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

This profile covers the role of the Department of Health & Human Services (HHS)’s Food & Drug Administration (FDA) in reviewing and authorizing investigational new drug applications (INDs) to conduct clinical trials using investigational drug or biological products in humans in accordance with the FDCAct, 21CFR50, and 21CFR312. Regulatory requirements for federally funded or sponsored human subjects research, known as the Common Rule (Pre2018-ComRule and RevComRule), which the HHS and its Office for Human Research Protections (OHRP) implements in subpart A of 45CFR46, are also examined. Lastly, additional HHS requirements included in subparts B through E of 45CFR46 are described in this profile, where applicable, using the acronym 45CFR46-B-E. (Please note: ClinRegs does not provide information on state-level requirements pertaining to clinical trials.)

Food & Drug Administration

As per the FDCAct, 21CFR50, and 21CFR312, the FDA is the regulatory authority that regulates clinical investigations of medical products in the United States (US). According to USA-92, the FDA is responsible for protecting public health by ensuring the safety, efficacy, and security of human and veterinary drugs, biological products, and medical devices.

An overview of the FDA structure is available in USA-33. Several centers are responsible for pharmaceutical and biological product regulation, including the Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER). Additionally, per USA-88, the Office of Clinical Policy (OCLP) develops clinical research policies, regulation, and guidance in collaboration with the FDA’s medical product centers.

Office for Human Research Protections and Common Rule Agencies

Per USA-93, the OHRP provides leadership in the protection of the rights, welfare, and well-being of human research subjects for studies conducted or supported by the HHS. The OHRP helps ensure this by providing clarification and guidance, developing educational programs and materials, maintaining regulatory oversight, and providing advice on ethical and regulatory issues in biomedical and social-behavioral research.

USA-65 states that the Common Rule (Pre2018-ComRule and RevComRule) outlines the basic provisions for institutional ethics committees (ECs) (referred to as institutional review boards (IRBs) in the US), informed consent, and Assurances of Compliance. See USA-18 and USA-65 for more information on US departments and agencies that follow the Common Rule, which are referred to as Common Rule departments/agencies throughout the profile.

The RevComRule applies to all human subjects research that is federally funded or sponsored by a Common Rule department/agency (as identified in USA-65), and: 1) was initially approved by an EC on or after January 21, 2019; 2) had EC review waived on or after January 21, 2019; or 3) was determined to be exempt on or after January 21, 2019. (Per USA-74, the RevComRule is also known as the “2018 Requirements.”) For 2018 Requirements decision charts consistent with the RevComRule, including how to determine if research is exempt, see USA-74. For more information about the RevComRule, see USA-66.

Per the RevComRule, the Pre2018-ComRule requirements apply to research funded by a Common Rule department/agency (as identified in USA-65) that, prior to January 21, 2019, was either approved by an EC, had EC review waived, or was determined to be exempt from the Pre2018-ComRule. Institutions conducting research approved prior to January 21, 2019 may choose to transition to the RevComRule requirements. The institution or EC must document and date the institution's determination to transition a study on the date the determination to transition was made. The research must comply with the RevComRule beginning on that date. For pre-2018 Requirements decision charts consistent with the Pre2018-ComRule, including how to determine if research is exempt, see USA-74.

USA-65 indicates that the FDA, despite being a part of the HHS, is not a Common Rule agency. Rather, the FDA is governed by its own regulations, including the FDCAct and 21CFR50. However, the FDA is required to harmonize with the Pre2018-ComRule and the RevComRule whenever permitted by law.

If a study is funded or sponsored by HHS, and involves an FDA-regulated product, then both sets of regulations will apply. See G-RevComRule-FDA for additional information.

International Alignment

Per USA-16, the US is a member of the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). The FDA has implemented the Guideline for Good Clinical Practice E6(R3) in US-ICH-GCP, along with other ICH guidance. See USA-19 for the implementation status of all ICH guidelines. Additionally, see USA-22 and USA-47 for links to ICH guidance documents implemented by the FDA.

Contact Information

Food & Drug Administration

As per USA-81, USA-90, and USA-91, the contact information for the FDA is as follows (Note: Each of the items listed below will not necessarily be found in all sources, which provide overlapping and unique elements):

Main FDA Telephone (general inquiries): (888) 463-6332

Food and Drug Administration
Center for Biologics Evaluation and Research (CBER)
10903 New Hampshire Avenue
Silver Spring, MD 20993-0002
CBER Telephone: (800) 835-4709 or (240) 402-8010
CBER Email (manufacturers assistance): Industry.Biologics@fda.hhs.gov
CBER Email (imports): CBERimportinquiry@fda.hhs.gov
CBER Email (exports): CBERExportCert@fda.hhs.gov

Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
Division of Drug Information
10903 New Hampshire Avenue
Building 51, Room 1109
Silver Spring, MD 20993
CDER Telephone (drug information): (301) 796-3400
CDER Email: druginfo@fda.hhs.gov

Office for Human Research Protections

Per USA-82, the contact information for the OHRP is as follows:

Office for Human Research Protections
1101 Wootton Parkway, Suite 200
Rockville, MD 20852
Telephone: (866) 447-4777 or (240) 453-6900
Email (general inquiries): OHRP@hhs.gov

Department of Health & Human Services

According to USA-83, the contact information for the HHS is as follows:

US Department of Health & Human Services
Hubert H. Humphrey Building
200 Independence Avenue, S.W.
Washington, D.C. 20201
Call Center: (877) 696-6775

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

Overview

In accordance with the FDCAct, 21CFR50, and 21CFR312, the Food & Drug Administration (FDA) has authority over clinical investigations for drug and biological products regulated by the agency. 21CFR312 specifies that the scope of the FDA’s assessment for investigational new drug applications (INDs) includes all clinical trials (Phases 1-4). Based on 21CFR56 and 21CFR312, institutional ethics committee (EC) review of the proposed clinical investigation may be conducted in parallel with the FDA review of the IND. However, EC approval must be obtained prior to the sponsor being permitted to initiate the clinical trial. (Note: Institutional ECs are referred to as institutional review boards (IRBs) in the United States (US)).

As delineated in 21CFR312 and USA-42, sponsors are required to submit an IND to the FDA to obtain an agency exemption to ship investigational drug(s) across state lines to conduct drug or biologic clinical trial(s). An IND specifically exempts an investigational drug or biologic from FDA premarketing approval requirements that would otherwise be applicable. 21CFR312 states that “‘IND’ is synonymous with ‘Notice of Claimed Investigational Exemption for a New Drug.’"

According to USA-42, the FDA categorizes INDs as either commercial or non-commercial (research) and classifies them into the following types:

• Investigator INDs - Submitted by physicians who both initiate and conduct the investigation, and who are directly responsible for administering or dispensing the investigational drug.

• Emergency Use INDs - Enable the FDA to authorize experimental drugs in an emergency situation where normal IND submission timelines cannot be met. Also used for patients who do not meet the criteria of an existing study protocol, or if an approved study protocol does not exist.

• Treatment INDs - Submitted for experimental drugs showing potential to address serious or immediately life-threatening conditions while the final clinical work is conducted and the FDA review takes place.

Per the G-PharmeCTD, non-commercial products refer to products not intended to be distributed commercially and include the above listed IND types.

As indicated in the G-IND-Determination, in general, human research studies must be conducted under an IND if all of the following research conditions apply:

• A drug is involved as defined in the FDCAct

• A clinical investigation is being conducted as defined in 21CFR312

• The clinical investigation is not otherwise exempt from 21CFR312

The G-IND-Determination states that biological products may also be considered drugs within the meaning of the FDCAct.

Further, per 21CFR312 and the G-IND-Determination, whether an IND is required to conduct an investigation of a marketed drug primarily depends on the intent of the investigation and the degree of risk associated with the use of the drug in the investigation. See 21CFR312 and the G-IND-Determination for detailed exemption conditions for marketed drugs.

Clinical Trial Review Process

As delineated in 21CFR312, the FDA's primary objectives in reviewing an IND are to ensure human participant safety and rights in all phases of the investigation. Phase 1 submission reviews focus on assessing investigation safety, and Phase 2 and 3 submission reviews also include an assessment of the investigation’s scientific quality and ability to yield data capable of meeting marketing approval statutory requirements. An IND may be submitted for one (1) or more phases of an investigation.

As per USA-41 and USA-94, the FDA’s Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER) receive IND submissions for drugs, therapeutic biological products, and other biologicals. Per the FDCAct and 21CFR312, an IND automatically goes into effect 30 calendar days from receipt, unless the FDA notifies the sponsor that the IND is subject to a clinical hold, or the FDA has notified the sponsor earlier that the trial may begin. A clinical hold is an order the FDA issues to delay or suspend a clinical investigation. If the FDA determines there may be grounds for imposing a clinical hold, an attempt will be made to discuss and resolve any issues with the sponsor prior to issuing the clinical hold order. See 21CFR312, the G-InvstgtrHold, and the G-HoldResp for more information on clinical holds.

According to USA-41, with respect to sponsor-investigators, once the FDA receives the IND, an IND number will be assigned and the application will be forwarded to the appropriate reviewing division. A letter will be sent to the sponsor-investigator providing notification of the assigned IND number, date of receipt of the original application, address where future submissions to the IND should be sent, and the name and telephone number of the FDA person to whom questions about the application should be directed.

As indicated in 21CFR312, the FDA may at any time during the course of the investigation communicate with the sponsor orally or in writing about deficiencies in the IND or about the FDA's need for more data or information. Furthermore, at the sponsor's request, the FDA will provide advice on specific matters relating to an IND.

21CFR312 indicates that once an IND is in effect, a sponsor must submit a protocol amendment if intending to conduct a study that is not covered by a protocol already contained in the IND, there is any change to the protocol that significantly affects the safety of subjects, or a new investigator is added to carry out a previously submitted protocol. A sponsor must submit a protocol amendment for a new protocol or a change in protocol before its implementation, while protocol amendments to add a new investigator or to provide additional information about investigators may be grouped and submitted at 30-day intervals. See 21CFR312 for more information on protocol amendments.

As per 21CFR312, if no subjects are entered into a clinical study for a period of two (2) years or more under an IND, or if all investigations under an IND remain on clinical hold for one (1) year or more, the IND may be placed by the FDA on inactive status. An IND that remains on inactive status for five (5) years or more may be terminated. See 21CFR312 for more information on inactive status.

21CFR312 indicates that the FDA may propose to terminate an IND based on deficiencies in the IND or in the conduct of an investigation under an IND. If the FDA proposes to terminate an IND, the agency will notify the sponsor in writing and invite correction or explanation within a period of 30 days. If at any time the FDA concludes that continuation of the investigation presents an immediate and substantial danger to the health of individuals, the FDA will immediately, by written notice to the sponsor, terminate the IND. See 21CFR312 for more information on FDA termination.

As stated in 21CFR312, the FDA will accept, as support for an IND, a well-designed and well-conducted foreign clinical study not conducted under an IND. The study must have been conducted in accordance with good clinical practice (GCP), and the FDA must be able to validate the data from the study through an onsite inspection if the agency deems it necessary. Although the FDA will not accept a study that does not meet those conditions as support for an IND, the FDA will still examine data from such a study. See 21CFR312 and the G-FrgnCT for more details on submitting data from a foreign clinical study not conducted under an IND as support for an IND.

For more information on CDER and CBER internal policies and procedures for accepting and reviewing applications, see USA-96 and USA-95, respectively.

Per the G-BiorsrchInspct, the FDA developed a Bioresearch Monitoring (BIMO) program to assess the quality and integrity of data submitted to the FDA in support of regulatory decision-making, as well as to provide for protection of the rights, safety, and welfare of human trial participants involved in FDA-regulated research. The BIMO program, which involves on-site inspections, investigations, and remote regulatory assessments, assesses compliance with statutory requirements and the FDA’s regulations governing the conduct of nonclinical and clinical studies, as well as applicable postmarketing activities. See the G-BiorsrchInspct and USA-20 for more information on FDA inspections and the BIMO program.

Expedited Processes

USA-84 further indicates that the FDA has several approaches to making drugs available as rapidly as possible:

• Breakthrough Therapy – expedites the development and review of drugs which may demonstrate substantial improvement over available therapy
• Accelerated Approval – allow drugs for serious conditions that fill an unmet medical need to be approved based on a surrogate endpoint
• Priority Review – a process by which the FDA’s goal is to take action on an application within six (6) months
• Fast Track – facilitates the development and expedites the review of drugs to treat serious conditions and fill an unmet medical need

See USA-84 and USA-85 for more information on each process. Additionally, see the FDCAct, as amended by the FDORA, for changes to the accelerated approval process.

Other Considerations

The G-RWDRWE-Reg, issued as part of the FDA’s Real-World Evidence (RWE) Program (see USA-17), discusses the applicability of the 21CFR312 IND regulations to various clinical study designs that utilize real-world data (RWD). See the G-RWDRWE-Reg for more information.

For information on the appropriate use of adaptive designs for clinical trials and additional information to provide the FDA to support its review, see G-AdaptiveTrials. Additionally, see the G-ExplrtryIND for FDA guidance regarding exploratory studies in humans.

For research involving cellular and gene therapy, see the guidance documents at USA-80.

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.

Food & Drug Administration

The Food & Drug Administration (FDA) does not levy a fee to review investigational new drug submissions.

However, per the FDCAct, the FDARA, and USA-45, the FDA has the authority to collect user fees from persons that submit certain human drug applications for review or that are named in approved applications as the sponsor of certain prescription drug products. See USA-45 for more information.

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

As indicated in 21CFR50, 21CFR56, and 21CFR312, the United States (US) has a decentralized process for the ethics review of clinical investigations. The sponsor must obtain institutional level ethics committee (EC) approval for each study. (Note: Institutional ECs are referred to as institutional review boards (IRBs) in the US.)

As set forth in 21CFR50, 21CFR56, and 21CFR312, all clinical investigations for drug and biological products regulated by the Food & Drug Administration (FDA) require institutional EC approval.

The Pre2018-ComRule and the RevComRule also require that human subjects research receive institutional EC approval. However, note that these regulations’ definition of “human subject” does not include the use of non-identifiable biospecimens. Therefore, the use of non-identifiable biospecimens in research does not, on its own, mandate the application of the Pre2018-ComRule to such research. However, the RevComRule does require federal departments or agencies implementing the policy to work with data experts to reexamine the meaning of “identifiable private information” and “identifiable specimen” within one (1) year of the effective date and at least every four (4) years thereafter. In particular, these agencies will collaboratively assess whether there are analytic technologies or techniques that could be used to generate identifiable private information or identifiable specimens.

(See USA-18 and USA-65 for more information on Common Rule departments/agencies, and the Regulatory Authority section for additional guidance on when the Pre2018-ComRule and the RevComRule apply to research.)

Per the RevComRule, for non-exempt research (or exempt research that requires limited EC review) reviewed by an EC not operated by the institution doing the research, the institution and the EC must document the institution's reliance on the EC for research oversight and the responsibilities that each entity will undertake to ensure compliance with the RevComRule. Compliance can be achieved in a variety of ways, such as a written agreement between the institution and a specific EC, through the research protocol, or by implementing an institution-wide policy directive that allocates responsibilities between the institution and all ECs not operated by the institution. Such documentation must be part of the EC’s records. The G-HHS-Inst-Engagemt can help an institution to determine if a research study can be classified as non-exempt.

Also see the International Council for Harmonisation’s Guideline for Good Clinical Practice E6(R3), which the FDA has implemented in US-ICH-GCP, for additional guidance on EC composition, functions, and operations.

Ethics Committee Composition

As stated in 21CFR56, the Pre2018-ComRule, and the RevComRule, an EC must be composed of at least five (5) members with varying backgrounds to promote complete and adequate research proposal review. The EC must be sufficiently qualified through member experience, expertise, and diversity, in terms of race, gender, cultural backgrounds, and sensitivity to issues such as community attitudes, to promote respect for its advice and counsel in safeguarding human participants’ rights and welfare. EC members must possess the professional competence to review research activities and be able to ascertain the acceptability of proposed research based on institutional commitments and regulations, applicable laws, and standards. In addition, if an EC regularly reviews research involving vulnerable populations, the committee must consider including one (1) or more individuals knowledgeable about and experienced in working with those participants. See the Vulnerable Populations section for details on vulnerable populations.

At a minimum, each EC must also include the following members:

• One (1) primarily focused on scientific issues
• One (1) focused on nonscientific issues
• One (1) unaffiliated with the institution, and not part of the immediate family of a person affiliated with the institution

No EC member may participate in the initial or continuing review of any project in which the member has a conflicting interest, except to provide EC requested information.

Additionally, 21CFR56 indicates that efforts must be made to ensure that no EC consists entirely of men or entirely of women, including the institution’s consideration of qualified persons of both sexes, so long as no selection is made to the EC on the basis of gender. No EC may consist entirely of members of one (1) profession.

Terms of Reference, Review Procedures, and Meeting Schedule

As delineated in 21CFR56, ECs must follow written procedures for the following:

• Conducting initial and continuing reviews, and reporting findings and actions
• Determining which projects require review more often than annually, and which projects need verification from sources other than the investigator that no material changes have occurred since the previous EC review
• Ensuring that changes in approved research are not initiated without EC review and approval except where necessary to eliminate apparent immediate hazards to participants
• Ensuring prompt reporting to the EC, institution, and FDA of changes in research activity; unanticipated problems involving risks to participants or others; any instance of serious or continuing noncompliance with these regulations or EC requirements or determinations; or EC approval suspension/termination

Per the Pre2018-ComRule and the RevComRule, ECs must establish and follow written procedures for the following:

• Conducting initial and continuing reviews, and reporting findings and actions to the investigator and the institution
• Determining which projects require review more often than annually, and which projects need verification from sources other than the investigator that no material changes have occurred since the previous EC review
• Ensuring prompt reporting to the EC of proposed changes in research and ensuring that investigators conduct the research in accordance with the terms of the EC approval until any proposed changes have received EC review and approval, except where necessary to eliminate apparent immediate hazards to participants
• Ensuring prompt reporting to the EC, the institution, and the Department of Health & Human Services (HHS)’ Office for Human Research Protections (OHRP) of any unanticipated problems involving risks to participants or others; any instance of serious or continuing noncompliance with these regulations or EC requirements or determinations; or EC approval suspension/termination

21CFR56, the Pre2018-ComRule, and the RevComRule further require that an institution, or where appropriate an EC, prepare and maintain adequate documentation of EC activities, including copies of all research proposals reviewed. The applicable records must be retained for at least three (3) years after completion of the research. For more details on the EC records included in this requirement, see the Pre2018-ComRule, the RevComRule, and 21CFR56.

See G-IRBProcs for detailed FDA guidance on EC written procedures to enhance human participant protection and reduce regulatory burden. The guidance includes a Written Procedures Checklist that incorporates regulatory requirements as well as recommendations on operational details to support the requirements.

Per 21CFR56, the Pre2018-ComRule, and the RevComRule, proposed research must be reviewed during convened meetings at which a majority of the EC members are present, including at least one (1) member whose primary concerns are nonscientific, except when an expedited review procedure is used. Research is only considered approved if it receives the majority approval of attending members.

Refer to the Pre2018-ComRule, the RevComRule, 21CFR56, the G-IRBProcs, and the G-IRBFAQs for detailed EC procedural requirements.

In addition, per the Pre2018-ComRule, the RevComRule, and the G-HHS-Inst-Engagemt, any institution engaged in non-exempt human subjects research conducted or supported by a Common Rule department/agency (as identified in USA-65) must also submit a written assurance of compliance to OHRP. According to USA-59, the Federalwide Assurance (FWA) is the only type of assurance of compliance accepted and approved by OHRP for HHS-supported or conducted non-exempt human subjects research. See USA-57 for more information on FWAs.

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.

Overview

21CFR56, 21CFR312, the Pre2018-ComRule, and the RevComRule state that the primary scope of information assessed by the institutional ethics committee (EC) (referred to as an institutional review board (IRB) in the United States (US)) relates to maintaining and protecting the dignity and rights of research participants and ensuring their safety throughout their participation in a clinical trial. As delineated in 21CFR56, the Pre2018-ComRule, and the RevComRule, the EC must also pay special attention to reviewing informed consent and to protecting the welfare of certain classes of participants deemed to be vulnerable. (See the Vulnerable Populations; Children/Minors; Pregnant Women, Fetuses, & Neonates; Prisoners; and Mentally Impaired sections for additional information about these populations). The EC is also responsible for ensuring a competent review of the research protocol, evaluating the possible risks and expected benefits to participants, and verifying the adequacy of confidentiality safeguards.

See USA-18 and USA-65 for more information on Common Rule departments/agencies, and the Regulatory Authority section for additional guidance on when the Pre2018-ComRule and the RevComRule apply to research.

Also see the International Council for Harmonisation’s Guideline for Good Clinical Practice E6(R3), which the Food & Drug Administration (FDA) has implemented in US-ICH-GCP, for additional EC responsibilities and requirements.

Role in Clinical Trial Approval Process

In accordance with 21CFR56 and 21CFR312, the FDA must review an investigational new drug application (IND) and an EC must review and approve the proposed study prior to a sponsor initiating a clinical trial. The institutional EC review of the clinical investigation may be conducted in parallel with the FDA review of the IND. However, EC approval must be obtained prior to the sponsor being permitted to initiate the clinical trial. According to 21CFR56, the Pre2018-ComRule, and the RevComRule, the EC may approve, require modifications in (to secure approval), or disapprove the research.

21CFR56, the Pre2018-ComRule, and the RevComRule indicate that the EC must ensure the following requirements are met prior to approving the study:

• Risks to participants are minimized and are reasonable in relation to anticipated benefits
• Participant selection is equitable
• Informed consent will be sought from each prospective participant or legal representative/guardian, and will be appropriately documented (the RevComRule also requires information regarding whether informed consent was appropriately waived)
• The research plan makes adequate provision for monitoring the data collected to ensure the safety of participants, where appropriate
• Adequate provisions are made to protect participant privacy and maintain confidentiality of data, where appropriate (per the RevComRule, the Department of Health & Human Services (HHS) will issue guidance to assist ECs in assessing what provisions are adequate to protect participant privacy and maintain the confidentiality of data)

Per the RevComRule, where limited EC review applies, the EC does not need to make the determinations outlined above. Rather, limited EC review includes determinations that broad consent will be/was obtained properly, that adequate protections are in place for safeguarding the privacy and confidentiality of participants, and (for secondary studies) that individual research results will not be returned to participants. See USA-18 and USA-65 for more information on Common Rule departments/agencies, and the Regulatory Authority section for additional guidance on when the Pre2018-ComRule and the RevComRule apply to research.

See 21CFR56, the Pre2018-ComRule, and the RevComRule for additional details on criteria for EC approval of research.

Refer to the G-RevComRule-FDA for information on the impact of the RevComRule on studies conducted or supported by the HHS that must also comply with FDA regulations.

21CFR56, the Pre2018-ComRule, and the RevComRule indicate that changes in approved research may not be initiated without EC review and approval except where necessary to eliminate apparent immediate hazards to participants.

Per 21CFR56, the Pre2018-ComRule, the RevComRule, and the G-IRBContRev, an EC has the authority to suspend or terminate approval of research that is not being conducted in accordance with the EC’s requirements or that has been associated with unexpected serious harm to participants. Any suspension or termination of approval will include a statement of the reasons for the EC’s action and will be reported promptly to the investigator, appropriate institutional officials, and the department or agency head (e.g., the FDA). See the G-IRBContRev for additional information and FDA recommendations on suspension or termination of EC approval.

See the G-IRBResp for FDA guidance for ECs on reviewing the adequacy of investigators and research sites, and determining if an IND or investigational device exemption is required. The FDA’s G-SubRecruit also provides guidance for ECs on reviewing participant recruitment methods.

Per the FDA’s G-IRBReview, an EC may review studies that are not performed on-site. When an institution has a local EC, the written procedures of that EC or of the institution should define the scope of studies subject to review by that EC. A non-local EC may not become the EC of record for studies within that defined scope unless the local EC or the administration of the institution agree. Any agreement to allow review by a non-local EC should be in writing. For more information, see G-IRBReview.

As stated in the G-IRBWaiver, sponsors and sponsor-investigators may request a waiver of EC requirements for drug and biological product studies regulated by the FDA. The most common circumstance for which the FDA receives a waiver request is when a sponsor wishes to conduct a foreign clinical study under an IND. In this case, typically sponsors utilize an independent ethics committee (IEC) that operates in accordance with good clinical practice (GCP). See the G-IRBWaiver for more information.

Additionally, see the G-IRBTransfer for FDA guidance on the regulatory responsibilities of ECs, clinical investigators, and sponsors when oversight of a previously approved, ongoing clinical investigation under the FDA’s jurisdiction is transferred from one (1) EC to another EC.

Expedited Review

21CFR56, the Pre2018-ComRule, and the RevComRule indicate that the FDA and HHS maintain a list of research categories that may be reviewed by an EC through an expedited review procedure (see the G-IRBExpdtdRev for the list). An EC may use the expedited review procedure to review the following:

• Some or all of the research appearing on the list and found by the reviewer(s) to involve no more than minimal risk
• Minor changes in previously approved research during the period (of one (1) year or less) for which approval is authorized
• Under the RevComRule, research for which limited EC review is a condition of exemption

21CFR56, the Pre2018-ComRule, and the RevComRule specify that under an expedited review procedure, the review may be carried out by the EC chairperson or by one (1) or more experienced reviewers designated by the chairperson from among the EC’s members. In reviewing the research, the reviewers may exercise all of the authorities of the EC except that the reviewers may not disapprove the research. A research activity may be disapproved only after review in accordance with the EC’s non-expedited review procedure.

Continuing Review and Re-approval

21CFR56 and the G-IRBContRev state that any clinical investigation must not be initiated unless the reviewed and approved study remains subject to continuing review at intervals appropriate to the degree of risk, but not less than once a year. The G-IRBContRev notes that when continuing review of the research does not occur prior to the end of the approval period specified by the EC, EC approval expires automatically. A lapse in EC approval of research occurs whenever an investigator has failed to provide continuing review information to the EC, or the EC has not conducted continuing review and re-approved the research by the expiration date of the EC approval. In such circumstances, all research activities involving human participants must stop. Enrollment of new participants cannot occur after the expiration of EC approval.

In addition, per the G-IRBContRev, research that qualified for expedited review at the time of initial review will generally continue to qualify for expedited continuing review. For additional information and FDA recommendations regarding continuing review, see the G-IRBContRev.

The Pre2018-ComRule similarly indicates that the EC must conduct reviews at intervals appropriate to the degree of risk, but not less than once per year. However, the RevComRule provides the following exceptions to the continuing review requirement, unless an EC determines otherwise:

• Research eligible for expedited review
• Research reviewed by the EC in accordance with the limited EC review described in Section 46.104 of the RevComRule
• Research that has progressed to the point that it involves data analysis and/or accessing follow-up clinical data from procedures that are part of clinical care

Exemptions under the Revised Common Rule

Per the RevComRule, certain categories of research are exempt from EC review, and some “exempt” activities require limited EC review or broad consent. Users should refer to Section 46.104 of the RevComRule for detailed information on research categories specifically exempt from EC review, or exempt activities requiring limited EC review or broad consent.

Further, the RevComRule modifies what constitutes research to specifically exclude the following types of research:

• Scholarly and journalistic activities
• Public health surveillance activities authorized by a public health authority to assess onsets of disease outbreaks or conditions of public health importance
• Collection and analysis of information, biospecimens, or records by or for a criminal justice agency for criminal investigative activities
• Authorized operational activities in support of intelligence, homeland security, defense, or other national security missions

USA-32 notes that the regulations do not specify who at an institution may determine that research is exempt, and that institutions should implement exemption policies that most effectively address the local setting and programs of research. The HHS retains final authority as to whether a particular human subjects research study conducted or supported by HHS is exempt.

See the G-IRBFAQs, the G-OHRP-IRBApprvl, and USA-32 for frequently asked questions regarding EC procedures, approval with conditions, example research, expedited review, limited review, continuing review, and exempt research.

Cooperative Research Studies

In the event of multicenter clinical studies, also known as cooperative research studies, taking place at US institutions that are subject to the RevComRule, the institutions must rely on a single EC to review that study for the portion of the study conducted in the US. The reviewing EC will be identified by the Common Rule department/agency (as identified in USA-18 and USA-65) supporting or conducting the research or proposed by the lead institution subject to the acceptance of the department/agency. The exceptions to this requirement include: when multicenter review is required by law (including tribal law) or for research where any federal department or agency supporting or conducting the research determines that the use of a single EC is not appropriate.

Designed to complement the RevComRule, per the NIHNotice16-094 and the NIHNotice17-076, the National Institutes of Health (NIH) issued a final policy requiring all institute-funded multicenter clinical trials conducted in the US to be overseen by a single EC, unless prohibited by any federal, tribal, or state law, regulation, or policy.

For more information on multicenter research, see the FDA’s G-CentralIRB and G-CoopRes. For more information on how new sites added to ongoing cooperative research can follow the same version of the Common Rule, see the HHS’ Office for Human Research Protections (OHRP)’s G-ComRuleCnsstncy.

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.

Many institutional ethics committees (ECs) (referred to as institutional review boards (IRBs) in the United States (US)) charge fees to review research proposals submitted by industry-sponsored research or other for-profit entities. However, this varies widely by institution. Neither the Department of Health & Human Services (HHS) nor the Food & Drug Administration (FDA) regulate institutional EC review fees. Because each EC has its own requirements, individual ECs should be contacted to confirm their specific fees.

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

As delineated in 21CFR56 and 45CFR46-B-E, the Department of Health & Human Services (HHS) and the HHS’ Food & Drug Administration (FDA) have mandatory registration programs for institutional ethics committee (ECs), referred to as institutional review boards (IRBs) in the United States (US). A single electronic registration system (USA-28) for both agencies is maintained by HHS’ Office for Human Research Protections (OHRP).

Registration, Auditing, and Accreditation

In accordance with the G-IRBReg-FAQs and USA-61, EC registration with the HHS OHRP system (USA-28) is not a form of accreditation or certification by either the FDA that the EC is in full compliance with 21CFR56, or by the HHS that the EC is in full compliance with 45CFR46-B-E. Neither EC competence nor expertise is assessed during the registration review process by either agency.

Food & Drug Administration

According to 21CFR56 and the G-IRBReg-FAQs, the FDA requires each EC in the US, that either reviews clinical investigations regulated by the agency under the FDCAct or reviews investigations intended to support research or marketing permits for agency-regulated products, to register electronically in the HHS OHRP system (USA-28). Only individuals authorized to act on the EC’s behalf are permitted to submit registration information. Non-US ECs may register voluntarily. The G-IRBReg-FAQs also indicates that while registration of non-US ECs is voluntary, the information the FDA receives from them is very helpful.

As stated in 21CFR56 and the G-IRBReg-FAQs, any EC not already registered in the HHS OHRP system (USA-28) must submit an initial registration prior to reviewing a clinical investigation in support of an investigational new drug application (IND). The HHS OHRP system (USA-28) provides instructions to assist users, depending on whether the EC is subject to regulation by only the OHRP, only the FDA, or both the OHRP and the FDA.

21CFR56 and the G-IRBReg-FAQs indicate that FDA EC registration must be renewed every three (3) years. EC registration becomes effective after review and acceptance by the HHS.

See 21CFR56 and the G-IRBReg-FAQs for detailed EC registration submission requirements.

Office for Human Research Protections

Per the Pre2018-ComRule and RevComRule, institutions engaging in research conducted or supported by a Common Rule department/agency (as identified in USA-18 and USA-65) must obtain an approved assurance that it will comply with the Pre2018-ComRule or RevComRule requirements and certify to the department/agency heads that the research has been reviewed and approved by an EC provided for in the assurance.

Per USA-59, a Federalwide Assurance (FWA) of compliance is a document submitted by an institution (not an EC) engaged in non-exempt human subjects research conducted or supported by HHS that commits the institution to complying with Pre2018-ComRule or RevComRule requirements. FWAs also are approved by the OHRP for federalwide use, which means that other federal departments and agencies that have adopted the Federal Policy for the Protection of Human Subjects (Pre2018-ComRule or RevComRule) may rely on the FWA for the research that they conduct or support. Institutions engaging in research conducted or supported by non-HHS federal departments or agencies should consult with the sponsoring department or agency for guidance regarding whether the FWA is appropriate for the research in question.

See USA-57 for more information on FWAs.

As stated in 45CFR46-B-E and USA-61, all ECs that review human subjects research conducted or supported by HHS and are to be designated under an OHRP FWA must register electronically with the HHS OHRP system (USA-28). EC registration becomes effective for three (3) years when reviewed and approved by OHRP. Per 45CFR46-B-E, an individual authorized to act on behalf of the institution operating the EC must submit the registration information.

Per USA-59, an institution must either register its own EC (an “internal” EC) or designate an already registered EC operated by another organization (“external” EC) after establishing a written agreement with that other organization. Additionally, each FWA must designate at least one (1) EC registered with the OHRP. The FWA is the only type of assurance of compliance accepted and approved by the OHRP.

See 45CFR46-B-E, USA-58, and USA-61 for detailed registration requirements and instructions.

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.

Overview

As delineated in 21CFR312, USA-42, and USA-52, the United States (US) requires the sponsor to submit an investigational new drug application (IND) for the Food & Drug Administration (FDA)'s review and authorization to obtain an exemption to ship investigational drug or biological products across state lines and to administer these investigational products in humans. Per 21CFR312 and the G-IND-Determination, whether an IND is required to conduct an investigation of a drug to be marketed (this includes biological products under the FDCAct) primarily depends on the intent of the investigation, and the degree of risk associated with the use of the drug in the investigation. See the Scope of Assessment section for more information.

In addition, per 21CFR56 and 21CFR312, institutional ethics committee (EC) (institutional review board (IRB) in the US) review of the clinical investigation may be conducted in parallel with the FDA review of the IND. However, EC approval must be obtained prior to the sponsor being permitted to initiate the clinical trial.

Regulatory Submission

According to 21CFR312, meetings between a sponsor and the FDA may be useful in resolving questions and issues raised during the course of a clinical investigation. The FDA encourages such meetings to the extent that they aid in the evaluation of the drug and in the solution of scientific problems concerning the drug, to the degree the FDA's resources permit. See 21CFR312 for more information on meetings with the FDA.

A sponsor who is conducting a clinical trial to support a future marketing application may ask to meet with the FDA for a special protocol assessment (SPA) to help ensure the clinical trial can support the application. For more information, see G-SPA.

Additionally, the G-FDAComm describes the FDA’s philosophy regarding timely interactive communication with IND sponsors, the scope of appropriate interactions between review teams and sponsors, the types of advice appropriate for sponsors to seek from the FDA in pursuing their drug development programs, and general expectations for the timing of FDA response to sponsor inquiries. See the G-FDAComm for more information.

According to the G-PharmeCTD, which implements FDCAct requirements, and as described in USA-34 and USA-53, commercial IND submissions must be submitted in the Electronic Common Technical Document (eCTD) format. Noncommercial INDs are exempt from this eCTD format submission requirement. “Noncommercial products” refer to products not intended to be distributed commercially, including investigator-sponsored INDs and expanded access INDs (e.g., emergency use and treatment INDs). However, the G-AltrntElecSubs indicates that sponsors and applicants who receive an exemption or a waiver from filing in eCTD format should still provide those exempted or waived submissions electronically, in an alternate format.

As stated in USA-34, the electronic submission of eCTD v4.0 to the FDA’s Center for Drug Evaluation and Research (CDER) or Center for Biologics Evaluation and Research (CBER) is supported for new INDs, as well as certain other submission types, beginning September 16, 2024. Only new applications may be submitted in v4.0, and forward compatibility functionality is not yet available. Electronic submissions made in eCTD format must utilize either v3.2.2 or v4.0, which are both currently supported by the FDA.

The G-AltrntElecSubs and USA-35 indicate that for both eCTD and alternate electronic formats, submissions should include only FDA fillable forms and electronic signatures. Scanned images of FDA fillable forms should not be submitted. In addition, before making an electronic submission, a pre-assigned application number should be obtained by contacting CBER or CDER. See USA-35 for more information on requesting an application number.

For more information and detailed requirements on eCTD submissions, see the G-PharmeCTD, USA-34, USA-35, and USA-36. Additionally, the G-CBER-ElecINDs provides instructions on how to submit an IND using an electronic folder structure on a CD-ROM.

According to the G-eCTDspecs, eCTD submissions sized 10 GB and under for most applications must be submitted via the Electronic Submissions Gateway (ESG), and the FDA also recommends the use of the ESG for submissions greater than 10 GB when possible. However, USA-44 specifies that the Electronic Submissions Gateway Next Generation (ESG NextGen) should be utilized for all electronic submissions to the FDA. See USA-102 for the ESG NextGen Unified Submission Portal (USP) Login and USA-37 for ESG NextGen submission user guides.

As indicated in the G-eCTDspecs, the FDA also accepts physical electronic media on a USB drive for submissions greater than 10 GB. For specific instructions on how to submit physical electronic media, email CDER at esub@fda.hhs.gov or CBER at esubprep@fda.hhs.gov. See the G-eCTDspecs for additional physical electronic media information.

The IND must be submitted in English. As indicated in 21CFR312, the sponsor must submit an accurate and complete English translation of each part of the IND that is not in English. The sponsor must also submit a copy of each original literature publication for which an English translation is submitted.

Based on information provided in 21CFR312, for paper IND submissions, the sponsor must submit an original and two (2) copies, including the original submission and all amendments and reports. According to USA-41 and USA-94, paper submissions of INDs should be sent to CDER or CBER at the following locations, as appropriate:

Drugs (submitted by Sponsor-Investigators):

Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
Central Document Room
5901-B Ammendale Rd.
Beltsville, MD 20705-1266

Therapeutic Biological Product (submitted by Sponsor-Investigators):

Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
Therapeutic Biological Products Document Room
5901-B Ammendale Rd.
Beltsville, MD 20705-1266

Center for Biologics Evaluation and Research-Regulated Products:

Food and Drug Administration
Center for Biologics Evaluation and Research (CBER)
Document Control Center
10903 New Hampshire Avenue
WO71, G112
Silver Spring, MD 20993-0002

(Note: Per USA-94, CBER also accepts electronic media via mail, but electronic or email submission is preferred.)

For more information on CDER and CBER internal policies and procedures for accepting and reviewing applications, see USA-96 and USA-95, respectively.

Ethics Review Submission

Each EC maintains its own procedures and processes for review. Consequently, there is no stated regulatory requirement for clinical trial submission processes.

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.

Regulatory Authority Requirements

As specified in 21CFR312, an investigational new drug application (IND) to the Food & Drug Administration (FDA) must include the following documents, in the order provided below:

• Cover sheet (Form FDA 1571 (USA-76)) (including, but not limited to: sponsor contact information, investigational product (IP) name, application date, phase(s) of clinical investigation to be conducted, and commitment that the institutional ethics committee (EC) (institutional review board (IRB) in the United States (US)) will conduct initial and continuing review and approval of each study proposed in the investigation)
• Table of contents
• Introductory statement and general investigational plan
• Investigator’s brochure (IB)
• Protocols
• Chemistry, manufacturing, and control data
• Pharmacology and toxicology data
• Previous human experience with the IP
• Additional information (e.g., drug dependence and abuse potential, radioactive drugs, pediatric studies)
• Relevant information (e.g., foreign language materials and number of copies - see Submission Process section for details)

For detailed application requirements, see 21CFR312. In addition, see USA-40 for other IND forms and instructions. Also see USA-100 for Phase 1 IND resources, and USA-39 for information on first in human Phase 1 INDs.

Furthermore, for information on the appropriate use of adaptive designs for clinical trials and additional information to provide to the FDA to support its review, see G-AdaptiveTrials.

The G-RWDRWE-Doc states that to facilitate the FDA’s internal tracking of submissions that include real-world data (RWD) and real-world evidence (RWE), sponsors and applicants are encouraged to identify in their submission cover letters certain uses of RWD/RWE. For more information, see the G-RWDRWE-Doc.

According to the G-PedStudyPlans, a sponsor who is planning to submit to the FDA a marketing application (or supplement to an application) for a new active ingredient, new indication, new dosage form, new dosing regimen, or new route of administration is required to submit an initial pediatric study plan (iPSP), if required by the Pediatric Research Equity Act (PREA). An exception to this is if the drug is for an indication granted an orphan designation. For additional details and recommendations to sponsors regarding the submission of an iPSP, see the G-PedStudyPlans.

See 21CFR312 and the G-IPCharge for additional submission requirements if a sponsor is seeking FDA authorization to charge for the use of its own IP in a clinical trial.

Ethics Committee Requirements

Each EC has its own application form and clearance requirements, which can differ regarding application content requirements.

Clinical Protocol

Per the NIHNotice17-064, and as provided in USA-29 and USA-27, the National Institutes of Health (NIH) and the FDA developed a clinical trial protocol template with instructional and example text for NIH-funded investigators to use when writing protocols for phase 2 and 3 clinical trials that require IND applications.

Additionally, the G-DecentralCT provides FDA recommendations for clinical trials with decentralized elements. According to the G-DecentralCT, the protocol should include specific instructions for limiting variability in the data collected. The protocol should specify which visits will be conducted at traditional clinical trial sites, which visits will be conducted remotely, and which visits can be left to participants’ choice. See the G-DecentralCT for additional guidance.

Also see the International Council for Harmonisation’s Guideline for Good Clinical Practice E6(R3), which the FDA has implemented in US-ICH-GCP, for additional guidance on clinical protocol contents.

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

As delineated in 21CFR56 and 21CFR312, institutional ethics committee (EC) (institutional review board (IRB) in the United States (US)) review of the clinical investigation may be conducted in parallel with the Food & Drug Administration (FDA)'s review of the investigational new drug application (IND). However, EC approval must be obtained prior to the sponsor being permitted to initiate the clinical trial.

Regulatory Authority Approval

Per the FDCAct and 21CFR312, initial INDs submitted to the FDA’s Center for Drug Evaluation and Research (CDER) or Center for Biologics Evaluation and Research (CBER) automatically go into effect in 30 calendar days, unless the FDA notifies the sponsor that the IND is subject to a clinical hold, or the FDA has notified the sponsor earlier that the trial may begin. As indicated in 21CFR312, the FDA will provide the sponsor with a written explanation of the basis for the hold as soon as possible, and no more than 30 days after the imposition of the clinical hold. See 21CFR312 for more information on clinical hold timelines. For more information on CDER and CBER internal policies and procedures for reviewing applications, see USA-96 and USA-95, respectively.

According to USA-41 and USA-42, clinical studies must not be initiated until 30 days after the FDA receives the IND, unless the FDA provides earlier notification that studies may begin.

Ethics Committee Approval

Each EC maintains its own procedures and processes for review. Consequently, there is no stated regulatory requirement for a standard timeline of review and approval of the clinical trial.

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.

Overview

In accordance with 21CFR312, USA-41, and USA-42, a clinical trial can only commence after the investigational new drug application (IND) is reviewed by the Food & Drug Administration (FDA), which will provide a written determination within 30 days of receiving the IND. No waiting period is required following the 30-day FDA review period, unless the agency imposes a clinical hold on the IND or sends an earlier notification that studies may begin. Per 21CFR312 and 21CFR56, ethics approval from an institutional ethics committee (EC) (known as institutional review board (IRB) in the United States (US)) is also required before a clinical trial can commence.

As per 21CFR312, once an IND has been submitted and following the 30-day review period, the sponsor is permitted to import an investigational product (IP). (See the Manufacturing & Import section for additional information).

See the G-CTPrtcptn for FDA guidance on enrollment practices to enhance participation in clinical trials.

Clinical Trial Agreement

Prior to the trial’s commencement, as addressed in the 21CFR312 and the G-1572FAQs, the sponsor must obtain from the investigator(s) a signed Statement of Investigator, Form FDA 1572 (USA-77). This form serves as the investigator’s agreement to provide certain information to the sponsor and to ensure compliance with the FDA’s clinical investigation regulations. Refer to the 21CFR312, the G-1572FAQs, and USA-40 for further information.

Also see the International Council for Harmonisation’s Guideline for Good Clinical Practice E6(R3), which the FDA has implemented in US-ICH-GCP, for additional guidance on clinical trial agreements.

Clinical Trial Registration

The FDAMA, the FDAAA, and 42CFR11 require the responsible party, either the sponsor or the principal investigator (PI) designated by the sponsor, to register electronically with the ClinicalTrials.gov databank (USA-78). Per the FDAAA and 42CFR11, the sponsor/PI must register no later than 21 calendar days after the first human participant is enrolled in a trial.

42CFR11 expands the legal requirements for submitting clinical trial registration information and results for investigational products that are approved, licensed, or cleared by the FDA. See the G-3674Cert for additional FDA guidance on certifying compliance with applicable requirements, including the requirement to register applicable clinical trials.

The National Institutes of Health (NIH) issued NIHTrialInfo to complement 42CFR11 requirements. This policy requires all NIH-funded awardees and investigators conducting clinical trials, funded in whole or in part by the NIH, regardless of study phase, type of intervention, or whether they are subject to the regulation, to ensure that they register and submit trial results to ClinicalTrials.gov (USA-78). See USA-98 for the NIH’s definition of a clinical trial.

See 42CFR11, the NIHTrialInfo, and USA-49 for detailed information on ClinicalTrials.gov (USA-78). See also the FDA’s G-DataBankPnlty for clarification on the types of civil money penalties that may be issued for failing to register a clinical trial.

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.

Safety Reporting Definitions

In accordance with 21CFR312, the G-SpnsrRpt, the G-InvstRpt, the US-ICH-E2A, 42CFR11, and USA-99, the following definitions provide a basis for a common understanding of safety reporting requirements in the United States (US) (Note: Each of the items listed below will not necessarily be found in all sources, which provide overlapping and unique elements):

• Adverse Event – Any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related
• Suspected Adverse Reaction – Any adverse event where there is a reasonable possibility that the drug caused the adverse event
• Adverse Reaction – Any adverse event caused by a drug. Adverse reactions are a subset of all suspected adverse reactions where there is reason to conclude that the drug caused the event
• Serious Adverse Event (SAE)/Serious Suspected Adverse Reaction – An adverse event/suspected adverse reaction that results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, causes persistent or significant disability/incapacity, results in a congenital anomaly/birth defect, or leads to a substantial disruption of the participant’s ability to conduct normal life functions
• Unexpected Adverse Event/Unexpected Suspected Adverse Reaction – An adverse event/suspected adverse reaction that is not listed in the investigator’s brochure (IB), or is not listed at the specificity or severity that has been observed in the study population; or if an IB is not required or available, is not consistent with the risk information described in the general investigational plan or elsewhere in the application
• Life-threatening Adverse Event/Life-threatening Suspected Adverse Reaction – An adverse event/suspected adverse reaction is considered “life-threatening” if, in the view of either the investigator or sponsor, its occurrence places the participant at immediate risk of death. It does not include an adverse event/suspected adverse reaction that, had it occurred in a more severe form, might have caused death

According to the G-HHS-AEReqs, the Department of Health & Human Services (HHS)’s 45CFR46 regulations (the Pre2018-ComRule, the RevComRule, and 45CFR46-B-E) do not define the terms “adverse event” or “unanticipated problems.” However, the Pre2018-ComRule and the RevComRule do contain requirements relevant to reviewing and reporting these incidents. See the G-HHS-AEReqs, the Pre2018-ComRule, and the RevComRule for further information.

See USA-18 and USA-65 for more information on Common Rule departments/agencies, and the Regulatory Authority section for additional guidance on when the Pre2018-ComRule and the RevComRule apply to research.

Additionally, see the International Council for Harmonisation’s Guideline for Good Clinical Practice E6(R3), which the Food & Drug Administration (FDA) has implemented in US-ICH-GCP, for guidance on safety reporting.

Safety Reporting Requirements

Investigator Responsibilities

As delineated in 21CFR312 and the G-InvstRpt, the investigator must comply with the following reporting requirements:

• SAEs, whether or not considered drug related, must be reported immediately to the sponsor
• Study endpoints that are SAEs must be reported in accordance with the protocol unless there is evidence suggesting a causal relationship between the drug and the event. In that case, the investigator must immediately report the event to the sponsor
• Non-SAEs must be recorded and reported to the sponsor according to the protocol specified timetable
• Report promptly to the ethics committee (EC) all unanticipated problems involving risk to human participants or others

The G-InvstRpt adds that although the investigator must immediately report any SAE to the sponsor, more data may be collected and submitted after submitting the initial report. For the purposes of the G-InvstRpt, the FDA interprets “immediately” to be as soon as feasible after the investigator recognizes an event is an SAE and obtains relevant information for the sponsor. The FDA recommends that this timeframe for submitting initial information also be specified in the protocol and anticipates that the timeframe for submission of initial information will generally not exceed one (1) calendar day.

Sponsor Responsibilities

As delineated in 21CFR312, the G-SpnsrRpt, and USA-99, the sponsor must report in an investigational new drug application (IND) safety report any suspected adverse reaction or adverse reaction that is both serious and unexpected. An adverse event is only required to be reported as a suspected adverse reaction if there is evidence to suggest a causal relationship between the drug and the adverse event. The sponsor is required to notify the FDA and all participating investigators in a written safety report of potential serious risks, from clinical trials or any other source, as soon as possible, but no later than 15 calendar days after the sponsor determines the information qualifies for reporting. Additionally, the sponsor must notify the FDA of any unexpected fatal or life-threatening suspected adverse reaction as soon as possible, but no later than seven (7) calendar days following receipt of the information. Any relevant information obtained by the sponsor that pertains to a previously submitted IND safety report must be submitted as a follow-up IND safety report. This report should be submitted without delay, as soon as the information is available, but no later than 15 calendar days after the sponsor initially receives the information.

Per 21CFR312, the G-SpnsrRpt, and USA-99,the sponsor must also report the following to the FDA in an IND safety report:

• Any findings from animal or in vitro testing, epidemiological studies, pooled analyses of multiple studies, or clinical studies (other than those reported in the safety report) that suggest a significant risk in humans exposed to the drug, regardless of whether they are conducted under the IND or by the sponsor
• Any clinically important increase in the rate of a serious suspected adverse reaction over that listed in the protocol or IB

In each IND safety report, the sponsor must identify all IND safety reports previously submitted to the FDA concerning a similar suspected adverse reaction and must analyze the significance of the suspected adverse reaction in light of previous, similar reports, or any other relevant information. Refer to 21CFR312, the G-SpnsrRpt, and USA-99 for more details on these safety reporting requirements.

The G-SpnsrRpt notes that the sponsor is ultimately responsible for evaluating the available information and deciding whether there is a reasonable possibility that the drug caused the adverse event, and therefore that the event meets the definition of a suspected adverse reaction. Aggregate analyses are needed for (1) anticipated SAEs for which it is difficult or impossible to make a causal determination based on a single case or a small number of cases; or (2) expected serious suspected adverse reactions that must be reported if there is a clinically important increase in the rate over that described in the protocol or IB. See the G-SpnsrRpt for additional FDA guidance on aggregate analyses.

The FDA’s G-DecentralCT indicates that to protect the safety and welfare of trial participants in a decentralized clinical trial, sponsors should implement a safety monitoring plan that takes the decentralized nature of the clinical trial into account and ensures that adverse events and medication errors are appropriately collected and adequately addressed. As in any clinical trial, the safety monitoring plan should describe how participants are expected to respond to and report adverse events, including where to seek medical assistance locally when necessary, and where to receive follow-up care. See the G-DecentralCT for more information.

As part of the clinical trial results information submitted to ClinicalTrials.gov (USA-78), 42CFR11 requires the responsible party, either the sponsor or the principal investigator (PI) designated by the sponsor, to submit three (3) tables of adverse event information. The tables should consist of the following summarized data:

• All SAEs
• All adverse events, other than SAEs, that exceed a frequency of five (5) percent in any arm of the trial
• All-cause mortalities

Per 42CFR11, this information must be submitted no later than one (1) year after the primary completion date of the clinical trial. Submission of trial results may be delayed as long as two (2) years if a responsible party submits a certification that: 1) the FDA has not approved, licensed, or cleared the investigational product (IP) being studied for any use before the primary completion date of the trial; and 2) the sponsor intends to continue with product development and is either seeking, or may at a future date seek, FDA approval.

See 42CFR11 for detailed adverse event reporting requirements.

Form Completion & Delivery Requirements

The G-SpnsrRpt indicates that as of April 1, 2026, IND safety reports of serious and unexpected suspected adverse reactions (which contain individual data from one (1) or more participants) should be submitted as individual case safety reports (ICSRs) to the FDA’s Adverse Event Monitoring System (AEMS) (formerly FDA Adverse Event Reporting System (FAERS)) (USA-50). As per the G-SpnsrRpt, the G-INDElecSubs, and USA-46, sponsors must submit such IND safety reports to USA-50 using either the Electronic Submissions Gateway Next Generation (ESG NextGen) or the Safety Reporting Portal (SRP) (USA-51). See USA-102 for the ESG NextGen Unified Submission Portal (USP) Login, as well as USA-37 and USA-44 for more information on ESG NextGen. Also see USA-46 for more information on making submissions to USA-50.

The G-SpnsrRpt notes that other types of required IND safety reports (overall findings or pooled analyses from published and unpublished in vitro, animal, epidemiological, or clinical studies and reports of increased rates of occurrences of expected serious suspected adverse reactions) should be submitted by the sponsor in a narrative format in electronic common technical document (eCTD) format, and should not be submitted to USA-50.

See USA-99 for additional information on submitting IND safety reports.

According to the G-SpnsrRpt and the G-INDElecSubs, submissions regarding non-commercial INDs are exempt from the above electronic submission requirements. The G-SpnsrRpt states that sponsors with INDs that are exempted from the electronic submission requirement, and who are not submitting IND safety reports of serious and unexpected suspected adverse reactions to USA-50 or the other types of IND safety reports with eCTD format submission requirements, should submit IND safety reports in an alternate electronic format or using other means of rapid communication. When utilizing an alternate electronic format (see the G-AltrntElecSubs) or other means of rapid communication, Form FDA 3500A (USA-75) may be used. For additional information on other reporting using Form FDA 3500A (USA-75), see the G-SpnsrRpt and USA-48.

Per USA-90, fatality reports to the Center for Biologics Evaluation and Research (CBER) should be sent to fatalities2@fda.hhs.gov.

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.

Interim and Annual Progress Reports

As specified in 21CFR312, the investigator must furnish all reports to the sponsor who is responsible for collecting and evaluating the results obtained. In addition, per 21CFR56, the Pre2018-ComRule, and the RevComRule, the institutional ethics committee (EC) (institutional review board (IRB) in the United States (US)) must have written procedures for determining which projects need verification from sources other than the investigator that no material changes have occurred since the previous EC review.

21CFR312 states that the sponsor must submit a brief annual progress report on the investigation to the Food & Drug Administration (FDA) within 60 days of the anniversary date that the investigational new drug went into effect. The report must contain the following information for each study:

• Title, purpose, and description of patient population, and current status
• Summary of the participants screened (e.g., failed screenings; participants enrolled, withdrawn, or lost to follow-up; and other challenges)
• Summary information - including information obtained during the previous year’s clinical and nonclinical investigations
• Description of the general investigational plan for the coming year
• Updated investigator’s brochure, if revised
• Description of any significant Phase 1 protocol modifications not previously reported in a protocol amendment
• Brief summary of significant foreign marketing developments with the drug
• A log of any outstanding business for which the sponsor requests a reply, comment, or meeting

As indicated in 42CFR11, trial updates must be submitted to ClinicalTrials.gov (USA-78) according to the following guidelines:

• Not less than once every 12 months for updated general trial registration information
• Not later than 30 calendar days for any changes in overall recruitment status
• Not later than 30 calendar days after the trial reaches its actual primary completion date, the date the final participant was examined or received an intervention for the purposes of final collection data for the primary outcome

Additionally, see the International Council for Harmonisation’s Guideline for Good Clinical Practice E6(R3), which the FDA has implemented in US-ICH-GCP, for guidance on clinical trial reports.

Final Report

As indicated in 21CFR312, an investigator must provide the sponsor with an adequate report shortly after completion of the investigator’s participation in the investigation. There is no specific timeframe stipulated for when the report should be completed.

Additionally, per 42CFR11, the responsible party must submit results for applicable investigational product (IP) clinical trials to USA-78 no later than one (1) year following the study’s completion date. Submission of trial results may be delayed as long as two (2) years if the responsible party submits a certification that indicates: 1) the FDA has not approved, licensed, or cleared the IP being studied for any use before the primary completion date of the trial; and 2) the sponsor intends to continue with product development and is either seeking, or may at a future date seek, FDA approval. The clinical trial results information must include data on the following:

• Participant flow
• Demographic and baseline characteristics
• Outcomes and statistical analysis
• Adverse event information
• The protocol and statistical analysis plan
• Administrative information

See USA-49 for more information and 42CFR11 for more detailed requirements. See NIHTrialInfo for specific information on dissemination of NIH-funded clinical trial data. See the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH)’s E3 Structure and Content of Clinical Study Reports (US-ICH-E3 and the US-ICH-E3-QA) for additional guidance on report structure.

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.

As per 21CFR312 and 21CFR50, a sponsor is defined as a person who takes responsibility for and initiates a clinical investigation. The sponsor may be an individual or pharmaceutical company, governmental agency, academic institution, private organization, or other organization. The sponsor does not actually conduct the investigation unless the sponsor is a sponsor-investigator. 21CFR312 and 21CFR50 define a sponsor-investigator as an individual who both initiates and conducts an investigation, and under whose immediate direction the investigational product is administered or dispensed.

In addition, 21CFR312 states that a sponsor may transfer responsibility for any or all obligations to a contract research organization (CRO). Any trial-related responsibilities transferred to and assumed by a CRO must be described in writing, and those obligations not covered by the written description will be deemed not to have been transferred. Further, a CRO that assumes any sponsor obligations must comply with the specific regulations delineated in 21CFR312 and will be subject to the same regulatory action as the sponsor for failure to comply with any obligation assumed under these regulations.

As indicated in 21CFR312, a sponsor may be either domestic or foreign.

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.

Overview

As set forth in 21CFR312, the sponsor is responsible for selecting the investigator(s) for the clinical trial and for ensuring that the investigator(s) are qualified by training and experience. Prior to permitting an investigator(s) to conduct a study, the sponsor must obtain the following:

• Signed investigator’s statement (Form FDA 1572 (USA-77))
• Curriculum vitae
• Clinical protocol
• Financial disclosure information

As addressed in the G-1572FAQs, Form FDA 1572 (USA-77) serves as the investigator’s agreement to provide certain information to the sponsor and to assure compliance with the Food & Drug Administration (FDA)'s clinical investigation regulations. Refer to the G-1572FAQs and USA-40 for further information.

In addition, 21CFR312 indicates that prior to the start of the study, the sponsor must provide the investigator(s) with the investigator’s brochure. The sponsor is also responsible for providing the investigator(s) with the information needed to conduct an investigation properly.

See G-InvstgtrResp for more information on investigator responsibilities.

As per the G-InvstgtrAdmin, the FDA may disqualify a clinical investigator from receiving investigational drugs (including biologics) if the FDA determines that the investigator has repeatedly or deliberately violated the agency’s regulations, or submitted false information to the sponsor or FDA in any required report. See the G-InvstgtrAdmin for more details.

The G-DecentralCT provides FDA recommendations for clinical trials with decentralized elements. The G-DecentralCT notes that because decentralized clinical trials may involve many contracted services, sponsors should ensure proper coordination of decentralized elements (e.g., use of remote trial personnel for at-home visits, use of local health care providers (HCPs), direct shipping of the investigational product to participants, etc.). Such contracted services may be performed by networks of local HCPs (e.g., local clinic networks, pharmacy chains). Sponsors should ensure these networks of local HCPs are qualified to perform the contracted activities. Sponsors should also keep a record of these networks and other contracted service providers, including their roles and assigned activities. See the G-DecentralCT for additional guidance.

Also see the International Council for Harmonisation’s Guideline for Good Clinical Practice E6(R3), which the FDA has implemented in US-ICH-GCP, for additional guidance on investigator selection, qualifications, and training.

Foreign Sponsor Responsibilities

No information is currently available.

Data and Safety Monitoring Board

As per 21CFR50, Data and Safety Monitoring Boards (DSMBs), (also known as Data Monitoring Committees (DMCs)), are not required by FDA regulations, except in the case of research conducted in emergency settings in which fulfilling the informed consent requirement is unfeasible. In this case, the FDA requires the establishment of an independent data monitoring committee to exercise oversight of the clinical investigation.

Additionally, the Pre2018-ComRule and the RevComRule indicate that for all human subjects research funded and/or sponsored by a Common Rule department/agency (as identified in USA-18 and USA-65), the institutional ethics committee (EC) (institutional review board (IRB) in the United States (US)) must ensure that, when appropriate, the research plan makes adequate provisions for monitoring the data collected during the study to ensure participant safety. Moreover, per the NIHDataSftyMntrng and USA-72, all National Institutes of Health (NIH)-funded clinical trials require a Data and Safety Monitoring Plan and monitoring should be commensurate with risk. DSMBs are also required for multi-site clinical trials with interventions that involve potential participant risk. See the NIHDataSftyMntrng and USA-72 for detailed Department of Health & Human Services (HHS)/NIH requirements.

Multicenter Studies

The RevComRule delineates that for all human subjects research funded and/or sponsored by a Common Rule department/agency, institutions that are located in the US and engaged in multicenter research/cooperative research studies must use a single EC to review the research. See the Scope of Review section, the RevComRule, the G-CentralIRB, and G-CoopRes for additional information.

See US-ICH-E17 for additional FDA guidance related to multi-regional clinical trials.

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.

Insurance

The United States (US) regulations do not require insurance.

Compensation

The G-IRBFAQs state that institutional policy, not Food & Drug Administration (FDA) regulation, determines whether compensation and medical treatment(s) will be offered and the conditions that might be placed on participant eligibility for compensation or treatment(s). Also see the International Council for Harmonisation’s Guideline for Good Clinical Practice E6(R3), which the FDA has implemented in US-ICH-GCP, which guides sponsors on providing compensation.

Injury or Death

As specified in 21CFR50, the Pre2018-ComRule, and the RevComRule, for research involving more than minimal risk, participants must be informed as to whether any compensation or medical treatments are available in the event of trial-related injuries. See the Required Elements section for additional information.

Trial Participation

As per the FDA’s G-SbjctPayment, compensation for participation is considered a recruitment incentive and not a benefit, and is often offered when the participant’s health benefits are remote or non-existent. Payment amounts and schedules should be presented to the institutional ethics committee (EC) (institutional review board (IRB) in the US) at the time of the initial review. The EC should ensure the payment amount and the proposed method and timing of disbursement are not coercive or present undue influence and are also included in the informed consent document. Payment to participants who withdraw may be made at the time that they would have completed the study. While the entire payment should not be contingent upon completion of the entire study, a small payment provided as an incentive for completion is acceptable to the FDA. Further, the FDA does not consider reimbursement for travel expenses to and from the clinical trial site and associated costs such as airfare, parking, and lodging to raise issues regarding undue influence.

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.

Quality Assurance/Quality Control

Per the US-ICH-E19, the Food & Drug Administration (FDA) has adopted the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH)’s E19 guidance, A Selective Approach to Safety Data Collection in Specific Late-Stage Pre-Approval or Post-Approval Clinical Trials. The document describes circumstances in which it may be appropriate to reduce the collection of safety data in late-stage pre-approval and post-approval clinical trials, e.g., long-term outcome trials, when appropriate and with agreement from regulatory authorities. See the US-ICH-E19 for more information.

Furthermore, the FDA’s G-CTEmrgncy provides general considerations to assist sponsors, institutional ethics committees (ECs) (institutional review boards (IRBs) in the United States (US)), and clinical investigators in assuring the safety of trial participants, maintaining compliance with good clinical practice (GCP), and minimizing risks to trial integrity during disasters and public health emergencies that may lead to a major disruption of clinical trial conduct and operations. See the G-CTEmrgncy for more information.

The G-DecentralCT provides FDA recommendations for clinical trials with decentralized elements. The G-DecentralCT states that to account for multiple sources of data collection in a decentralized clinical trial, the sponsor should include at least the following in a data management plan or other trial-related documents: data origin and data flow from all sources to the sponsor (e.g., a diagram that depicts the flow of data from creation to final storage); methods and technologies used for remote data acquisition from trial participants, trial personnel, and contracted service providers (e.g., local clinical laboratory facilities and local health care providers who perform trial-related activities); and a list identifying service providers for data collection, handling, and management.

The G-DecentralCT further indicates that to protect the safety and welfare of trial participants in a decentralized clinical trial, sponsors should implement a safety monitoring plan that takes the decentralized nature of the clinical trial into account and ensures that adverse events and medication errors are appropriately collected and adequately addressed. When applicable, the safety monitoring plan should describe the type of information that will be collected by a digital health technology, how that information will be used and monitored, and what action trial participants or personnel should take in response to abnormal findings or electronic alerts. See the G-DecentralCT for additional information.

See the G-eHealthRecords for the FDA’s guidance related to the use of electronic health records in clinical research, and see the G-RemoteData for recommendations on the use of digital health technologies for remote data acquisition from participants in clinical investigations that evaluate medical products. Furthermore, see the G-ESourceData for FDA guidance regarding the capture, review, and retention of electronic source data, particularly for use in filling the predefined fields in an electronic case report form.

Additionally, the G-CovariatesCT provides the FDA’s recommendations for the use of covariates in the analysis of randomized, parallel group clinical trials that are applicable to both superiority trials and noninferiority trials. See the G-CovariatesCT for more information.

The G-RWDRWE-Reg, issued as part of the FDA’s Real-World Evidence (RWE) Program (see USA-17), discusses the applicability of the 21CFR312 investigational new drug application (IND) regulations to various clinical study designs that utilize real-world data (RWD). See the G-RWDRWE-Reg for more information.

See the FDA’s G-EnrchStrat for enrichment strategies that can be used in clinical investigations intended to demonstrate the effectiveness of drug and biological products, and the G-DataCollect for recommendations on the use of a standardized approach for collecting and reporting race and ethnicity data in submissions for clinical trials.

Additionally, see USA-47 for a list of FDA clinical trials related guidance documents.

See USA-97 for information on the National Institutes of Health (NIH)’s data management and sharing policy, the NIHDataMngmnt, which applies to all research that is funded or conducted in whole or in part by the NIH, and results in the generation of scientific data. Additionally, see USA-6 for other scientific data sharing policies, including genomic data.

Also see the International Council for Harmonisation (ICH)’s Guideline for Good Clinical Practice E6(R3), which the FDA has implemented in US-ICH-GCP, for additional guidance on sponsor responsibilities involving quality management, assurance, and control. Additionally, see USA-69 for 10 guiding principles that industry and product developers can consider when using artificial intelligence (AI) to advance drug and biological product development.

Monitoring Requirements

The FDA’s G-RiskMntrng states that for each clinical trial, the sponsor should develop a monitoring plan that describes the monitoring methods, responsibilities, and requirements for the trial. The monitoring plan should include a brief description of the study, its objectives, and the critical data and study procedures, with particular attention to data and procedures that are unusual in relation to clinical routine. The monitoring plan should also require training of study site staff. Additionally, the plan should communicate the specific risks to be addressed by monitoring and should provide those involved in monitoring with adequate information to effectively carry out their duties. The FDA also encourages greater use of centralized monitoring practices, where appropriate, with correspondingly less emphasis on on-site monitoring. Centralized monitoring techniques should be used to the extent appropriate and feasible to:

• Supplement or reduce the frequency and extent of on-site monitoring with monitoring activities that can be done as well or better remotely, or with monitoring activities that can be accomplished using centralized processes only. Examples include monitoring data quality through routine review of submitted data, as well as completing administrative and regulatory tasks.
• Target on-site monitoring by identifying higher-risk clinical sites (e.g., sites with data anomalies or a higher frequency of errors, protocol violations, or dropouts relative to other sites).

For more FDA guidance on a risk-based approach to monitoring and monitoring plans, see the G-RiskMntrng and the G-RiskMntrngQA. Also see the ICH’s Guideline for Good Clinical Practice E6(R3), which the FDA has implemented in US-ICH-GCP, for additional guidance on sponsor responsibilities involving monitoring and auditing.

Premature Study Termination/Suspension

As delineated in 21CFR312, if the sponsor determines the investigational product (IP) presents an unreasonable and significant risk to the participants, the sponsor must discontinue the associated study as soon as possible, and no later than five (5) working days after making the determination. The sponsor must also notify the FDA, all ECs, and all investigators who have participated in the study about the termination. Additionally, the sponsor must ensure the disposition of all remaining stock of the IP and provide the FDA with a full report on the sponsor’s actions.

The G-InfrmdCnsnt, which is the FDA’s discussion of the regulations in 21CFR50, further states that if a study is terminated, participants should be provided with as much information as possible regarding the reason for the termination. Such a discussion provides an opportunity to address questions that participants may have about an IP that was administered to them (e.g., immediate safety concerns, ability to participate in another clinical trial, and appropriate waiting period to do so) and what long-term follow up may be available or necessary.

21CFR312 indicates that if the FDA terminates an IND based on deficiencies in the IND or in the conduct of an investigation under an IND, the sponsor must end all clinical investigations conducted under the IND and recall or otherwise provide for the disposition of all unused supplies of the drug. See 21CFR312 for more information on FDA termination.

Also see the ICH’s Guideline for Good Clinical Practice E6(R3), which the FDA has implemented in US-ICH-GCP, for additional guidance on sponsor responsibilities involving premature termination or suspension of a trial.

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.

Electronic Data Processing System

As per the Food & Drug Administration (FDA)’s G-DecentralCT, electronic systems can be used to perform multiple functions to manage decentralized clinical trial (DCT) operations. Training should be provided to all parties (e.g., trial personnel, local health care providers, and trial participants) who are using electronic systems to support the conduct of DCTs. Electronic systems that are used to produce and process trial records required by the FDCAct and FDA regulations are subject to 21CFR11. These systems must ensure data reliability, security, privacy, and confidentiality.

See 21CFR11 and the G-Part11 for general FDA regulations and guidance on electronic records and systems. Additionally, see the G-ElecSyst for guidance specific to clinical investigations.

Also see the International Council for Harmonisation (ICH)’s Guideline for Good Clinical Practice E6(R3), which the FDA has implemented in US-ICH-GCP, for guidance on data handling and processing, including the use of computerized systems.

Records Management

According to 21CFR312, the sponsor must maintain complete and accurate records showing financial interest paid to clinical investigators by the sponsor, as well as records concerning all other financial interests of investigators.

As set forth in 21CFR312, the sponsor must retain the above records and reports for at least two (2) years after a marketing application (known as a new drug application (NDA)) is approved for the drug; or if an NDA is not approved, until two (2) years after shipment and delivery of the IP is discontinued and the FDA has been notified. Additionally, upon request from the FDA, the sponsor must permit an officer or employee to access, copy, and verify any records and reports relating to the clinical investigation. Upon written request by the FDA, the sponsor must also submit the records or reports (or copies of them) to the agency.

Also see the ICH’s Guideline for Good Clinical Practice E6(R3), which the FDA has implemented in US-ICH-GCP, for additional guidance on record keeping and management.

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.

Responsible Parties

As stated in USA-86, the HIPAA Privacy Rule establishes the conditions under which protected health information (PHI) may be used or disclosed by covered entities for research purposes (Per USA-87, the Privacy Rule is located at 45CFR160 and Subparts A and E of 45CFR164; see USA-87 for more information). The Privacy Rule builds upon protections, described in Department of Health & Human Services (HHS) (the Pre2018-ComRule and the RevComRule) and Food & Drug Administration (FDA) (21CFR50 and 21CFR56) regulations, that help ensure the privacy of participants and the confidentiality of information. (Please note: ClinRegs does not provide information on state-level personal data protection requirements.)

Per the Privacy Rule, a covered entity means: a health plan; a healthcare clearinghouse; or a healthcare provider who transmits any health information in electronic form in connection with a transaction covered by the Privacy Rule.

Data Protection

According to the FDA’s G-CertCnfdntlty, a Certificate of Confidentiality (CoC) is intended to help protect the privacy of human subject research participants from whom identifiable, sensitive information is being collected or used in furtherance of the research. CoCs must be issued for federally funded human subject research that collects or uses identifiable, sensitive information (mandatory CoCs). For non-federally funded research, issuance of CoCs is not required but may be issued at the discretion of the FDA (discretionary CoCs). If an institutional ethics committee (EC) (institutional review board (IRB) in the United States (US)) determines that data collected in a clinical trial are sufficiently sensitive to warrant requesting a CoC, then the EC may request that a CoC be obtained in order to secure EC approval. Any disagreement between an EC, sponsor, and/or investigators regarding the need to request a CoC for a study should be resolved by communications among the parties. See the G-CertCnfdntlty for more information on CoCs.

28CFR202 prohibits certain data transactions that involve giving a country of concern or covered person access to: 1) bulk US sensitive personal data that involves bulk human ‘omic data; or 2) to human biospecimens from which bulk human ‘omic data could be derived. Human ‘omic data includes human genomic data, human epigenomic data, human proteomic data, and human transcriptomic data. However, 28CFR202 notes that there is an exemption for data transactions involving regulatory approval data, which refers to sensitive personal data that is de-identified or pseudonymized and that is required to be submitted to a regulatory entity, or is required by a regulatory entity to be submitted to a covered person, to obtain or maintain authorization or approval to research or market a drug, biological product, device, or combination product. Data transactions that are necessary to obtain or maintain regulatory authorization or approval to research or market a drug, biological product, device, or combination product may also be exempt. See 28CFR202 for more information on countries of concern, exempt transactions, and reporting requirements.

NIH Privacy Requirements

The NIHPrvcy indicates that the HHS’ National Institutes of Health (NIH) follows the PrvcyAct, which includes procedures for: 1) protecting records that can be retrieved by personal identifiers such as a name, social security number, or other identifying number or symbol, and 2) persons to access their identifiable records and to request correction(s) of these records. See the NIHPrvcy and the PrvcyAct for more information.

Consent for Processing Personal Data

Per USA-86, the Privacy Rule defines the means by which individuals will be informed of uses and disclosures of their medical information for research purposes, and their rights to access information about themselves held by covered entities. Researchers may obtain, create, use, and/or disclose individually identifiable health information in the course of conducting research. Under the Privacy Rule, covered entities are permitted to use and disclose PHI for research with individual authorization, or without individual authorization under limited circumstances. To use or disclose PHI without authorization by the research participant, a covered entity must obtain one (1) of the following:

• Documented EC or privacy board approval
• Representations from the researcher that the use or disclosure of the PHI is solely to prepare a research protocol (or for similar purposes preparatory to research), the researcher will not remove any PHI from the covered entity, and PHI for which access is sought is necessary for the research purpose
• Research on protected health information of decedents
• Limited data sets with a data use agreement
• Research use/disclosure with individual authorization
• Accounting for research disclosures

See USA-86 for more information on these circumstances.

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.

Obtaining Consent

In all United States (US) clinical trials, a freely given informed consent is required to be obtained from each participant in accordance with the requirements set forth in 21CFR50 for Food & Drug Administration (FDA) regulated clinical trials, and the Pre2018-ComRule or the RevComRule for federally funded or sponsored clinical trials. (See USA-18 and USA-65 for more information on Common Rule departments/agencies, and the Regulatory Authority section for additional guidance on agency-specific compliance.) Department of Health & Human Services (HHS)-funded or sponsored clinical trials must also comply with 45CFR46-B-E.

As per 21CFR50, the Pre2018-ComRule, and the RevComRule, the informed consent form (ICF) is viewed as an essential document that must be reviewed and approved by an institutional ethics committee (EC) (institutional review board (IRB) in the US).

Per the G-RevComRule-FDA, the informed consent requirements of the RevComRule are not inconsistent with FDA regulations. Therefore, there may not be a need for sponsors or investigators to develop, and have ECs review, two (2) separate ICFs for research that must comply with both the RevComRule and FDA regulations. (See the Required Elements section for ICF content details.) Per the RevComRule, which took effect January 21, 2019, for each clinical trial conducted or supported by a federal department or agency, one (1) EC-approved ICF used to enroll subjects must be posted by the awardee or the federal department or agency component conducting the trial on a publicly available federal website that will be established as a repository for such ICFs. According to USA-12, two (2) federal websites have been identified to meet this requirement: ClinicalTrials.gov (USA-78) and a docket folder on Regulations.gov (USA-79). According to the RevComRule, if the federal department or agency supporting or conducting the clinical trial determines that certain information should not be made publicly available on a federal website (e.g., confidential, commercial information), such federal department or agency may permit or require redactions to the information posted. The ICF must be posted on the federal website after the clinical trial is closed to recruitment and no later than 60 days after the last study visit by any subject, as required by the protocol.

According to 21CFR50, the Pre2018-ComRule, and the RevComRule, no investigator may involve a human being as a participant in research unless the investigator has obtained the legally effective informed consent of the participant or the legal representative/guardian. The participant or the legal representative/guardian should also be given adequate time to consider whether to participate to minimize the possibility of coercion or undue influence.

As indicated in 21CFR50, the Pre2018-ComRule, and the RevComRule, no informed consent, whether oral or written, may contain any language that causes the participant or the legal representative/guardian to waive or appear to waive legal rights, or that releases or appears to release the investigator, sponsor, institution or its agents from liability for negligence.

Additionally, per the RevComRule, participants must be provided with the information that a “reasonable person” would want to have in order to make an informed decision and an opportunity to discuss that information. Furthermore, the RevComRule requires that the informed consent, except for broad consent, must begin with a concise and focused presentation of the key information and organized to facilitate comprehension. Broad consent may be obtained in lieu of informed consent only with respect to the storage, maintenance, and secondary research uses of private identifiable information and identifiable biospecimens.

In addition, per 21CFR50, the Pre2018-ComRule, and the RevComRule, the ICF may be presented as either a full length written ICF or as a short form stating the consent requirements have been presented orally. The full length written ICF may be presented orally but must then be provided to the participant or a legal representative/guardian to read before it is signed.

As per the FDA’s G-DecentralCT, obtaining informed consent remotely may be considered as part of a decentralized clinical trial. EC oversight is required to ensure the process is adequate and appropriate. See the G-DecentralCT for more information.

See the FDA’s G-ElectronicIC for recommendations on the use of electronic systems and processes that may employ multiple electronic media to obtain informed consent for both HHS-regulated human subject research and FDA-regulated clinical investigations of medical products.

See the G-InfrmdCnsnt for the FDA’s discussion of the regulations in 21CFR50. Also, see USA-60 for additional information regarding informed consent.

Additionally, see the FDA’s G-SEInfrmdCnsnt for guidance intended to help small businesses better understand the informed consent requirements set forth in 21CFR50.

Also see the International Council for Harmonisation’s Guideline for Good Clinical Practice E6(R3), which the FDA has implemented in US-ICH-GCP, for additional guidance on obtaining consent.

Re-Consent

According to 21CFR50 and the G-IRBFAQs, participants who are enrolled and actively participating in a study must be informed of significant new findings which may relate to their willingness to continue participation in the study.

The G-IRBFAQs indicates that the FDA does not require re-consenting of participants who have completed their active participation in the study, or of participants who are still actively participating when the change will not affect their participation. One such case is when the change will be implemented only for subsequently enrolled participants.

Language Requirements

21CFR50, the Pre2018-ComRule, and the RevComRule state that any information provided must be in a language understandable to the participant or the legal representative/guardian.

As delineated in the FDA’s G-InfrmdCnsnt, when non-English speaking participants are enrolled in a study, ECs and investigators must ensure that the information provided to prospective participants or their legal representative/guardian is in a language that is understandable to them. The EC must review and approve all consent documents that are to be used by investigators to document the informed consent. When translation and interpretation are needed for written and oral information to be presented to participants, the FDA recommends that the EC review and approve reasonable procedures for ensuring that the translations will be prepared by a qualified individual or entity, and that interpretation assistance is available. The FDA also recommends that whenever non-English speaking participants are enrolled in a study, appropriate interpreter services be made available throughout the course of the study.

USA-63 also states that when an oral presentation of the ICF is provided, the witness present should be fluent in both English and the participant’s language, and the translator may serve as the witness. See the G-InfrmdCnsnt and USA-63 for detailed information.

Documenting Consent

As set forth in 21CFR50, the Pre2018-ComRule, and the RevComRule, the participant or a legal representative/guardian must sign and date an EC-approved written ICF. A written copy of the form must be given to the participant or a legal representative/guardian. In addition, the RevComRule explicitly allows electronic signatures for consent documentation.

Per 21CFR50, the Pre2018-ComRule, and the RevComRule, if the consent information is only presented orally using the short form, the participant or the legal representative/guardian must sign the form, the witness must sign both the short form and a copy of the summary once consent has been provided, and the person obtaining the consent must sign a copy of the summary. A copy of both the summary and the short form must be given to the participant or the legal representative/guardian.

The FDA’s G-InfrmdCnsnt further states that participants who cannot write can instead indicate their consent by "making their mark" on the consent document. In these situations, a note should be included in participant case histories indicating the reason for the lack of a signature and date as required in 21CFR50. The date consent was obtained should be recorded in this note. See 21CFR11 and the G-Part11 for general FDA regulations and guidance on electronic signatures. Additionally, see the G-ElecSyst for guidance specific to clinical investigations.

Waiver of Consent

Per the Pre2018-ComRule and the RevComRule, the EC may waive the requirement to obtain a signed ICF if it finds any of the following:

• The ICF would risk a breach of confidentiality by linking the participant to the study
• The research presents minimal risk and involves no procedures for which written consent is required outside of the study

The RevComRule also adds that the EC may waive the requirements to obtain a signed ICF if the participants are part of a distinct cultural group or community in which signing the form is not the norm, the research presents minimal risk, and there is an alternative approach to document informed consent.

The Pre2018-ComRule and the RevComRule further indicate that in cases where the documentation requirement is waived, the EC may require the investigator to provide the participant or the legal representative/guardian with a written statement regarding the research.

In addition, 21CFR50, the RevComRule, and the Pre2018-ComRule state that for an EC to approve a general waiver or alteration of consent, the EC must find that:

• The research involves no more than minimal risk
• The research could not practicably be carried out without the requested waiver or alteration
• The waiver or alteration will not adversely affect the rights and welfare of the participants
• Whenever appropriate, the participant or the legal representative/guardian will be provided with additional pertinent information after participation

21CFR50 and the RevComRule also state that for an EC to approve the general waiver or alteration of consent, the EC must find that if the research involves using identifiable private information or identifiable biospecimens, the research could not practicably be carried out without using such information or biospecimens in an identifiable format.

Furthermore, the Pre2018-ComRule and the RevComRule specify that although voluntary informed consent is always a requirement for every trial, the EC may approve a waiver or alteration of consent if the study involves a public benefit and service program conducted by or subject to the approval of state or local officials and could not be carried out without the waiver or alteration.

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