. The sponsor retains legal responsibility even if the function is delegated. To ensure participant safety, reporting should not be delayed by debates about reporting responsibility. If the sponsor does not report a breach to the MHRA but the investigator or institution believes a serious breach has occurred, due diligence is necessary. Investigators or institutions should consider whether to continue with the trial and/or report the breach directly to the MHRA. If the sponsor obtains clear and unequivocal evidence that a serious breach has occurred, the default position should be for the sponsor to notify the MHRA first, within seven (7) days, and investigate and take action simultaneously or after notification. In this case, the sponsor should not wait to obtain all the details of the breach prior to notification. In other cases, some degree of investigation and assessment may be required by the sponsor prior to notification, to confirm that a serious breach has occurred. It is expected that this investigation is expedited to meet the timeline as closely as possible. If in doubt about whether and when to notify, contact the MHRA GCP Team via GCP.SeriousBreaches@mhra.gov.uk. Organizations should also consider if there are any other relevant MHRA units that should be notified.

Per the SrsBreachNotif, GBR-9, and CTIMP-Condtns, the EC must also be notified of a serious breach within seven (7) days. The SrsBreachNotif instructs that organizations should use the MHRA form (GBR-108) to ensure all required information is submitted, and the form should be sent as an MS Word document. Wherever possible, the MHRA will provide an acknowledgement of receipt for notifications. It is recommended that the organization also informs the relevant chief investigator and/or principal investigators (as applicable) of the breach to facilitate the implementation of corrective and preventative actions.

Per the G-RiskAssmt, the 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. 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 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. In addition, see GBR-34 for resources and training on developing and implementing people-centered research.

Monitoring Requirements

Per GBR-18, sponsors should define a monitoring strategy that focuses on critical data and processes, ensuring timely identification of issues that may affect participant safety or data integrity. Proportionate approaches are supported through resources listed at GBR-18. Sponsors should ensure there are clear processes for the identification and escalation of issues, identified through monitoring, as well as implementing and documenting corrective and preventive actions. Further, the sponsor of a clinical trial is responsible for establishing and maintaining robust quality systems, including designing and implementing a formal audit plan. 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 standard operating procedures (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
• System audits, which look at the performance of specific functions, such as the systems and processes used for data management

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 GCP as described in GCP-Inspct and GBR-91. 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 GCP-Inspct for pre-inspection documentation and other resources. Also see Inspct-Resp for information on formulating responses to GCP inspection findings. Per G-RiskAssmt, GCP inspectors will also review risk assessments. The G-Ovrsight provides additional guidance to assist sponsors and those conducting trials on implementing adequate oversight and monitoring processes for clinical trials of investigational medicinal products (CTIMPs).

Premature Study Termination/Suspension

Per the MHCTR and the EndingCT, the sponsor must provide written notice to the MHRA that a clinical trial has ended (and this notice should also be provided to the EC). Where a clinical trial is terminated early, this notice must be provided within 15 days.

MHCTR states that the MHRA may require a trial, or the conduct of the trial at a particular trial location, be suspended or terminated if it has objective grounds for considering that any condition, restriction, or limitation which applies to the conduct of the trial is no longer satisfied; has information raising doubts about the safety or scientific validity of the trial; or the trial has lapsed and the sponsor has not notified the MHRA that the trial has ended. The notice will specify whether it applies to the trial generally or to one (1) or more trial locations; whether it requires suspension or termination of the trial in whole or in part; any period of suspension and any conditions to be satisfied before the trial, or the conduct of the trial at a particular location, may be recommenced; and whether suspension or termination takes effect immediately on receipt of the notice or on a specified date. Except where it appears to the MHRA that there is an imminent risk to the health or safety of any of the participants of the clinical trial, the MHRA must give the sponsor or investigator at least one (1) week’s written notice that it is minded to issue a notice suspending or terminating the trial, in whole or in part, or the conduct of the trial at a particular location, and the reasons why. The sponsor or investigator may, within one (1) week of the date of the notice, furnish the MHRA with written representations as to whether the trial, or the conduct of the trial at a particular location, should be so suspended or terminated. A person on whom a suspension or termination notice has been served may, within 28 days, or such extended period as the MHRA may allow, give notice of their wish to make written or oral representations to the appropriate committee.

Per the EndingCT, if the clinical trial that has ended was approved through the combined review process, the end-of-trial declaration form (GBR-133) should be submitted through the combined review part of IRAS (GBR-125). If approved through separate applications to the MHRA and the EC, it should be submitted to the MHRA via MHRA Submissions (GBR-13) and to the EC via email. For trials terminated prior to the date or event specified in the protocol:

• The end of trial declaration will be reviewed by the MHRA and requests for additional information may be raised
• Once MHRA has sufficient information, the sponsor will be informed that the end of trial declaration has been accepted
• Details of where the results have been published should be provided to MHRA and the EC within 12 months of trial completion (except for some pediatric trials involving the use of authorized medicinal products)

Also see GBR-91, which the MHRA has implemented in ICH-UKimp, for additional guidance on sponsor responsibilities involving premature termination or suspension of a trial. In addition, the MHCTR advises that the investigator and sponsor must have regard to all relevant guidance with respect to conducting a clinical trial.

Also see GBR-18 and GBR-128 for more information and resources.

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-GCP for additional information.

The Therapeutic Goods Administration (TGA) has adopted the United States Food & Drug Administration (FDA)’s Use of Electronic Health Record Data in Clinical Investigations - Guidance for Industry (AUS-82). For more information, see AUS-82.

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-GCP, the 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.

The TGA has adopted the European Medicines Agency (EMA)’s Guideline on the Content, Management and Archiving of the Clinical Master File (Paper and/or Electronic) (AUS-75). For more information on the clinical trial master file, see AUS-75.

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.

Electronic Data Processing System

The MHCTR states that the sponsor’s functions include the development and maintenance of trial-specific computerized systems, which supports compliance with good clinical practice (GCP), including the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH), as amended from time to time. ICH-UKimp indicates that the United Kingdom (UK) is implementing the ICH’s Guideline for Good Clinical Practice E6(R3) (GBR-91) and the ICH’s General Considerations for Clinical Studies E8(R1) (GBR-104), among others. Per GBR-18, the trial-specific computerized system must be fit for its intended use and appropriately validated, ensuring that electronic data meets GCP and regulatory requirements. See GBR-18 for additional resources.

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.

Records Management

Per MHCTR and the CTRecords, the sponsor must keep a trial master file (TMF) for a clinical trial and ensure that the TMF is readily available at all reasonable times for inspection by the Medicines and Healthcare Products Regulatory Agency (MHRA) or any person appointed by the sponsor to audit the arrangements for the trial. The TMF must always contain the essential documents relating to that clinical trial. The sponsor must ensure that any alteration to a document contained in the TMF is traceable. The sponsor and the chief investigator (CI) must ensure that the documents contained, or which have been contained, in the TMF (including documents contained in electronic form) are retained for at least the period of 25 years beginning with the day after the conclusion of the trial and that during that period are readily available to the MHRA upon request and complete and legible. If, at the date of the expiration of the 25 years, the data generated by the trial is being used to support an application for a UK marketing authorization, the sponsor must ensure the documents are retained for a period of at least two (2) years beginning with the day after the UK marketing authorization is granted. Further, the sponsor and CI must ensure that the medical files of trial participants are retained for a period of at least 25 years beginning with the day after conclusion of the trial, or such period as is required by any other enactment, if longer. The sponsor must appoint individuals to be responsible for archiving the documents in the TMF and restrict access to those appointed individuals. See CTRecords and GBR-91 for guidance on what is an essential document.

Per the UKannot-E6R3, in relation to GBR-91, transfer of ownership of essential records must be documented by the sponsor but does not have to be reported to the UK authorities. If the transfer of ownership is related to a change in sponsor, this must be reported to the authorities as a modification of an important detail.

Regarding transitional arrangements, CTRecords specifies that for trials submitted before April 28, 2026, the old rules (pre-2025-amendments) continue to apply for TMF documents. This means the sponsor and CI must keep the TMF documents for at least five (5) years after the trial ends and ensure they remain complete, legible, and readily available to the MHRA upon request. If the trial data is being used to support a UK marketing authorization application when the 5-year period ends, the sponsor must keep the essential records for at least two (2) years after the UK marketing authorization is granted. The sponsor and CI must keep trial participants’ medical files for at least 25 years after the trial ends, or longer if another law requires it. For all trials involving an authorized product, other trial documentation must be kept for as long as the product remains authorized. The final clinical study report must be kept for five (5) years after the product is no longer authorized.

CTRecords states that documents must not be destroyed before the end of the retention period. If documents have been damaged or destroyed accidentally then an assessment should be conducted to determine the extent and impact of the lost or damaged documents. If the assessment is found to impact the ability to present the documents for inspection, then a serious breach notification should be considered.

Per GBR-18, the sponsor should maintain documented procedures for computerized trial-specific systems, including system validation, user training, access and permissions management, security and integrity controls, change control and system updates, back up, disaster recovery and incident management, and ongoing technical support and maintenance. See GBR-18 for additional resources.

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. Additionally, see the Office of the Australian Information Commissioner (OAIC)’s guidelines on the APP (G-APP) for more information.

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 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.

Responsible Parties

For purposes of data protection requirements, the UK-GDPR the UK-DPAct, and the G-GDPR delineate the following responsible parties (Note: Each of the items listed below will not necessarily be found in all sources, which provide overlapping and unique elements):

• Controller – the natural or legal person, public authority, agency or other body which, alone or jointly with others, determines the purposes and means of the processing of personal data
• Processor – a natural or legal person, public authority, agency or other body which processes personal data on behalf of the controller
• Recipient – a natural or legal person, public authority, agency or another body, to which the personal data are disclosed, whether a third party or not; however, public authorities which may receive personal data in the framework of a particular inquiry in accordance with domestic law must not be regarded as recipients
• Third party – a natural or legal person, public authority, agency, or body other than the data subject, controller, processor and persons who, under the direct authority of the controller or processor, are authorized to process personal data

Per the UK-GDPR and the UK-DPAct, the data protection legislation requires 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.

Data Protection

Per the UK-GDPR, the UK-DPAct, the G-GDPR, and GBR-89, the controller must comply with the following principles of the data protection legislation:

• Lawfulness, fairness, and transparency
• Purpose limitation (See the DUAA for clarifications on purpose limitation and further processing)
• Data minimization
• Accuracy
• Storage limitation
• Integrity and confidentiality (security)
• Accountability

As stated in the UK-GDPR, the UK-DPAct, the G-GDPR, and GBR-89, it must be shown that each data processing activity has a lawful basis under United Kingdom (UK) 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 required 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. Per GDPR-Trspcy, to help ensure research participants have all the information they need to make an informed decision about the use of their data, sponsors are expected to use the Medicines and Healthcare Products Regulatory Agency (MHRA) template at GDPR-Trspcy, which includes information on:

• When the GDPR wording should be used
• If individual bespoke GDPR wording is used
• If the GDPR wording in open studies is updated
• Instructions for use
• The GDPR transparency wording for all sponsors
• Definitions
• Communicating GDPR information to children and young people

For international transfers of personal information, per the UK-GDPR, a controller or processor may transfer personal data to a third country or international organization only where the transfer is covered by adequacy regulations, is subject to appropriate safeguards, or relies on a derogation for a specific situation, and otherwise complies with the UK-GDPR and any applicable transfer restrictions. The GBR-138 contains guidance, templates, and other resources that are suitable for all types of organizations, and covers areas such as adequacy regulations, appropriate safeguards, completing a transfer risk assessment, using an exception, and receiving personal information from the European Economic Area.

As explained in the DUAA-Org, the DUAA amends, but does not replace, the UK-GDPR and the UK-DPAct. The DUAA-Sum contains a summary of clarifications on changes to data protection law from the DUAA amendments. DUAA-Cmmct brings many of the provisions of the DUAA into force, including those related to the definition of research, consent to processing for purposes of scientific research, and transfers of personal data to third countries. See GBR-136 and DUAA-Org for more details on the DUAA and what it means for organizations and research. See DUAA-Sum for additional clarifications on data protection, including safeguards and restrictions when using automated decision-making. In addition, GBR-100 contains additional templates to help sponsors comply with the UK-GDPR.

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 Health Research Authority (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.

Per GBR-100, children must be provided with the same information as adults regarding what will be done with their personal data, even if consent is sought from the parent/legal guardian. The UK-GDPR states that information provided to individuals should be in a concise, transparent, intelligible, and easily accessible form, using clear and plain language.

For variations among the UK countries regarding accessing identifiable data without consent, see information on the Confidentiality Advisory Group at the UKwide-Rsrch, CAG-Applcts, and GBR-38.

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 United States (US) 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 Data-US-UK, 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 Data-US-UK, GBR-22, and GBR-23 for additional information about the UK Extension to the Data Privacy Framework.

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-GCP and the G-NatlStmt. According to the AU-ICH-GCP, if requirements specified in the G-NatlStmt appear to differ from those specified in the AU-ICH-GCP, the Therapeutic Goods Administration (TGA) recommends compliance with the G-NatlStmt.

As per the AU-ICH-GCP, 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-GCP 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-GCP, 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-GCP, 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-GCP 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-GCP 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.

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, which states that a person gives informed consent to take part in a clinical trial only if the decision is given freely after that person is informed of the nature, significance, implications, and risks of the trial.

Further, the MHCTR requires the following conditions to obtain consent from an adult able to consent or who has given consent prior to the onset of incapacity:

• The participant has had an interview with the investigator, or another member of the investigating team, in which there was an opportunity to understand the objectives, risks, and inconveniences of the trial and the conditions under which it is to be conducted
• The participant has been informed of the right to withdraw from the trial at any time
• The participant has given informed consent to take part in the trial
• The participant may, without being subject to any resulting detriment, withdraw from the clinical trial at any time by revoking informed consent
• The participant has been provided with a contact point where more information about the trial may be obtained

Regarding ethics committee (EC) review, the MHCTR stipulates that where the EC receives a valid request for approval, it must consider the measures used to seek and obtain informed consent for participation in the trial.

G-ConsentPIS states that the investigator(s) must provide detailed research study information to the participant or legal representative/guardian. The oral and written information concerning the trial 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. A signature on a consent form does not in itself make consent valid. A person’s agreement with each statement contained in the consent form can be indicated by initialing or ticking boxes, or by providing the answers ‘yes’ or ‘no’ after each statement. The form itself is then signed by the parties involved in the consent conversation. 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.) Testing the PIS with an appropriate group of people (patient groups or other members of the public) is strongly encouraged to ensure the language used is appropriate, the PIS format aids understanding, and the PIS covers risks and benefits that are relevant to potential participants. EC approval is not needed to test the PIS in this manner. For more guidance on the PIS, see the PrtInfoQty-Stds, the PrtInfo-DesignPrin, and GBR-14, which include frequently asked questions (FAQs), information principles, and standards. G-ConsentPIS provides PIS and consent form templates suitable for different types of research.

The MHCTR and MHCTR-Chgs further provide that the protocol may make provisions for simplified arrangements for obtaining and evidencing consent if the following conditions are met:

• The investigational medicinal product (IP) is authorized for use in the UK and is used in accordance with that authorization
• The IP is given to the participant during that participant’s routine health care
• The participant receives no additional medication and undergoes no additional intervention or diagnostic procedure, solely for the purposes of the clinical trial

As explained in the MHCTR-Chgs, if a sponsor is planning to use simplified arrangements, these will need to be detailed in the protocol including the reason for obtaining consent using simplified arrangements, the information to be provided to the participant, the means of providing that information, and the means by which consent shall be evidenced. These arrangements may include proportionate approaches to the information provided, the way consent discussions are undertaken, and how consent is evidenced, provided that consent remains informed, freely given, explicit, and prospectively obtained. Any such arrangements must be clearly described in the protocol and approved by an EC. See the MHCTR-Chgs for additional information.

Per the Cnst-Proprt, the Health Research Authority (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

For more guidance on obtaining consent, see GBR-69, GBR-18, and GBR-9.

Regarding consent in good clinical practice (GCP), the MHCTR requires that all clinical trials must be conducted in accordance with the conditions and principles of GCP, including the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) GCP, as amended from time to time. ICH-UKimp indicates that the UK is implementing the ICH’s Guideline for Good Clinical Practice E6(R3) (GBR-91) and the ICH’s General Considerations for Clinical Studies E8(R1) (GBR-104), among others. As explained in the UKannot-ICH, the Medicines and Healthcare Products Regulatory Agency (MHRA) has issued UK-specific annotations—UKannot-E6R3 and UKannot-E8—which discuss consent requirements.

In addition, the MHCTR requires that clinical trials must be conducted in accordance with the principles of the Declaration of Helsinki (GBR-81) except where it would be a contravention of the MHCTR.

Re-Consent

Per GBR-18, during a clinical trial if new information arises during a study that may affect participants' willingness to continue, they should be re-consented using updated, EC-approved documents.

Language Requirements

As stated in the MHCTR, applications to the EC and the MHRA and any accompanying material, such as the informed consent material, should be presented in English.

Documenting Consent

The MHCTR states that consent must be evidenced in writing, dated, and signed, or otherwise marked, by that person so as to indicate consent, or if the person is unable to sign or to mark a document, is communicated (whether by talking, using sign language or any other means) in the presence of at least one (1) witness and recorded in writing. As provided in the G-ConsentPIS, consent for clinical trials of investigational medicinal products (CTIMPs) must be in writing. Electronic methods for documenting consent, including the use of electronic signatures, are also considered to be 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

The MHCTR-Chgs states that consent must not be waived or presumed.

Based on the AU-ICH-GCP 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 ICF, 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

As required in the MHCTR, informed consent is only valid if the person’s decision is given freely after being informed of the nature, significance, implications, and risks of the trial. The G-ConsentPIS specifies that the participant information sheet (PIS) should include the following:

• Title – Head the document “Patient information sheet,” “Participant information sheet,” or “Information about the research;” use a consistent study title across documents, understandable to the intended audience, and explaining the study in simple English
• Invitation – Make clear that potential participants are being invited to consider taking part and that participation is entirely voluntary; briefly explain how they were identified and why they were selected
• Summary of the research – Provide a short, clear summary explaining why the research is being done, what research question is being addressed, why it is relevant/important, what is being studied or tested, what participants will have to do, who is eligible, where the study will take place, and how long it will last
• Purpose and background – Explain the purpose of and background to the research, giving enough context for participants to understand why the study is being conducted
• What taking part involves – Describe what will happen to participants during and after the research study, including what they will have to do and what taking part will mean for them
• Research vs standard care – For studies involving therapeutic interventions, clearly explain which elements are research and which constitute standard care
• Alternatives to participation – Explain alternatives to taking part, especially in therapeutic trials involving patients
• Possible benefits – Describe the potential benefits participants might expect from taking part, where applicable
• Possible disadvantages, risks, inconveniences, or restrictions – Explain the potential risks, disadvantages, inconveniences, or restrictions participants might expect
• Treatment that may be withheld
• Participant responsibilities
• Results and study arm information – Explain when and how participants will find out the results of the study, and when/how it is planned to reveal which arm of the study they have been on, where applicable
• What if something goes wrong? – Explain what will happen if something goes wrong during the study
• Withdrawal from the study – Explain what will happen if the participant does not want to carry on with the study
• Confidentiality – Explain whether and how the participant’s information will be kept confidential
• Use and publication of results – Explain what will happen to the results of the study
• Organization and funding – State who is organizing and funding the study
• Patient and public involvement – Explain how patients and the public have been involved in the study
• Review/approval – State who has reviewed and approved the study
• Further information and contact details
• Version control of the information sheet
• Consent process – Explain the consent process, including how consent will be sought and documented

Next, G-ConsentPIS indicates that a consent form should be used to record the consent process and the participant’s agreement to take part in the study. The form should be on headed paper or equivalent, including where consent is recorded electronically, and include the following information:

• Study identifiers – Study title and IRAS ID; a study identification number may also be included
• Site/participant identifiers
• Multiple consent forms – Clear labels if using more than one (1) consent form, for example for different types of participants or different UK nations
• Content of form – Information should be appropriate for the type of study and the participants involved
• PIS acknowledgement – A statement confirming that the participant has read the PIS, including its date and version number, and has had the opportunity to consider the information, ask questions, and receive satisfactory answers
• Voluntary participation and withdrawal – A statement that participation is voluntary and that the participant is free to withdraw at any time without giving a reason, and without medical care or legal rights being affected
• Access to medical notes/data – A statement that relevant sections of medical notes and study data may be looked at by individuals from the company or regulatory authorities, and that the participant gives permission for access to those records
• Future research/data sharing – Where appropriate, a statement that information collected about the participant will be used to support other research in the future and may be shared anonymously with other researchers
• General practitioner notification – Where appropriate, include a statement that the participant agrees to their General Practitioner being informed of their participation
• Agreement to participate – Include a clear statement that the participant agrees to take part in the study
• Specific agreement for each item – Provide a box after each item for participants to initial, tick, or answer “yes” or “no” to indicate specific agreement with each statement
• Legal representatives – If consent forms are used by legal representatives, ensure the language addresses them appropriately and makes clear that they are being asked to give consent on behalf of, or advice with respect to, a child/young person or adult lacking capacity
• Itemizing specific elements – For some studies, consider itemizing specific elements of consent so participants can clearly indicate agreement to particular parts of the study

See the G-ConsentPIS for examples and templates on various scenarios. For more information about informed consent required elements, see Cnst-Proprt, GBR-18, GBR-100, and GBR-69.

Regarding consent in good clinical practice (GCP), the MHCTR requires that all clinical trials must be conducted in accordance with the conditions and principles of GCP, including the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) GCP, as amended from time to time. ICH-UKimp indicates that the UK is implementing the ICH’s Guideline for Good Clinical Practice E6(R3) (GBR-91) and the ICH’s General Considerations for Clinical Studies E8(R1) (GBR-104), among others. As explained in the UKannot-ICH, the Medicines and Healthcare Products Regulatory Agency (MHRA) has issued UK-specific annotations—UKannot-E6R3 and UKannot-E8—which discuss consent requirements.

In addition, the MHCTR requires that clinical trials must be conducted in accordance with the principles of the Declaration of Helsinki (GBR-81) except where it would be a contravention of the MHCTR.

Overview

In accordance with the AU-ICH-GCP 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-GCP 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-GCP 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-GCP 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-GCP 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-GCP (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.

Overview

Per the REC-Policy, the ethics committee (EC) helps to ensure that proposed research conforms to recognized ethical standards, which includes respecting the dignity, rights, safety, and well-being of the people who will take part. The MHCTR requires that all clinical trials must be conducted in accordance with the conditions and principles of good clinical practice (GCP), including the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) GCP, as amended from time to time. ICH-UKimp indicates that the UK is implementing the ICH’s Guideline for Good Clinical Practice E6(R3) (GBR-91) and the ICH’s General Considerations for Clinical Studies E8(R1) (GBR-104), which address the rights laid out in this section. As explained in the UKannot-ICH, the Medicines and Healthcare Products Regulatory Agency (MHRA) has issued UK-specific annotations—UKannot-E6R3 and UKannot-E8—which discuss consent requirements.

In addition, the MHCTR requires that clinical trials must be conducted in accordance with the principles of the Declaration of Helsinki (GBR-81) except where it would be a contravention of the MHCTR.

The Right to Participate, Abstain, or Withdraw

As set forth in the MHCTR and the G-ConsentPIS, the participant 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 and the G-ConsentPIS, a potential research participant 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 UKannot-E6R3 and the UKannot-E8, confidentiality of information that could identify participants should be protected in accordance with the UK-GDPR, the UK-DPAct, and the G-GDPR.

The Right of Inquiry/Appeal

The MHCTR states that the research participant should be provided with contact information to obtain further information about the trial.

The Right to Safety and Welfare

The MHCTR requires the EC to ensure there are measures to protect and promote the interests of participants and the general public.

The AU-ICH-GCP 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-GCP, 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.

The MHCTR states that for minors or incapacitated adults who need urgent treatment, the usual informed consent requirements may not apply if urgent trial-related action is needed and it is not reasonably practicable to obtain consent first. Any such action must follow a procedure approved by the ethics committee (EC) when it gave its favorable opinion. As stated in the G-ConsentPIS and the Rsrch-Emrgcy, emergency research is when treatment needs to be given urgently, and it is necessary to take urgent action for the purposes of the study. In some emergency situations, potential participants may lack capacity to give consent themselves, and obtaining consent from a legal representative is not reasonably practicable. The United Kingdom (UK) allows adults and children not able to consent for themselves to be recruited into clinical trials of investigational medicinal products (CTIMPs) 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 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/guardian as soon as possible

The Rsrch-Emrgcy provides that adults may regain their capacity to give consent and should then be involved in the ongoing consent process. In most cases, it is appropriate to ask them to give their own consent when and if they are able. If investigators intend to ask participants who regain capacity for their ongoing consent, they should inform the legal representative/guardian of this at the outset of asking. In addition, an appropriate Participant Information Sheet and consent form should be prepared for the participants themselves.

Per the PubHlth-Emrgcy, in a public health emergency, fast-track approval is an option during exceptional circumstances (e.g., bird flu and Ebola). Fast-track ethics review is subject to the same scrutiny as other studies. Before an application can be made, the first step is to request fast-track approval by emailing Hra.approval@hra.nhs.uk with a summary of the study. See the Scope of Review section for more details.

The MHCTR requires that all clinical trials must be conducted in accordance with the conditions and principles of good clinical practice (GCP), including the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) GCP, as amended from time to time. ICH-UKimp indicates that the UK is implementing the ICH’s Guideline for Good Clinical Practice E6(R3) (GBR-91) and the ICH’s General Considerations for Clinical Studies E8(R1) (GBR-104), which address the rights laid out in this section. As explained in the UKannot-ICH, the Medicines and Healthcare Products Regulatory Agency (MHRA) has issued UK-specific annotations—UKannot-E6R3 and UKannot-E8—which discuss consent requirements.

See the G-ConsentPIS for additional UK-nation specific guidance and GBR-18 for additional resources.

Overview

The AU-ICH-GCP 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 upon 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.

Overview

As per the MHCTR, 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 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 should 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.

The MHCTR requires that all clinical trials must be conducted in accordance with the conditions and principles of good clinical practice (GCP), including the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) GCP, as amended from time to time. ICH-UKimp indicates that the UK is implementing the ICH’s Guideline for Good Clinical Practice E6(R3) (GBR-91) and the ICH’s General Considerations for Clinical Studies E8(R1) (GBR-104), which address the rights laid out in this section. As explained in the UKannot-ICH, the Medicines and Healthcare Products Regulatory Agency (MHRA) has issued UK-specific annotations—UKannot-E6R3 and UKannot-E8—which discuss consent requirements.

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

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-GCP 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

AUS-71 further states that 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. Additionally, AUS-80 indicates that refusal to assent or withdrawal of assent by a child should be respected. Over the course of a clinical study, it may be necessary to reassess the assent of a child in recognition of their advancing age, evolving maturity, and competency, especially for long-term studies or studies that may require sample retention. During clinical studies, it is required to obtain adequate informed consent for continued participation from pediatric participants once a child reaches the age of legal consent. Local regulations related to confidentiality and privacy of pediatric participants must be followed.

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.

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 G-ConsentPIS, GBR-4, and GBR-9, 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