Overview

In accordance with the MHCTR and the MHCTR2006, the Medicines and Healthcare Products Regulatory Agency (MHRA) is responsible for reviewing, evaluating, and approving applications for clinical trials using registered or unregistered investigational products (IPs). (Note: IPs are known as investigational medicinal products (IMPs) in the United Kingdom (UK)). The MPHFR and the G-MHRA-CTApp specify that the scope of the MHRA’s assessment includes all clinical trials (Phases I-IV). The G-MHRA-CTApp permits MHRA’s review process to be conducted in parallel with the ethics committee (EC) review, stating that an EC opinion may be obtained before, during, or after the MHRA application submittal. However, pursuant to the MHCTR and the MHCTR2006, the clinical trial must be authorized by the MHRA, and an EC established and recognized by the United Kingdom Ethics Committee Authority (UKECA) must provide a favorable opinion in relation to the trial prior to the trial’s commencement. (See the Ethics Committee topic for detailed information on the EC review and approval process.)

According to the G-MHRA-CTApp and Additional Resource (A), the sponsor or his/her designated representative must also apply for a European Clinical Trials Database (EudraCT) number by registering a clinical trial in the EudraCT database. (See Clinical Trial Lifecycle topic, Submission Process subtopic for additional details.)

Brexit

The UK will leave the European Union on March 29, 2019. The following information describes what will happen if a transition “deal” is enacted in the UK and what will happen if no deal is enacted.

Scenario 1: UK-EU Brexit Deal Implementation

A “deal” means both the UK government and the EU sign a Withdrawal Agreement that is ratified by the UK Parliament and the European Parliament by March 29, 2019.

Per G-BrexitDeal-LifeScienceImp, G-BrexitDeal-TechInfo, and Additional Resource (B), the UK and the European Union (EU) agreed to the terms of a Brexit implementation period that will start on March 30, 2019 and last until December 31, 2020. This period will give organizations time to plan with confidence for the UK’s withdrawal from the EU. Before this implementation period, the UK remains a full member of the EU. During the implementation period, the UK will no longer be a Member State of the EU, but EU rules and regulations will remain in place to provide certainty and continuity. Expected to come into effect during 2020, the new EU Clinical Trials Regulation (Additional Resource (H)) would therefore, apply to the UK under the terms of the time-limited implementation period. If the EU Clinical Trials Regulation does not come into force during the implementation period, the UK’s laws will remain aligned with parts of the EU’s Clinical Trials Regulation that are within the UK’s control. Per Additional Resources (B), (C), and (D), the EU Clinical Trials Regulation will ensure a greater level of harmonization of the rules for conducting clinical trials throughout the EU. It introduces an authorization procedure based on a single submission via a single EU portal, an assessment procedure leading to a single decision, rules on participant protection and informed consent, and transparency requirements.

Scenario 2: No Brexit Deal

As delineated in G-NoBrexitDeal-CT, if there is no Brexit deal enacted in the UK on March 29, 2019 when the UK leaves the EU, then MHCTR remains in force and MHRA will align where possible with the EU Clinical Trials Regulation once it becomes effective in the EU.

The G-NoBrexitDeal-CT-Note provides specific implications of a “no-deal” scenario for clinical trials, which are listed below. These proposals are still subject to parliamentary approval of the changes to the relevant statutory instruments that are required to bring these proposals into law.

• Existing approvals will continue to be recognized
• The sponsor or legal representative must be in the UK or approved country, which will initially include EU/European Economic Area (EEA) countries
• IPs that have been certified by a Qualified Person in an approved country, which will initially include EU countries, will not need to be recertified in the UK; however, within 12 months of Brexit, a system must be put in place by the holder of the manufacturers license to ensure the IPs were certified in the EU or EEA
• All UK relevant suspected unexpected serious adverse reactions (SUSARs) will need to be submitted to the MHRA via UK-based IT systems
• Clinical trials should continue to be registered in an international registry

For more information, see G-NoBrexitDeal-CT-Note.

Clinical Trial Review Process

Application Submission

The MHCTR, the G-MHRA-CTApp, and Additional Resource (E) specify that the MHRA coordinates the clinical trial application process. Per Additional Resource (G), upon receipt of a clinical trial application, the MHRA’s Clinical Trials Unit (CTU) validates it and sends the sponsor or his/her designated legal representative an acknowledgement letter. If the application is valid, the CTU assessment period begins from the date of receipt (Day 0). If the application is not valid, the sponsor or his/her designated representative will be informed of the deficiencies, and he/she must provide a completely new application. According to the MHCTR, if the sponsor or his/her designated representative does not receive a request for additional information from the MHRA within 30 days, the application is considered as authorized. (See the Clinical Trial Lifecycle topic, Timeline of Review subtopic for additional details.)

In addition, as stated in the G-MHRA-CTApp, certain first-in-human (Phase I) trials with specific risk factors may require the MHRA’s CTU to seek advice from an Expert Advisory Group/the Commission on Human Medicines before giving approval. See the G-MHRA-CTApp for examples of which trials require expert advice and for detailed requirements.

Notification Scheme Submission

As set forth in the G-MHRA-CTApp and Additional Resources (E), (F), and (G), in lieu of a standard application, a sponsor or his/her designated representative may submit a notification of a clinical trial to the MHRA under the Notification Scheme when conducting “Type A” trials. Type A trials are those in which the potential risk associated with an IP is determined to be no higher than that of standard medical care, and involve medicinal products licensed in any EU Member State that meet the following criteria:

• They relate to the licensed range of indications, dosage and form, or,
• They involve off-label use established by practice and supported by published evidence and/or guidelines

See the G-MHRA-CTApp and Additional Resources (E), (F), and (G) for detailed Notification Scheme requirements.

Upon receipt of a valid notification, the MHRA will send an acknowledgement letter to the sponsor or his/her designated representative stating that the trial may proceed if it does not raise an objection within 14 days. If the MHRA does not send a Notification Objection letter, the acknowledgement letter serves as the authorization.

If the MHRA raises objections, the submission is assessed as a standard request for authorization (refer to information under the Application Submission heading above), and the CTU initial assessment is performed within 30 days of receipt of a valid application.

Governance Approval

Per Additional Resource (J), all project-based research must also apply for governance and legal compliance approvals from the appropriate lead UK Health Department. The Integrated Research Application System (IRAS) facilitates this process. As described in Additional Resources (K) and (L), approval from the Health Research Authority (HRA) is required for all project-based research in the National Health Service (NHS) led from England. As of April 16, 2018, this has been extended to include all project-based research in the NHS in England or Wales. HRA and Health and Care Research Wales (HCRW) approval brings together the assessment of governance and legal compliance. For any new studies led from Scotland or Northern Ireland but have English and/or Welsh NHS sites, the national R&D coordinating function of the lead nation will share information with the HRA and HCRW assessment teams, who can issue HRA and HCRW approval for English and Welsh sites and thereby retain existing compatibility arrangements. Studies led from England or Wales with sites in Northern Ireland or Scotland will be supported through existing UK-wide compatibility systems, by which each country accepts the centralized assurances, as far as they apply, from national coordinating functions without unnecessary duplication. For details on HRA’s assessment criteria and standards for approval, see Additional Resource (M).

(See the Clinical Trial Lifecycle topic, Submission Process and Submission Content subtopics for detailed submission requirements.)

Overview

As set forth in GAfREC and Additional Resource (A), the United Kingdom (UK) has a centralized recognition process for ethics committees (ECs), (known as research ethics committees (RECs) in the UK). Per GAfREC and Additional Resource (A), the UK Health Departments have authorized the Research Ethics Service (RES) in England, within the Health Research Authority (HRA), to serve as the lead administrative body to coordinate the development of operational systems for ECs. See GAfREC for more detail about HRA functions related to the RES in the United Kingdom. ECs are recognized or established by the United Kingdom Ethics Committee Authority (UKECA), the HRA, or the Ministers of Health Departments of the four (4) UK nations (England, Northern Ireland, Scotland, and Wales).

As stated in GAfREC, the RES encompasses England’s Department of Health and Social Care (DHSC), Northern Ireland’s Department of Health, the Scottish Government Health and Social Care Directorates, the Welsh Government’s Department of Health and Social Services as well as the ECs that are collectively recognized or established by these authorizing bodies. The UK Health Departments have authorized England’s HRA to perform some functions on behalf of the other head offices. A list of recognized ECs within the RES is available through Additional Resource (C).

All recognized RES ECs are required to comply with the provisions delineated in GAfREC, Guideline for Good Clinical Practice E6 (R2) (EU-ICH-GCPs), and Additional Resource (A). However, specific ECs within the RES are recognized, or otherwise designated, to review certain types of research proposals. In accordance with the MHCTR and the MHCTR2006, ECs recognized to conduct reviews of clinical trials for investigational medicinal products (CTIMPs) are authorized by the statutory body, the UKECA, and are of central importance in this topic. Please refer to the Ethics Committee topic, Authorizing Body subtopic for additional details on the RES and the UKECA.

RES EC Composition

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

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

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

Terms of Reference and Review Procedures

In addition to complying with composition requirements, GAfREC, the EU-ICH-GCPs, and Additional Resource (A) state that an EC must also adopt written standard operating procedures (SOPs). The SOPs should cover the entire review process from application submission to opinion and notification, amendments, and annual reporting. For detailed EC procedures and information on other administrative processes, see GAfREC, the EU-ICH-GCPs, and Additional Resource (A).

Overview

According to GAfREC, the Guideline for Good Clinical Practice E6 (R2) (EU-ICH-GCPs), and Additional Resource (B), the primary scope of information assessed by ethics committees (ECs) recognized by the United Kingdom Health Departments’ Research Ethics Service (RES) relates to maintaining and protecting the dignity and rights of research participants and ensuring their safety throughout their participation in a clinical trial. (Note: ECs are known as research ethics committees (RECs) in the UK).

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

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

Role in Clinical Trial Approval Process

As described in Additional Resources (B), (C), (D), and (E), the type of EC responsible for approval (known as a “favorable opinion” in the UK) within the RES depends on the type of research being conducted. As discussed in the preceding subtopic, ECs recognized to conduct reviews of clinical trials for investigational medicinal products (CTIMPs) must be authorized by the United Kingdom Ethics Committee Authority (UKECA). Per GAfREC, RES-recognized ECs established under Health Department policy within each of the four (4) UK nations (England, Northern Ireland, Scotland, and Wales) review research studies other than CTIMPs.

As indicated in the MHCTR, the MHCTR2006, and GAfREC, CTIMP applications require the favorable opinion of a UKECA-recognized EC, and approval by the Medicines and Healthcare Products Regulatory Agency (MHRA) prior to the sponsor or his/her designated legal representative initiating the trial. The G-MHRA-CTApp permits MHRA’s review process to be conducted in parallel with the EC review, stating that an EC opinion may be obtained before, during, or after the MHRA application has been electronically submitted to the Integrated Research Application System (IRAS). Therefore, to prepare an EC application, an IRAS account must be created. Per Additional Resource (G), IRAS does not change the requirements for review, including authorizations or signatures, of any regulatory authority or National Health Service (NHS) body. Therefore, it requires different authorizations depending on the type of study and the applicable review bodies.

Prior to submitting an application, the trial must first be registered in the EU Clinical Trials Register, which provides a EudraCT number. According to Additional Resource (B), the chief investigator (CI) must submit the electronic application to IRAS on the same day that a booking is made to schedule an EC review through the NHS Research Ethics Committee (REC)’s Central Booking Service (CBS). The EudraCT number should also be included with the application. (See the Clinical Trial Lifecycle topic, Trial Initiation subtopic for additional information.)

According to the MHCTR, GAfREC, and Additional Resource (B), for all studies, the RES requires the CI to obtain only one (1) EC review (referred to as the “main EC”) for a project taking place in the UK, regardless of the number of sites. Furthermore, Additional Resource (B) states that the CI should be based in the UK and that the REC may agree exceptionally to an application being submitted by a CI based outside the UK, but should consider as part of the ethical review whether adequate arrangements are in place for supervision of the study in the UK. Per Additional Resource (B), a site-specific assessment (SSA) may be necessary for multicenter clinical trials. The SSA is not a separate ethical review, but forms part of the single ethical review of the research. In the case of international studies, an application must be made to an EC in the UK, whether or not the study has a favorable ethical opinion from a committee outside the UK, and whether or not it has started outside the UK.

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

While there is no stated expiration date for an EC approval in the MHCTR, GAfREC, or the Additional Resources, IRAS (Additional Resource (F)) requires identification of an expected end date for the study. A change to the definition of the end of the study is a substantial amendment. Extension of the study beyond the period specified in the application form is a non-substantial amendment. See Additional Resource (H) for guidance on what changes qualify as a substantial amendment, which requires notification to the EC and MHRA.

Overview

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

Overview

Research Ethics Service (RES)

As stated in GAfREC, the United Kingdom (UK) Health Departments’ Research Ethics Service (RES) encompasses England’s Department of Health and Social Care (DHSC), Northern Ireland’s Department of Health, the Scottish Government Health and Social Care Directorates, the Welsh Government’s Department of Health and Social Services, as well as the ethics committees (ECs) (known as research ethics committees (RECs) in the UK) collectively recognized or established by these authorizing bodies. The UK Health Departments have authorized the Health Research Authority (HRA), which is sponsored by England’s DHSC, to serve as the lead administrative body to coordinate the development of RES operational systems for ECs recognized or established by the United Kingdom Ethics Committee Authority (UKECA), the HRA, or the Ministers or Health Departments of the four (4) UK nations (England, Northern Ireland, Scotland, and Wales), including their respective head offices.

A head office represents each of the health departments within the four (4) UK nations and serves as the appointing authority for the recognized ECs. Per GAfREC and Additional Resource (A), within England’s DHSC, the HRA is the head office with appointing authority for the RES. The official RES head offices (i.e., appointing authorities) for the other nations are represented by the Health and Social Care Research and Development (HSC R&D) Division within Northern Ireland’s HSC Public Health Agency (Additional Resource (B)); the Chief Scientist Office (CSO) within the Scottish Government Health and Social Care Directorates (Additional Resource (C)); and the Ethics Service within the Health and Care Research Wales (Additional Resource (D)). The head offices work together to maintain a consistent approach in operating the RES ECs.

UK Ethics Committee Authority (UKECA)

As set forth in the MHCTR, the MHCTR2006, and GAfREC, the UKECA is responsible for establishing, recognizing, and monitoring ECs that review applications for clinical trials of investigational medicinal products (CTIMPs). As indicated in the MHCTR and Additional Resource (E), the UKECA recognizes two (2) types of ECs for new CTIMPs applications:

• Type 1: Reviews Phase 1 clinical trials in healthy volunteers taking place anywhere in the UK
• Type 3: Reviews clinical trials in patients taking place anywhere in the UK

New applications are no longer allocated for review by ECs with Type 2 recognition. Additionally, per Additional Resource (F), when the UKECA recognizes an EC, it must specify the following:

• Whether the EC may act for the entire UK, or, only for a particular area of the UK
• The description/class of clinical trial for which the EC may provide ethics review

Per GAfREC and Additional Resource (E), the HRA is responsible for providing advice, assistance, and operational support to all UK ECs recognized by the UKECA.

As indicated in Additional Resource (F), the HRA chairs UKECA business, which is reviewed at the bimonthly Four Nations’ Meeting attended by England’s DHSC, Northern Ireland’s HSC, Scotland’s CSO, and the Health and Care Research Wales.

Registration, Auditing, and Accreditation

As delineated in GAfREC and Additional Resource (E), the RES is responsible for ensuring the quality of the ECs, including the UKECA ECs, through regular monitoring, auditing, and accrediting their operations and performance.

Health Research Authority (HRA)

In accordance with the CareAct2014 and Additional Resource (G), the HRA is a non-departmental public body established in 2015 and sponsored by England’s DHSC to standardize regulatory practices relating to health and social care research, and to encourage safe and ethical research conducted across the UK. According to GAfREC and Additional Resource (E), the UK Health Departments have authorized the HRA in England to serve as the lead administrative body to coordinate the development of RES operational systems for ECs recognized or established by the UKECA, the HRA, or the Ministers or Health Departments of the four (4) UK nations (including their respective head offices). The RES is a core function of the HRA.

As indicated in GAfREC and Additional Resource (I), the HRA, in support of the RES and UKECA, supports two (2) main types of ECs in the UK:

• Authorized ECs – those authorized by the RES to review all applications except those relating to CTIMPs
• Recognized ECs – those recognized by the UKECA, a statutory body established under the MHCTR, to review applications relating to CTIMPs. Recognized ECs may also review non-CTIMP research.

Overview

In accordance with the MHCTR, the MHCTR2006, the G-MHRA-CTApp, and Additional Resource (A), the United Kingdom (UK) requires the sponsor or his/her designated legal representative to obtain clinical trial authorization from the Medicines and Healthcare Products Regulatory Agency (MHRA) prior to initiating the trial. The MHCTR, the G-MHRA-CTApp, and Additional Resource (B) also state that if the sponsor is not based in the European Economic Area (EEA), he/she must appoint a legal representative located in the EEA.

The G-MHRA-CTApp permits MHRA’s review process to be conducted in parallel with the ethics committee (EC) review, stating that an EC opinion may be obtained before, during, or after the MHRA application submittal.

According to the G-MHRA-CTApp and Additional Resources (D) and (E), the sponsor or his/her designated representative must apply for a EudraCT number, which is a prerequisite to creating a clinical trial application as well as submitting an EC application to the Integrated Research Application System (IRAS) – the UK’s electronic system for applying for and managing research approvals. The EudraCT number is a unique European Union (EU)-wide reference number assigned to a trial that is used by the review bodies (the MHRA and ECs) to exchange trial-related information. Only after receiving a EudraCT number can the sponsor or his/her designated representative generate a clinical trial application electronically via the EU’s EudraCT database or the UK’s IRAS database. Both systems provide a saved data file in the form of an XML file, which is stored on the sponsor’s or his/her designated representative’s local hard drive, can be shared across both systems, and can be generated into PDF files. However, per Additional Resource (F), IRAS is the most efficient submission option because it enables researchers to enter the information required by the UK review bodies only once, rather than having to complete several separate application forms to obtain these permissions and approvals.

As described in Additional Resource (F), other relevant approvals can be sought on the IRAS site. For example, applicants can request inclusion in the NIHR Clinical Research Network (NIHR CRN) Portfolio, which comprises high-quality clinical research studies that receive support services from the Clinical Research Network in England.

(See Clinical Trial Lifecycle topic, Submission Content subtopic for detailed submission content requirements).

Submitting the Clinical Trial Application

Per G-MHRA-CTApp, clinical trial applications to MHRA can be submitted electronically using the Heads of Medicines Agencies (HMA) Common European Submission Portal (CESP).

MHRA
Information Processing Unit
Medicines & Healthcare Products Regulatory Agency
10 South Colonnade
Canary Wharf
LONDON
E14 4PU
UK

Assembly and Number of Copies

Based on information provided in the G-MHRA-CTApp, and Additional Resources (D), (E), (G), and (H), once the sponsor or his/her designated representative obtains a EudraCT number by registering his/her clinical trial application in the EudraCT database, he/she must download and complete the clinical trial application form on EudraCT or IRAS. Per the G-MHRA-CTApp, XML and PDF versions must be created for the form, and all documents to be included in the application package must have copy and paste functionality. When completed, the form should be saved and signed electronically, and submitted along with the rest of the required documents.

Application files may be saved and prepared on a local computer prior to uploading to EudraCT, IRAS, or the HMA CESP for submission to the MHRA. Information included in the submission package will be used to validate the application; incomplete applications will be rejected. Per the G-MHRA-CTApp and Additional Resource (H), the CESP is only used to submit files, not to download files to a local computer. Refer to Additional Resources (D), (E), (G), and (L) for detailed EudraCT application submission instructions, Additional Resource (F) for IRAS submission information, and the G-MHRA-CTApp and Additional Resource (H) for CESP submission information. (See Clinical Trial Lifecycle topic, Submission Content subtopic for documentation to be included in the application package.)

According to Additional Resource (I), all EC forms and their associated supporting documentation should be submitted electronically via IRAS, thereby eliminating the need to submit any hard copies. Additional Resources (A) and (I) state that the chief investigator (CI) must submit the electronic application to IRAS on the same day that a booking is made to schedule an EC review through the National Health Service (NHS) Research Ethics Committee (REC)’s Central Booking Service (CBS). Detailed instructions about submitting EC applications through IRAS are available at Additional Resources (F) and (K).

Clinical Trial Application Language Requirements

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

Overview

As set forth in the MHCTR, the MHCTR2006, the G-MHRA-CTApp, and Additional Resource (A), the Medicines and Healthcare Products Regulatory Agency (MHRA) requires the sponsor or his/her designated legal representative to apply for clinical trial authorization, and the chief investigator (CI) or principal investigator (PI) to apply for a favorable opinion from a recognized ethics committee (EC). (See the Ethics Committee topic for detailed coverage of EC operations and responsibilities.)

MHRA Requirements

As specified in the MHCTR and the G-MHRA-CTApp, a clinical trial application submission should contain PDF and XML files for each of the following documents sent to the MHRA:

• Cover letter (when applicable, this should include a statement that the submission is for a Phase I trial eligible for the shortened assessment time)
• Sponsor or designated representative name and contact information
• Investigator(s) contact information
• Clinical Trial Application
• Protocol and description of proposed trial
• Copy of EC opinion, if available
• Investigator’s Brochure (IB) or document replacing the IB
• Investigational Medicinal Product Dossier (IMPD) or simplified IMPD
• Non-Investigational Medicinal Product (NIMP) Dossier (if required)
• Informed consent form (ICF)
• Scientific advice - A summary of scientific advice from any Member State or the European Medicines Agency (EMA) regarding the trial (if available)
• EMA Decision - A copy of the EMA’s Decision on the Pediatric Investigation Plan and the opinion of the Pediatric Committee (if applicable)
• Investigational Medicinal Product (IMP) labeling content (or justification for its absence)
• Manufacturer’s Authorization for Investigational Medicinal Products (MIA(IMP)) plus Qualified Person (QP) declaration on Good Manufacturing Practice (GMP) for each manufacturing site
• Manufacturer or importer contact information

Refer to the MHCTR and the G-MHRA-CTApp for detailed submission information.

EC Requirements

As per the MHCTR, the Guideline for Good Clinical Practice E6 (R2) (EU-ICH-GCPs), and Additional Resource (B), ECs require the CI to submit the following documentation for ethics approval:

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

Additionally, according to Additional Resource (E), the CI must submit the electronic application to the Integrated Research Application System (IRAS) on the same day that a booking is made to schedule an EC review through the National Health Service (NHS) Research Ethics Committee’s Central Booking Service (CBS). EC reviews are booked through the CBS and will be booked in the first available slot for an EC that is suitable for the type of study. ECs are geographically located across the UK. Applicants are strongly encouraged to attend meetings in person. Some studies must be reviewed by an EC that is flagged for the type of research to take place.  Refer to Additional Resource (E) for detailed submission and booking instructions.

Clinical Protocol

According Additional Resource (F) and the EU-ICH-GCPs, the clinical protocol should contain the following elements:

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

For complete protocol requirements, refer to Additional Resource (F) and the EU-ICH-GCPs.

Overview

Based on the MHCTR, the MHCTR2006, GAfREC, and Additional Resource (A), the sponsor or his/her designated representative must submit an application for clinical trial authorization to the Medicines and Healthcare Products Regulatory Agency's (MHRA), and the chief investigator (CI) must submit an application to a recognized ethics committee (EC) to obtain a favorable opinion prior to the trial’s commencement. The G-MHRA-CTApp permits MHRA’s review process to be conducted in parallel with the EC review, stating that an EC opinion may be obtained before, during, or after the MHRA application submittal to the Integrated Research Application System (IRAS), EudraCT, or the Heads of Medicines Agencies (HMA) Common European Submission Portal (CESP).

MHRA Approval

Clinical Trial Application Submission

As per the MHCTR and the G-MHRA-CTApp, the MHRA review and approval process for a clinical trial application takes 30 days. For Phase 1 trials, the average is 14 days. According to the G-MHRA-CTApp, if the sponsor or his/her designated representative is required to submit an amended application, the MHRA provides a response to the amendment within 60 days of receipt of the original application. Additionally, responses for Phase 1 healthy volunteer studies will be reviewed within an average of 14 days, and studies using gene therapy, somatic cell therapy (including xenogenic cell therapy) products or products containing genetically modified organisms will be reviewed within 90 days or receipt of the original application.

The MHCTR and the G-MHRA-CTApp specify that the MHRA coordinates the clinical trial application process. Upon receipt, the MHRA’s Information Processing Unit conducts an application validation. If the application is validated, the sponsor or his/her designated legal representative is sent an acknowledgement letter. The MHRA’s Clinical Trials Unit (CTU) assessment period begins from the date of receipt (Day 0) of a valid application. According to the MHCTR, if the sponsor or his/her designated representative does not receive a request for additional information from the MHRA within 30 days, the clinical trial application is treated as authorized.

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

Notification Scheme Submission

The G-MHRA-CTApp and Additional Resource (C) indicate that in place of a standard application, a notification of a clinical trial may be submitted for “Type A” trials. This includes trials involving medicinal products licensed in any EU Member State that meet the following criteria:

• they relate to the licensed range of indications, dosage and form, or,
• they involve off-label use established by practice and supported by published evidence and/or guidelines

Type A trials include studies in which the potential risk associated with an investigational medicinal product is determined to be no higher than that of standard medical care. See the G-MHRA-CTApp and Additional Resource (C) for detailed Notification Scheme requirements.

Upon receipt of the notification, the MHRA sends an acknowledgement letter to the sponsor or his/her designated representative stating that the trial may proceed if an objection is not raised within 14 days. If the MHRA does not send a Notification Objection letter, the acknowledgement letter serves as the authorization. If the MHRA raises objections, the submission is treated as a standard request for authorization, and the CTU initial assessment is performed within 30 days. For the purposes of this calculation, the day of receipt of the valid notification by the Clinical Trials Unit is Day 0.

Ethics Committee Approval

As specified in the MHCTR, GAfREC, and Additional Resources (A) and (G), an EC must give its opinion within 60 calendar days of receipt of a valid application. When an EC requires further information before confirming its opinion, it may give a provisional opinion, and it is permitted to make one (1) written request for further information, clarification, or changes to documentation. The time it takes for the EC to receive a complete response to the request does not count against the 60-day timeline. Studies using gene therapy, somatic cell therapy (including xenogenic cell therapy) products or products containing genetically modified organisms will take 90 days, or 180 days if a specialist group or committee is consulted. For other exceptions, see GAfREC and the MHCTR.

As delineated in Additional Resource (A), the CI is responsible for submitting an application to an EC via IRAS. Additional Resource (D) indicates that the CI must submit the electronic application to IRAS on the same day that a booking is made to schedule an EC review through the National Health Service (NHS) Research Ethics Committee’s Central Booking Service (CBS).

Per Additional Resource (A), a site-specific assessment (SSA) is required for multicenter clinical trials. The SSA is not a separate ethical review, but forms part of the single ethical review of the research.

In the case of international studies, an application must be made to an EC in the UK, whether or not the study has a favorable ethical opinion from a committee outside the UK, and whether or not it has started outside the UK. See the Ethics Committee topic, Scope of Assessment subtopic for additional information on the “main EC.”

Overview

In accordance with the MHCTR, the MHCTR2006, GAfREC, and Additional Resource (A), a clinical trial can only commence after the sponsor or his/her designated representative receives authorization from the Medicines and Healthcare Products Regulatory Agency (MHRA) and the chief investigator (CI) receives an approval from a recognized ethics committee (EC). No waiting period is required following the applicant’s receipt of these approvals.

The MHCTR, the G-MHRA-CTApp, and Additional Resource (B) also state that if the sponsor is not based in the European Economic Area (EEA), it is a statutory requirement for the sponsor to appoint a legal representative located in the EEA. The G-MHRA-CTApp permits MHRA’s review process to be conducted in parallel with the EC review, stating that an EC opinion may be obtained before, during, or after the MHRA application submittal. Furthermore, Additional Resource (A) states that the CI should be based in the United Kingdom (UK). In rare cases when this is not required, adequate arrangements must be in place for supervision of the study in the UK.

In addition, per the MHCTR, the G-MHRA-CTApp, and Additional Resource (D), a Manufacturer’s Authorization for Investigational Medicinal Products (MIA(IMP)) must be obtained by the person responsible for the manufacture or importation of any investigational product (IP) (known as investigational medicinal product (IMP) in the UK) to be used in the trial. The sponsor or his/her designated representative must include a copy of the MIA(IMP) in the clinical trial application submission to the MHRA. (See Clinical Trial Lifecycle topic, Submission Content subtopic, and the Investigational Products topic, Manufacturing & Import subtopic for detailed submission and IMP requirements respectively).

As stated in the MHCTR and Additional Resource (E), which comply with the European Medicines Agency’s implementation of the Guideline for Good Clinical Practice E6(R2) (EU-ICH-GCPs), all investigators must possess appropriate qualifications, training, and experience. The trials should be conducted in compliance with the EU-ICH-GCPs, and laboratory practices for investigational products must comply with the UK-GLPs.

Governance Approval

Per Additional Resource (G), all project-based research must also apply for governance and legal compliance approvals from the appropriate lead UK Health Department. The Integrated Research Application System (IRAS) facilitates this process. As described in Additional Resources (H) and (I), approval from the Health Research Authority (HRA) is required for all project-based research in the National Health Service (NHS) led from England. As of April 16, 2018, this has been extended to include all project-based research in the NHS in England or Wales. HRA and Health and Care Research Wales (HCRW) approval brings together the assessment of governance and legal compliance. For any new studies that are led from Scotland or Northern Ireland but have English and/or Welsh NHS sites, the national research and development coordinating function of the lead nation will share information with the HRA and HCRW assessment teams, who can issue HRA and HCRW approval for English and Welsh sites and thereby retain existing compatibility arrangements. Studies led from England or Wales with sites in Northern Ireland or Scotland will be supported through existing UK-wide compatibility systems, by which each country accepts the centralized assurances, as far as they apply, from national coordinating functions without unnecessary duplication. For more information on HRA’s assessment criteria and standards for approval, see Additional Resource (J).

Clinical Trial Agreement

According to Additional Resource (K) and (L), contracts and agreements should be in place prior to the initiation of a trial. Among the agreements, the sponsor or his/her designated representative is required to sign a letter of agreement with the participating institution(s) before the trial begins to demonstrate site capability and capacity. National templates are available in Additional Resources (K) and (L). In addition, the investigators and the sponsor or his/her designated representative must sign an agreement specific to the clinical trial.

EC Confirmation of Review and Approval

The MHCTR and the MHCTR2006 mandate that the sponsor or his/her designated representative is responsible for ensuring that the CI has obtained confirmation of the EC’s approval. Per the G-MHRA-CTApp, an EC opinion may be obtained before, during, or after the MHRA application has been electronically submitted to IRAS, the EudraCT database, or the Common European Submission Portal (CESP). The final favorable opinion letter can be obtained from IRAS. The MHRA Clinical Trials Unit is also automatically notified of all EC opinions as soon as they are issued.

As per the MHCTR, and Additional Resource (A), the sponsor or his/her designated representative should also notify the EC of any substantial amendments to the protocol, and submit all relevant documents in support of such amendments. These amendments may not be implemented without a favorable opinion from the EC. (See Ethics Committee topic, Scope of Review subtopic and Clinical Trial Lifecycle topic, Submission Content subtopic for additional details on the EC review and approval process).

Clinical Trials Registry

As per Additional Resources (M) and (N), effective September 30, 2013, the sponsor or investigator is required to register the clinical trial in a publically accessible database as a condition of a favorable ethical opinion. HRA recognizes any register covered by the World Health Organization (WHO) list or the International Committee of Medical Journal Editors (ICMJE). Failure to register in this database will be treated as a breach of good research practice.

Overview

According to Additional Resources (A), (B), and (C), the following definitions provide a basis for a common understanding of the United Kingdom’s (UK’s) safety reporting requirements:

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

Per the G-MHRA-CTAuth, the Medicines and Healthcare Products Regulatory Agency (MHRA) recommends full compliance with reference safety information contained in Additional Resource (D) by January 1, 2019. The guidance was developed by the Clinical Trials Facilitation Group of the Heads of Medicines Agencies.

Reporting Requirements for AEs/ADRs

Investigator Responsibilities

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

Sponsor Responsibilities

According to the MHCTR, the G-MHRA-CTAuth, and Additional Resources (A) and (E), the sponsor is required to record and report all relevant information about fatal or life-threatening SUSARs as soon as possible, but no later than seven (7) calendar days, to the MHRA, to the competent authorities of any other European Economic Area (EEA) Member State other than the UK, in which the trial is being conducted, and to the EC. Any additional relevant information should be sent within eight (8) days of the initial report. The sponsor must also report any non-fatal or non-life-threatening SUSARs no later than 15 calendar days following first awareness of the event. Per Additional Resource (B), the investigator and the sponsor share responsibility for the assessment and evaluation of adverse events with regard to seriousness, causality, and expectedness.

As per the MHCTR, the G-MHRA-CTAuth, and Additional Resources (A), (B), and (D), the sponsor or his/her designated representative must also provide the MHRA and the EC with an annual list of SUSARs related to all trials, both within and outside of the UK, and within 60 days of the reporting date. The list of SUSARs is provided in an annual report, which is referred to as a Development Safety Update Report (DSUR). The DSUR also provides all new available safety information received during the reporting period. According to Additional Resource (E), the Development International Birth Date (DIBD) is used to determine the start of the annual period for the DSUR. This date is the sponsor’s first authorization to conduct a clinical trial in any country worldwide. The start of the annual period for the DSUR is the month and date of the DIBD. See the G-MHRA-CTAuth for detailed DSUR submission instructions.

See the MHCTR and Additional Resources (A), (B), and (D) for detailed reporting requirements for the investigator and sponsor.

Form Completion & Delivery Requirements

As per the MHCTR, the G-MHRA-CTAuth, and Additional Resource (A), all SUSARs must be reported electronically by the sponsor or his/her designated representative and the institutions responsible for trial safety reporting by using the MHRA’s eSUSAR website or the EudraVigilance System. See the G-MHRA-CTAuth and Additional Resources (B), (F), (G), and (H) for detailed reporting requirements.

Data Monitoring Committee (DMC)

Although there is no statutory requirement under the MHCTR for a Data Monitoring Committee (DMC), according to Additional Resource (I), researchers should prepare and present interim reports to DMCs, as applicable. For more information on assessing the need for, establishing, and responsibilities and procedures of DMCs, see Additional Resource (J).

The Guideline for Good Clinical Practice E6(R2) (EU-ICH-GCPs) recommends establishing a DMC to assess the progress of a clinical trial, including the safety data and the critical efficacy endpoints at intervals, and to recommend to the sponsor whether to continue, modify, or stop a trial.

Overview

As indicated in the G-MHRA-CTAuth and Additional Resources (A), (B), (C), and (D), the investigator and the sponsor share responsibility for submitting progress reports on the status of a clinical trial and for submitting a final study report upon the trial’s completion. These requirements comply with the progress and final reporting requirements delineated in the European Medicines Agency’s implementation of the Guideline for Good Clinical Practice E6 (R2) (EU-ICH-GCPs).

Interim/Progress Reports

As stated in Additional Resource (A), the investigator is required to send progress reports to interested parties, including the sponsor and the ethics committee (EC), throughout the trial. In accordance with Additional Resources (A), (B), (C), and (D), the chief investigator (CI) is responsible for submitting progress reports annually, or more frequently if requested by the EC, on the status of a clinical trial. The CI must complete the annual progress report form listed in Additional Resource (E) and send it to the main EC, or, the EC reviewing the original application. See Ethics Committee topic, Scope of Assessment subtopic for additional information on the “main EC.”

Final Report

According to the G-MHRA-CTAuth, the sponsor must upload the end of trial summary results to EudraCT. For pediatric clinical trials, the sponsor should post the summary within six (6) months of the end of the trial; all other trials are within one (1) year of the end of the trial. A declaration of the end of a clinical trial should be sent to MHRA within 90 days of the global end of the trial. The sponsor does not need to submit the clinical trial summary report to the MHRA. However, the sponsor must send a short confirmation email to CT.Submission@mhra.gov.uk once the results have been uploaded to EudraCT with ‘End of trial: result-related information: EudraCT XXXX-XXXXXX-XX’ as the subject line. The submission may only be sent following the MHRA’s receipt of the Declaration of the End of a Clinical Trial Form. End of trial declarations must be submitted via the Common European Submission Portal (CESP).

As per Additional Resource (C), which complies with the EU-ICH-GCPs, the investigator is also required to submit a summary of the final study report to the main EC within one (1) year of the trial’s conclusion. There is no standard format for final reports. However, the minimum information to be provided to the EC should include whether the trial achieved its objectives, the main findings, and arrangements for publication or dissemination of research.

Overview

As per the MHCTR, the MHCTR2006, and Additional Resources (A), (B), (C), and (D), the sponsor is defined as an individual, company, institution, or organization who takes ultimate responsibility for the initiation, management, and financing (or arranging the financing) of a trial. The sponsor must ensure that the trial design meets appropriate standards, and arrange for the trial to be properly conducted and reported. In addition, per Additional Resource (F), the sponsor is the individual, organization, or partnership that takes on overall responsibility for proportionate, effective arrangements being in place to set up, run, and report a research project.

In accordance with the Guideline for Good Clinical Practice E6(R2) (EU-ICH-GCPs), the United Kingdom (UK) also permits a sponsor to transfer any or all of its trial-related duties and functions to a contract research organization (CRO) and/or institutional site(s). However, the ultimate responsibility for the trial data’s quality and integrity always resides with the sponsor. Any trial-related responsibilities transferred to a CRO should be specified in a written agreement. The CRO should implement quality assurance and quality control.

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

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

As stated in the MHCTR, the sponsor must either be established in the European Economic Area (EEA), or designate a legal representative who is established in the EEA. The MHCTR and Additional Resources (A) and (C) also specify that the sponsor may delegate any or all of his/her trial-related duties and functions to a CRO. However, the sponsor must ensure that this arrangement is formally agreed upon and documented.

For purposes of data protection requirements, the GDPR, the UK-DPAct, and the G-GDPR delineate that the sponsor acts as the “controller” in relation to research data. This is because the sponsor determines what data is collected for the research study through the protocol, case report form, and/or structured data fields in a database.

Overview

In accordance with the MHCTR, the MHCTR2006, the G-MHRA-CTApp, and Additional Resources (A) and (B), the sponsor or his/her designated representative is responsible for submitting a clinical trial application to the Medicines and Healthcare Products Regulatory Agency (MHRA) to obtain authorization to conduct a clinical trial. The MHCTR, the G-MHRA-CTApp, and Additional Resource (B) also state that if the sponsor is not based in the European Economic Area (EEA), it is a statutory requirement for the sponsor to appoint a legal representative located in the EEA.

As delineated in the G-MHRA-CTApp, and Additional Resources (C) and (D), to complete the clinical trial application package, the sponsor or his/her designated representative must apply for a EudraCT number, which is a prerequisite to creating a clinical trial application. The EudraCT number is a unique European Union (EU)-wide reference number assigned to a trial that is used by the review bodies (the MHRA and the ethics committees (ECs)) to exchange trial-related information. Only after receiving a EudraCT number can the sponsor or his/her designated representative generate a clinical trial application via the EU’s EudraCT database or the UK’s Integrated Research Application System (IRAS)'s database. Both systems provide a saved data file in the form of an XML file, which is stored on the sponsor’s or his/her designated representative’s local hard drive, can be shared across both systems, and can be generated into PDF files. However, per Additional Resource (E), IRAS is the most efficient submission option because it enables researchers to enter the information required by all UK review bodies only once, rather than having to complete several separate application forms to obtain these permissions and approvals.

The submission package may then be uploaded to EudraCT, IRAS, or the Heads of Medicines Agencies’ (HMA) Common European Submission Portal (CESP) for submission to the MHRA. Per the G-MHRA-CTApp and Additional Resource (G), the CESP is only used to submit files, not to download files to a local computer. Refer to Additional Resources (C), (D), (F), and (I) for detailed EudraCT application submission instructions, and Additional Resource (G) for CESP submission information. (See the Clinical Trial Lifecycle topic, Submission Content subtopic for documentation to be included in the application package.)

In addition to the completed application, per the MHCTR and the G-MHRA-CTApp, the sponsor or his/her designated representative must provide the MHRA with a copy of the EC opinion (if available), the clinical protocol, the investigator’s brochure, a signed declaration by the investigators, a certificate of good manufacturing practice for the manufacture of the trial medicine, and other documentation covered in the Clinical Trial Lifecycle topic, Submission Content subtopic.

Overview

As set forth in the MHCTR and the MHCTR2006, it is a legal requirement for an insurance and indemnity provision to be made to cover the liability of the investigator and sponsor for trial related injuries. The MHCTR does not ascribe responsibility to the sponsor or his/her designated representative to obtain insurance and indemnity. However, Additional Resources (A), (B), and (C), state that the sponsor or his/her designated representative is responsible for ensuring adequate insurance and indemnity arrangements are in place to cover the sponsor’s and the investigator’s potential liability, and for providing a copy of this coverage in the clinical trial application submission.

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

See the Sponsorship topic, Compensation subtopic and Informed Consent topic, Compensation Disclosure subtopic for specific details related to sponsorship compensation obligations.

Overview

As specified in the MHCTR, the sponsor or his/her designated representative is responsible for providing compensation to research participants and/or their legal heirs in the event of Phase I trial-related injuries or death.

According to Additional Resource (A), the sponsor or his/her designated representative may be required to follow the principles set forth in the Association of the British Pharmaceutical Industry (ABPI)’s guidelines to comply with the United Kingdom (UK)’s participant compensation and treatment requirements due to Phase I trial-related injuries.

The guidelines state that the sponsor should furnish written assurance to the investigator that the sponsor will agree to pay compensation to participants and/or his/her legal heirs in the event of trial-related injuries or death whenever a causal relationship with participation is demonstrated. The investigator, in turn, communicates this information to the relevant ethics committees (ECs).

See the Informed Consent topic, Compensation Disclosure subtopic for additional information.

Overview

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

The sponsor must also obtain the investigator(s) and the institution(s) agreement to:

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

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

Per Additional Resource (C), MHRA accepts a risk-adapted approach to trial management. Early in the protocol design stage, researchers should ask what are the critical processes and critical data for this trial and how best can any risks and/or vulnerabilities identified in these areas be mitigated. For more information on risk-adapted trial management, see Additional Resource (C).

Data Protection

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

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

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

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

As described in the G-GDPR, with regard to transparency, the sponsor should understand whether personal data is collected indirectly from a third party or directly, as these determine the actions to take to comply with data protection requirements. In most cases, the sponsor will need to provide transparency information about the legal basis and other details of processing personal data starting from May 25, 2018. See the table in G-GDPR, which sets out the specific transparency requirements for personal data. In addition, Additional Resource (G) contains a series of templates by the Health Research Authority (HRA) with suggested transparency language. Further, the sponsor should take measures to ensure data is processed securely, giving consideration to security, storage, and pseudonymization/anonymization when possible. For details on complying with security and storage requirements, see Additional Resources (G) and (H). For additional information about consent and individual rights, see the Informed Consent topic, Documentation and Required Elements subtopics.

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

Electronic Data Processing System

According to the EU-ICH-GCPs, when using electronic trial data handling processing systems, the sponsor must ensure and document that the electronic data processing system conforms to the sponsor’s established requirements for completeness, accuracy, reliability, and consistency of intended performance. To validate such systems, the sponsor should use a risk assessment approach that takes into consideration the system’s intended use and potential to affect human subject protection and reliability of trial results. In addition, the sponsor must maintain SOPs that cover system setup, installation, and use. The SOPs should describe system validation and functionality testing, data collection and handling, system maintenance, system security measures, change control, data backup, recovery, contingency planning, and decommissioning. With respect to the use of these computerized systems, the responsibilities of the sponsor, investigator, and other parties should be clear, and the users should receive relevant training.

Record Management

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

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

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

Audit Requirements

As part of its QA system, the EU-ICH-GCPs notes that the sponsor should ensure the trial is monitored. If or when the sponsor performs an audit, the purpose of the audit should be to evaluate trial conduct and compliance with the protocol, SOPs, the EU-ICH-GCPs, and other applicable regulatory requirements. The sponsor should appoint auditors to review the clinical trial. The sponsor should ensure that the auditors are qualified by training and experience, and auditor’s qualifications should be documented. The sponsor must also ensure that the audit is conducted in accordance with his/her own SOPs and the auditor observations are documented. The sponsor should develop a systematic, prioritized, risk-based approach to monitoring clinical trials. The extent and nature of monitoring is flexible and permits varied approaches that improve effectiveness and efficiency. The sponsor may choose on-site monitoring, a combination of on-site and centralized monitoring, or, where justified, centralized monitoring. The sponsor should document the rationale for the chosen monitoring strategy (e.g., in the monitoring plan).

Premature Study Termination/Suspension

The G-MHRA-CTAuth states that if a trial is prematurely terminated or suspended, the sponsor should inform the MHRA and the ethics committee (EC) no later than 15 days after the termination or suspension. The notification should be made as a substantial amendment using the notification of amendment form (Additional Resource (I)), and explain what has been stopped and the reasons for the suspension. To terminate a trial, the sponsor should complete the end-of-trial declaration form (Additional Resource (J)) and include a brief explanation of the reasons for ending the trial. Both types of forms should be submitted using Heads of Medicines Agencies (HMA) Common European Submission Portal (CESP).

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

Multicenter Studies

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

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

Data Monitoring Committee (DMC)

Although there is no statutory requirement under the MHCTR for a Data Monitoring Committee (DMC), according to Additional Resource (E), researchers should prepare and present interim reports to DMCs, as applicable. For more information on assessing the need for, establishing, and responsibilities and procedures of DMCs, see Additional Resource (F).

The EU-ICH-GCPs recommends establishing a DMC to assess the progress of a clinical trial, including the safety data and the critical efficacy endpoints at intervals, and to recommend to the sponsor whether to continue, modify, or stop a trial.

Overview

As set forth in the European Medicines Agency’s implementation of the Guideline for Good Clinical Practice E6 (R2) (EU-ICH-GCPs) and Additional Resource (A), the sponsor is responsible for selecting the investigator(s) and the institution(s) for the clinical trial, taking into account the appropriateness and availability of the study site and facilities. The MHCTR2006 and Additional Resource (A) indicate that the sponsor must also ensure that the investigator(s) are qualified by training and experience. Additionally, the sponsor must define and allocate all study related duties and responsibilities to the relevant parties participating in the study.

As delineated in the MHCTR, the MHCTR2006, the EU-ICH-GCPs, and Additional Resource (B), prior to entering into an agreement with the investigator(s) and the institution(s) to conduct a study, the sponsor should provide the investigator(s) with the protocol and an investigator’s brochure. Per the EU-ICH-GCPs, if a multicenter trial is going to be conducted, the sponsor must organize a coordinating committee or select coordinating investigators.

Although there is no statutory requirement under the MHCTR for a Data Monitoring Committee (DMC), according to Additional Resource (C), researchers should prepare and present interim reports to DMCs, as applicable. For more information on assessing the need for, establishing, and responsibilities and procedures of DMCs, see Additional Resource (D). The EU-ICH-GCPs recommends establishing a DMC to assess the progress of a clinical trial, including the safety data and the critical efficacy endpoints at intervals, and to recommend to the sponsor whether to continue, modify, or stop a trial.

Per Additional Resource (E), adding a new trial site or change of principal investigator constitutes a substantial amendment, which requires notification to the ethics committee (EC). Sites that were listed as potential sites on the original ethics application do not need to be submitted as a substantial amendment. For more information about the amendment process and ethics notification, see Additional Resource (D).

Foreign Sponsor Responsibilities

As per the MHCTR and Additional Resource (F), if the sponsor is not based in the European Economic Area (EEA), it is a statutory requirement for the sponsor to appoint a legal representative located in the EEA. Additional foreign sponsor requirements are listed in Section 5.2 of the EU-ICH-GCPs.

Overview

In all United Kingdom (UK) clinical trials, a freely given informed consent must be obtained from each participant in accordance with the requirements set forth in the MHCTR, the MHCTR2006, and the Guideline for Good Clinical Practice E6 (R2) (EU-ICH-GCPs). As per the MHCTR, the MHCTR2006, and Additional Resource (B), the informed consent form (ICF) is viewed as an essential document that must be reviewed and approved by an ethics committee (EC) recognized by the United Kingdom Ethics Committee Authority (UKECA) (henceforth referred to as a “recognized EC”) and operating according to standard operating procedures (Additional Resource (B)) issued by England’s Health Research Authority (HRA), formerly the National Research Ethics Service. The ICF must be provided to the EC with the clinical trial application. (See the Informed Consent topic, Required Elements subtopic for details on what should be included in the form.)

The MHCTR and G-ConsentPIS, state that the investigator(s) must provide detailed research study information to the participant and/or his/her legal representative(s) or guardian(s). The MHCTR and G-ConsentPIS also specify that the oral and written information concerning the trial, including the ICF, should be easy to understand and presented without coercion or unduly influencing a potential participant to enroll in the clinical trial. The participant, and his/her legal representative(s) or guardian(s), should also be given adequate time to consider whether to participate. Per G-ConsentPIS, the Participant Information Sheet (PIS) supports the consent process to help ensure participants have been adequately informed. In addition, the PIS forms part of the transparency information that must be provided to participants under the data protection legislation for the use and processing of personal data. Per the GDPR and UK-DPAct, consent to participate in research is not the same as consent as the legal basis for processing personal data under the data protection legislation. For more information about the sponsor’s and investigator’s responsibilities to comply with the data protection requirements (e.g., transparency, safeguards, and data rights), see the Sponsorship topic.

As provided in G-ConsentPIS, consent can be documented electronically or in writing. A physical or electronic copy of the signed consent form will still need to be provided to the participant. To record consent electronically, electronic signatures will likely be needed. Because there are different forms and classifications of electronic signatures, the researcher should determine what is appropriate for the particular study.

Re-Consent

According to Additional Resource (C), changes to the protocol might lead to a modification of the PIS and any new participant information should be appended. If there is a need to obtain new consent from the participants, the procedure should be described and approved by the EC before such changes are implemented. The participant and/or his/her legal representative(s) or guardian(s) will also be required to re-sign the revised ICF and receive a copy of any amended documentation.

Per the G-GDPR, because consent is not a legal basis for processing data under data protection legislation, in most cases researchers will not need to obtain re-consent from existing participants or legal representatives to comply with new data protection requirements.

Language Requirements

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

Documentation Copies

The MHCTR states that the participant and/or the participant’s legal representative(s) or guardian(s), and the investigator(s) must sign and date the ICF. Where the participant is illiterate, and/or his/her legal representative(s) or guardian(s) is illiterate, verbal consent should be obtained in the presence of and countersigned by an impartial witness.

Overview

As delineated in the MHCTR, the MHCTR2006, and the Guideline for Good Clinical Practice E6 (R2) (EU-ICH-GCPs), prior to beginning a clinical trial, the chief investigator (CI) is required to obtain a favorable opinion from a recognized ethics committee (EC) for the written informed consent form (ICF) and any other information being provided to the research participant and/or his/her legal representative(s) or guardian(s).

No Coercion

As per the G-ConsentPIS, none of the oral and written information concerning the research study, including the written ICF, should contain any language that causes the participant and/or his/her legal representative(s) and/or guardian(s) to waive or to appear to waive his/her legal rights, or that releases or appears to release the investigator(s), the institution, the sponsor, or their representatives from their liabilities for any negligence.

Participant Information Sheet

Per the G-Consent PIS, 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. As indicated in the G-GDPR and Additional Resource (B), the Health Research Authority (HRA) has developed a series of templates 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 (i.e., before or after May 25, 2018).

Per the GDPR and UK-DPAct, consent to participate in research is not the same as consent as the legal basis for processing under the data protection legislation. For more information about the sponsor’s and investigator’s responsibilities to comply with the data protection requirements (e.g., the lawful basis to hold and use personal data, transparency, safeguards, and data rights), see Sponsorship topic.

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

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

ICF Required Elements

Based on the MHCTR and Additional Resource (A), the ICF should include the following statements or descriptions, as applicable:

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

(See the Informed Consent topic, Compensation Disclosure and Vulnerable Populations subtopics and the Specimens topic, Consent for Specimens subtopic for further information.)

For more information about informed consent required elements, see Additional Resources (A), (B), (C), and (D).

Overview

In accordance with the MHCTR, the G-ConsentPIS, and Additional Resource (A), the informed consent form (ICF) should contain a statement describing the compensation or medical treatment a participant can receive for participating in a clinical trial.

Compensation for Participation in Research

As stated in the MHCTR and the Guideline for Good Clinical Practice E6 (R2) (EU-ICH-GCPs), ethics committees should consider, in particular, the provision of indemnity or compensation in the event of injury or death attributable to the trial.

Compensation for Injury

As per the MHCTR and the EU-ICH-GCPs, the ICF should contain a statement advising the participant of available compensation and medical treatment in the event of any trial-related injury in a clinical trial.

(See the Informed Consent topic, Required Elements subtopic for additional details on what should be included in the ICF, and the Sponsorship topic, Compensation subtopic for information on sponsor requirements.)

Overview

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

The Right to Participate, Abstain, or Withdraw

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

The Right to Information

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

The Right to Privacy and Confidentiality

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

Per the GDPR, the UK-DPAct, the G-GDPR, and Additional Resource (A), 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 GDPR specifies what data individuals have the right to be informed about (i.e., privacy information). In addition, as delineated in the GDPR, the UK-DPAct, the G-GDPR, and Additional Resource (A), 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 GDPR, then the PIS may need to be revised as a non-substantial amendment. For more information about the sponsor’s (called the “controller” in the GDPR) data protection requirements, see the Sponsorship topic, Quality, Data & Records Management subtopic.

The Right of Inquiry/Appeal

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

The Right to Safety and Welfare

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

Overview

The MHCTR, the MHCTR2006-No2, the MHCTR-BSQ, and Additional Resource (A) make provisions to protect the rights of a research participant during the informed consent process when a clinical trial of an investigational product is complicated by special circumstances. Special circumstances include medical emergencies and when a participant is mentally incapacitated.

Medical Emergencies

As delineated in the G-ConsentPIS and Additional Resources (A) and (C), in an emergency, if the signed informed consent form (ICF) cannot be obtained from the research participant, the consent of his/her legal representative(s) or guardian(s) should be obtained. If the prior consent of the participant or his/her legal representative(s) or guardian(s) cannot be obtained, the participant’s enrollment should follow measures specified in the protocol, and the ethics committee (EC) must provide documented approval in order to protect the participant’s rights, safety, and well-being. The participant or his/her legal representative(s) or guardian(s) should provide consent as soon as possible.

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

Mentally Incapacitated Persons

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

Overview

As per the MHCTR and Additional Resources (B) and (C), in all United Kingdom (UK) clinical trials, research participants selected from vulnerable populations must be provided additional protections to safeguard their health and welfare during the informed consent process. Additional Resources (B), (C), and (D) characterize vulnerable populations as those who are dependent on others and are unable to express their opinion freely or make their own decisions. These participants may include children, persons with mental or physical incapacities, persons with incurable diseases, persons in nursing homes, unemployed or impoverished persons, patients in emergency situations, ethnic minority groups, homeless persons, nomads, prisoners, detainees, refugees, members of a group with a hierarchical structure, such as students, subordinate hospital and laboratory personnel, pharmaceutical industry employees, members of the armed forces, and persons kept in detention.

See the Informed Consent topic, and the subtopics of Children/Minors; Pregnant Women, Fetuses & Neonates; and Mentally Impaired for additional information about these vulnerable populations.

Overview

According to the MHCTR, a minor is an individual under 16 years of age. However, per Additional Resource (B), in situations where the MHCTR does not apply, a minor is an individual under 18 years of age.

As set forth in the MHCTR, the MHCTR2006, the G-ConsentPIS, and Additional Resources (B) and (C) (, when the research participant is a minor, informed consent should be obtained from his/her legal representative(s) and/or guardian(s). As per Additional Resource (B), legally, the researcher needs only to obtain consent from one (1) person with parental responsibility; however, consent from all legal representative(s) and/or guardians is encouraged.

Additionally, precautions against possible physical and mental harms should be exercised. All pediatric participants should be informed to the fullest extent possible about the study in language and terms that they are easily able to understand. The rights of the minors should also be respected for their voluntary decision to participate in a clinical study.

The MHCTR, the MHCTR2006, and Additional Resources (B), (C), and (D) state that a study may only be conducted on minors if several conditions are fulfilled including:

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

See the MHCTR, the MHCTR2006, and Additional Resources (B) and (C) for detailed requirements. The G-ConsentPIS provides style guidance and suggestions for presenting age-appropriate information in the participant information sheet.

Assent and Minor Privacy Requirements

As delineated in Additional Resource (B), if a minor is deemed competent to give assent to decisions about participation in research, the investigator(s) must obtain that assent in addition to the consent of his/her legal representative(s) and/or guardian(s). If the child does not assent, this should be respected.

Furthermore, Additional Resource (B) states that a minor’s ability to assent or consent is based on his/her ability to understand and assess options, rather than on his/her age. For a minor to be able to have the capacity to make a particular decision, he/she must be able to:

• Comprehend and retain information material to the decision, especially the consequences of having or not having any intervention
• Use and weigh this information in a decision-making process
• Reach and communicate a decision

In addition, Additional Resource (B) specifies that if the competent minor specifically asks for the family not to be involved, and they cannot be persuaded otherwise, his/her privacy should be respected.

Overview

As set forth in Additional Resource (A) any research studies involving women capable of becoming pregnant and breastfeeding women require additional safeguards to ensure the research conforms to appropriate ethical standards and upholds societal values.

According to Additional Resource (A), the following conditions are required for research to be conducted with this population:

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

No relevant provisions.

Overview

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

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

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

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

See the MHCTR, G-ConsentPIS, and Additional Resource (A) for detailed requirements.

Overview

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

Overview

According to the MHCTR, the MHCTR2006, the G-MHRA-CTApp, and the G-MHRA-GMP/GDP, the Medicines and Healthcare Products Regulatory Agency (MHRA) is responsible for authorizing the manufacture or import of investigational products (IPs) (known as investigational medicinal products (IMPs) in the United Kingdom (UK)) to be used in a trial. A Manufacturer’s Authorization for Investigational Medicinal Products (MIA(IMP)) must be obtained by the person responsible for the manufacture or importation of any IP to be used in the trial. The sponsor or his/her designated representative must include a copy of the MIA(IMP) in the clinical trial application submission to the MHRA. The applicant must complete the form listed in Additional Resource (B) to obtain an MIA(IMP) from the MHRA. The MHRA will approve the manufacture or import of an IP after the clinical trial application has been approved.

As per the MHCTR, the MHCTR2006, the G-MHRA-GMP/GDP, Additional Resources (C) and (D), and the EU Good Manufacturing Practice Directive, the MIA(IMP) holder must also comply with the Good Manufacturing Practice (GMP) guidelines and provide an IMP Certificate of Analysis. In addition, the MHCTR, the MHCTR2006, the G-MHRA-GMP/GDP, Additional Resource (C), the EU Good Manufacturing Practice Directive, and the EU Good Clinical Practice Directive, specify that the holder of an MIA(IMP) must always have the services of at least one Qualified Person (QP) at his/her disposal. The QP must satisfy the qualification and experience requirements delineated in the aforementioned sources. The QP’s primary legal responsibility is to certify batches of IPs prior to using in a clinical trial, or prior to releasing for sale and placing on the market. See Part 6 and Schedule 6 of the MHCTR for detailed applicant requirements.

Overview

In accordance with the MHCTR, the MHCTR2006, the EU Good Clinical Practice Directive, and the EU Clinical Trials Regulation, the sponsor or his/her designated representative is responsible for complying with the principles of good clinical practice (GCP) as specified in the European Medicines Agency’s implementation of the Guideline for Good Clinical Practice E6 (R2) (EU-ICH-GCPs), and for providing investigators with an Investigator’s Brochure (IB). The IB must contain all of the relevant information on the investigational product(s) (IPs) (known as investigational medicinal products (IMPs) in the United Kingdom (UK)) obtained through the earlier research phases, including preclinical, toxicological, safety, efficacy, and adverse events data. The sponsor or his/her designated representative should also update the IB as significant new information becomes available.

IB Content Requirements

As specified in the EU-ICH-GCPs, the IB must provide coverage of the following areas:

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

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

As defined in the EU-ICH-GCPs, the sponsor is also accountable for supplying the IMP, including the comparator(s) and placebo, if applicable. The MHCTR, the MHCTR2006, the G-MHRA-GMP/GDP, and Additional Resources (C), (D), and (F) also specify that the sponsor or his/her designated representative must ensure that the products are manufactured in accordance with current Good Manufacturing Practice (GMP) guidelines. (See Investigational Products topic, Product Management subtopic for additional information on IP supply, storage, and handling requirements).

Certificate of Analysis and Drug Manufacturing Certificate Requirements

As stated in Additional Resource (E), the Manufacturer’s Authorization for Investigational Medicinal Products (MIA(IMP)) holder must provide the Medicines and Healthcare Products Regulatory Agency (MHRA) with documentation including the following:

• MIA(IMP) license of final Qualified Person (QP) releasing site
• MIA(IMP) license of placebo manufacturing site (if different from final QP releasing site)
• Certified QP release statement
• Import QP release certificate (if applicable)
• QP declaration
• IP certificate of analysis

Overview

Labeling for investigational products (IPs) (known as investigational medicinal products (IMPs) in the United Kingdom (UK)) must comply with the requirements set forth in the MHCTR, the MHCTR2006, Additional Resource (A), the EU Good Manufacturing Practice Directive, and the European Medicines Agency’s implementation of the Guideline for Good Clinical Practice E6 (R2) (EU-ICH-GCPs). Per Additional Resource (C), labeling for IPs must ensure protection of the participant and traceability, to enable identification of the product and trial, and to facilitate proper use of the IP. As specified in Additional Resources (A) and (B), for an IP to be used in a clinical trial, it must be properly labeled in the official language of the country where the trial is being conducted.

As set forth in Additional Resources (A) and (B), the following labeling information must be included on the primary package label (or any intermediate packaging), and the outer packaging:

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

As per the MHCTR and Additional Resource (B), a sample of the labeling is required as part of the clinical trial application submission. (See Clinical Trial Lifecycle topic, Submission Content subtopic for detailed clinical trial application submission requirements). In addition, Additional Resource (B) states that the IP should be coded and labeled in a manner that protects the blinding, if applicable. Furthermore, according to Additional Resource (A), the IP must also be suitably packaged in a manner that will prevent contamination and unacceptable deterioration during transport and storage.

Overview

In accordance with the MHCTR, the MHCTR2006, and the EU Good Clinical Practice Directive, the sponsor or his/her designated representative is responsible for complying with the principles of good clinical practice (GCP) as specified in the European Medicines Agency’s implementation of the Guideline for Good Clinical Practice E6 (R2) (EU-ICH-GCPs) and for providing investigators with an Investigator’s Brochure (IB). The IB must contain all of the relevant information on the investigational product(s) (IPs) (known as investigational medicinal products (IMPs) in the United Kingdom (UK)) obtained through the earlier research phases, including preclinical, toxicological, safety, efficacy, and adverse event data. The sponsor should also update the IB as significant new information becomes available.

Investigational Product Supply, Storage, and Handling Requirements

As defined in the MHCTR, the EU-ICH-GCPs, and Additional Resource (C), the sponsor must supply the investigator(s)/institution(s) with the IP(s), including the comparator(s) and placebo, if applicable. The sponsor should not supply either party with the IP(s) until obtaining Medicines and Healthcare Products Regulatory Agency (MHRA) approval and a favorable opinion from a recognized ethics committee (EC).

The sponsor must ensure the following:

• IP product quality and stability over the period of use
• IP manufactured according to EU Good Manufacturing Practice Directive
• Proper coding, packaging and labeling of the IMP(s)
• IP use record including information on the quantity, loading, shipment, receipt, dispensing, handling, reclamation and destruction of the unused IP
• Acceptable storage temperatures, conditions, and times for the IP
• Written procedures including instructions for handling and storage of the IP, adequate and safe receipt, dispensing, retrieval of unused IP(s), and return of unused IP(s) to the sponsor
• Timely delivery of the IP(s)
• Establishment of management and filing systems for the IPs
• Sufficient quantities of the IP for the trial

Refer to the MHCTR, the EU-ICH-GCPs, and Additional Resource (C) for detailed, sponsor-related IP requirements.

Record Requirements

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

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

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

Overview

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

• Relevant material: As per the UK-HTA, CODE E, and Additional Resources (A) and (B), “relevant material” or “human tissue” is any material from a human body, other than gametes, that consists of, or includes, cells. This also includes blood (except where held for transplantation). Hair and nails from living persons are specifically excluded from this definition, as are gametes and embryos outside the body.
• Substance/active substance: Additional Resource (C) defines “substance” as any matter regardless of origin which may be human (e.g., blood and blood products), animal, vegetable, or chemical.

Overview

As set forth in the UK-HTA, the HTRegs, and Additional Resource (A), the Human Tissue Authority (HTA) regulates the storage and use of specimens (known as “relevant materials” or “human tissue” in the United Kingdom (UK)) from the living, and the removal, storage, use, and licensing of relevant materials/human tissue from the deceased for specified health-related purposes in the UK. The UK-HTA refers to specified purposes as “scheduled purposes.” Note that per Additional Resources (A) and (B), an HTA license is not needed for storage of specimens for certain research projects that have been approved by an ethics committee (EC). HTA and the UK Health Departments’ Research Ethics Service (RES) have agreed that an EC can give generic ethical approval for a research tissue bank’s arrangements for collection, storage, and release of specimens, provided the specimens in the bank are stored on HTA-licensed premises. This approval can extend to specific projects receiving non-identifiable tissue from the bank. The specimens do not then need to be stored on HTA-licensed premises, nor do they need project-specific ethical approval. However, a license is required for specimens stored for which there is no ethical approval (e.g., in large biobanks).

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

Relevant Materials/Human Tissue

As specified in the UK-HTA, the HTA has jurisdiction regarding the import and export of relevant materials/human tissue, and complies with the Code of Practice on import and export set forth in CODE E. According to the UK-HTA, CODE E, and Additional Resource (C), the import and export of relevant material/human tissue is not in itself a licensable activity under the UK-HTA. However, once the material is imported, storage of this material may be licensable if it is deemed to be for a specified or scheduled purpose.

If relevant material/human tissue is being imported or exported for an application, the HTRegs specify that this must be carried out under the authority of a license or third party agreement with an establishment licensed by the HTA to store material for human application.

CODE E requires imported material to be procured, used, handled, stored, transported, and disposed of in accordance with the donor’s consent. In addition, due regard should be given to safety considerations, and with the dignity and respect accorded to human bodies, body parts, and tissue as delineated in CODE E. Any individual or organization wishing to import human bodies, body parts, and tissue into England, Wales or Northern Ireland must comply with the guidelines set forth in CODE E.

Exported material should also be procured, used, handled, stored, transported and disposed of, in accordance with the donor’s consent, with due regard for safety considerations, and with the dignity and respect accorded to human bodies, body parts, and tissue as stated in CODE E. This includes providing donors with adequate information upon taking consent, that their samples may be transported as exported samples for use abroad. It is the responsibility of the recipient country to ensure that, prior to export, the material is handled appropriately and that the required country standards have been met.

Overview

In accordance with the UK-HTA, Code A, and Additional Resources (A), (B), and (C), prior to collecting, storing, or using a research participant’s specimens (known as relevant material/human tissue in the United Kingdom (UK)), consent from the participant and/or his/her legal representative(s) and ethics committee (EC) approval must be obtained. The scope of the UK-HTA provisions specifically cover England, Northern Ireland, and Wales. The UK-HTA licensing requirements do not apply in Scotland, with the exception of those provisions relating to the use of DNA. Scotland complies with the Scotland-AnatAct and the Scotland-HTA for the removal, retention, use, licensing, and import of human organs, tissue, and tissue samples specifically removed post mortem, and subsequently used for research.

Per G-ConsentPIS, the Participant Information Sheet (PIS) supports the consent process to help ensure participants have been adequately informed. In addition, the PIS forms part of the transparency information that must be provided to participants under the data protection legislation for the use and processing of personal data. As delineated in the GDPR and UK-DPAct, personal data includes genetic data and biological samples. G-GDPR indicates that for the purposes of the GDPR, the legal basis for processing data for health and social care research should not be consent. This means that requirements in GDPR relating to consent do not apply to health and care research, and therefore, do not change the consent requirements to participate in a clinical trial and remove human tissue samples. For more information about the sponsor and investigator’s responsibilities to comply with the data protection requirements (e.g., transparency, safeguards, and data rights), see the Sponsorship topic.

Human Genetic Research Consent Requirements

As set forth in the UK-HTA and Additional Resources (C), (D), and (E), the UK-HTA considers it a UK-wide offense to have relevant material/human tissue with the intention of conducting a DNA analysis or using the results of this analysis without “qualifying consent” from a participant and/or his/her legal representative(s), unless the information is being used for an “excepted purpose.” The UK-HTA states that “qualifying consent” is consent required in relation to the analysis of DNA manufactured by the human body. An “excepted purpose” is defined as the following:

• Medical diagnosis/treatment
• Coroner purposes
• Crime prevention/detection
• Prosecution
• National security
• Court/tribunal order
• An existing holding to be used for research

In addition to participant consent, EC approval is required for the analysis of DNA in material from the living, where the research is not within the terms of consent for research from the person whose body manufactured the DNA. Please refer to the UK-HTA, and Additional Resources (C), (D), (E), and (F) for detailed DNA analysis consent requirements.

Human Tissue/Relevant Material Consent Requirements

In accordance with the UK-HTA, Code A, and Additional Resources (A), (B), and (C), prior to removing, storing, or using any living or deceased person’s organs, tissues, or cells for the purpose of research in connection with disorders in, or the functioning of the human body, investigators must obtain “appropriate consent” from the trial participants and/or their legal representative(s) as well as EC approval. The UK-HTA and Code A define “appropriate consent” in terms of the person who may give consent. This person may be either the trial participant, his/her legal representative (referred to as “nominated representative” in the UK-HTA), or, in the absence of either of these, the consent of a person in a “qualifying relationship” with the participant immediately before he/she dies.

As indicated in the UK-HTA and Code A, in the case of a living child donor, “appropriate consent” must be obtained from the child’s legal representative(s). If the child has died, the written consent must be obtained prior to the child’s death in the presence of at least one (1) witness, or, it must be signed at the direction of the child concerned, in his/her presence, and in the presence of at least one (1) witness.

As indicated in the UK-HTA and Code A, in the case of an adult donor, 18 years or older, his/her consent must be obtained prior to removing any materials from his/her body. If the adult has died, his/her written consent is only valid when it is signed by the person prior to his/her death in the presence of at least one (1) witness at his/her direction, or it is contained in the person’s will. An adult donor may also appoint one (1) or more people (“nominated representative(s)”) to consent on his/her behalf in the event of his/her death. This consent may be obtained orally or in writing. If the deceased donor has neither provided consent nor an appointed or nominated representative, appropriate consent may be given by someone in a “qualifying relationship” with the donor immediately prior to his/her death. Refer to the UK-HTA and Code A to obtain a complete list of relatives in hierarchical order who may qualify to provide this consent.

In the case of obtaining materials from an adult donor who lacks the capacity to consent, and neither a decision to consent or not consent is in force, the UK-HTA, the MCA2005, and Additional Resources (C) and (E) state that approval by an EC is required. In addition, a living person’s organs, tissues, or cells may be stored and used without consent if the investigator is unable to identify the individual and it is being used for an EC-approved research project. Please refer to the UK-HTA and Code A for detailed consent requirements.

See the Informed Consent topic, Required Elements and Participant Rights subtopics for additional information on informed consent.