2. General Questions

2.1 Name of Regulatory Authority

The UK regulatory authority responsible for clinical trial approvals, oversight, and inspections in the United Kingdom (UK) is the Medicines and Healthcare Products Agency (MHRA). The MHRA grants permission for clinical trials to be conducted in the UK. The MHRA is responsible for reviewing, evaluating, and approving applications for clinical trials using registered or unregistered investigational medicinal products (IMPs). (Note: IPs are known as investigational medicinal products (IMPs) in the United Kingdom (UK)). The scope of the MHRA’s assessment includes all clinical trials (Phases I-IV).

MHRA’s contact information:

• Medicines and Healthcare Products Regulatory Agency, 10 South Colonnade, Canary Wharf, LONDON
   E14 4PU, UK. Phone: +44 (0)20-3080-6000.
• General Email: info@mhra.gov.uk
• Data Protection Email: DataProtection@mhra.gov.uk
• Importing Investigational Products from Approval Countries Email: gmpinspectorate@mhra.gov.uk
• Clinical Research Office: Email: clintrialhelpline@mhra.gov.uk, Phone: +44 020-3080-6456
• In addition, the G-CTAuth includes other email addresses for specific purposes related to submissions.

2.2 Name of Ethics Committee

There are numerous Research Ethics Committees (RECs) across the UK. See Listings, contact information, and meeting dates for Research Ethics Committees (RECs) within the UK Health Departments’ Research Ethics Service.

2.3 Clinical Trial Application Language

Applications and any accompanying material, such as the Informed Consent Form (ICF) content, should be presented in English.

2.4 Is regulatory approval required from both regulatory authorities and/or EC?

In line with international standards, before a clinical trial of a medicine can begin, a Research Ethics Committee (REC) must give a favorable opinion and the MHRA must issue an authorization.

2.5 Can regulatory authority and EC submission be done in parallel?

Yes. As of 1 January 2022, applications for clinical trials involving CTIMPS (Clinical Trial of an Investigational Medical Product) must be prepared, submitted, and reviewed via the combined review service. This offers CTIMP applicants and sponsors a single application route and coordinated review by MHRA and the research ethics committee, leading to a single UK decision.

Applications for combined review are prepared and submitted in a new part of the Integrated Research Application System (IRAS). 

Please also refer to MHRA's “Combined Review of clinical trials of investigational medicinal products”.

2.6 Requirement of any import permit/license before investigational product/study product is shipped from point of origin

Sponsor of a UK clinical trial using IMPs imported into Great Britain from countries on an ‘approved country for import’ list (initially, all EU and EEA countries) will require a UK Manufacturing and Import Authorization (MIA(IMP)) holder to put in place an assurance system to check these IMPs have been certified by a Qualified Person (QP) in a listed country, before release to the trial. 

This assurance system must be overseen by a QP, however the IMPs would not require recertification. The routine tasks relating to the verification of QP certification in a listed country may be delegated by the QP named on the UK MIA(IMP) to appropriate personnel operating within their MIA(IMP) quality system. The QP named on the UK MIA(IMP) that is responsible for this verification process may be resident in the UK or a listed country. Any manufacturing activity or importation from a non-listed country must be certified by a QP who is resident in the UK.

A Sponsor may perform verification of QP certification in a listed country themselves if they are the holder of a UK MIA(IMP). Alternatively, they may outsource this verification to a third party who holds a UK MIA(IMP).

IMPs coming directly to Great Britain from third countries that are not on the approved country for import list will continue to require import and QP certification in the UK by the MIA(IMP) holder as per the existing requirements.

All the requirements for importing IMP to the UK can be found on the MHRA website under the guidance page “Importing Investigational Medicinal Products (IMP) from countries on a list to Great Britain”.

2.7 Biological Specimen Export Requirements

For exporting human tissue for research overseas, there is no legal requirement for licensing or ethical approval. However, applications may be made voluntarily to an NHS REC. The REC will confine its review to the activities to be conducted in the UK, in particular the arrangements for informed consent. 

It will not undertake detailed scrutiny of overseas research projects. Where appropriate, these should be ethically reviewed in the host country. 

When seeking consent from donors, it is good practice to inform them of plans to export their human tissue outside the UK for use in valid scientific research by overseas collaborators. 

In the HTA Code of Practice and Standards on Research (Code E), there is detailed guidance for individuals and establishments involved in the export of human tissue for research (paragraphs 110-114). 

2.8 Are studies of GMOs permitted (e.g., GMOs used in vaccines/vaccine manufacture and other modified products)?

Yes. The UK regulatory framework for GMO-IMP authorization is based primarily on “The Genetically Modified Organism (Contained Use) Regulation 2014” for contained use (CU). In principle, based on the characteristics of the genetically modified (GM) product (i.e. replication ability, possibility of shedding, survival in the environment), GMOs could be approved according to deliberate release (DR) procedures as defined in “Genetically Modified Organisms (Deliberate Release) Regulation 2002”.

GMO studies carried out under the Medicines for Human Use (Clinical Trials) Regulations 2004, require a clinical trials authorization (CTA) from MHRA and approval by an appropriate research ethics committee, which may be the Gene Therapy Advisory Committee (CTAG; a multi-center research ethics committee). Compliance with the Good Clinical Practice (GCP) and quality control (QC) requirements set out by MHRA/EMA is mandatory in these cases, including the generation of source material and preparation of therapeutic products in accordance with the principles of good manufacturing practice (GMP).

Before clinical research studies involving genetically modified microorganisms (GMMs) can commence, compliance with either the Contained Use Regulations or the Deliberate Release Regulations must be ensured. The requirements of the two sets of regulations differ considerably and therefore a choice must be made by those proposing the clinical trial as to which set of regulations apply. This choice will be largely dependent on the nature of the GMM, and the trial protocol.

Detailed guidance on the use of genetically modified microorganisms in a clinical setting, produced in association with all relevant agencies, is available online. However, this legislation applies only to Great Britain (England, Scotland and Wales). Northern Ireland has distinct parallel legislation with analogous procedures.

2.9 Is in-country sponsor presence/representation required?

Yes, a clinical trial sponsor needs to be established in the UK or a country on an approved country list which initially includes the European Union (EU)/European Economic Area (EEA) countries per the Guidance on the list of approved countries for clinical trials and IMPs. If this is not the case, then the sponsor must have a legal representative who is so established.

The HRA Roles and Responsibilities document defines that if a sponsor(s) of a CTIMP is not established in the UK or on an approved country list (which initially includes EU/European Economic Area (EEA) countries), it is a statutory requirement to appoint a legal representative based in the UK or a country on the approved country list for the purposes of the trial. Details of the legal representative should be entered in the ‘legal representative’ section of IRAS.

The legal representative:

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

2.10 Is there any mandatory requirement to identify a local PI or can a PI be based in a foreign country? 

Yes, a PI is the lead researcher for a research project at a particular site. There should be one PI for each research site. In the case of a single-site study, the chief investigator and the PI will normally be the same person. It is a statutory requirement to appoint a legal representative based in the UK or a country on the approved country list for the purposes of the trial.

Although it is not explicitly mentioned where the PI should be located, it can be inferred, from the roles and responsibilities of the PI, that PI should be locally based. 

There are two types of sites in the UK:

• National Health Service (NHS) sites
• Non-NHS sites (private sites)

Additional definitions for “trial site” and “investigator” can be found within the IRAS portal under “Interventional Research.”

2.11 Is there any mandatory requirement to identify a local chief or coordinating investigator? 

The chief investigator is the overall lead researcher for a research project. In addition to their responsibilities, if they are members of a research team, chief investigators are responsible for the overall conduct of a research project.

The chief Investigator’s responsibilities are set out in more detail in the UK Policy Framework for Health and Social Care Research. Guidance produced by HRA-MHRA on who can act as the CI for CTIMPs taking place in the UK includes a definition of the term ‘Authorized Health Professional’ and examples of which professions this term applies to.

Statutory Instrument (SI) - The Medicines for Human Use (Clinical Trials) Regulations 2004/1031 defines "Chief investigator" as being:

1. in relation to a clinical trial conducted at a single trial site, the investigator for that site, or 
2. in relation to a clinical trial conducted at more than one trial site, the authorized health professional, whether or not he is an investigator at any particular site, takes primary responsibility for the conduct of the trial.

It is to be noted that MHRA is proposing a change in the legislation (under consultation review). They wish to facilitate trial conduct by expanding the professional groups of who can be an Investigator (e.g. expand to air ambulance paramedics) as currently defined in the definitions for ‘authorized health professional’ and ‘health care professional’ and clarify in guidance how the chief investigator and other coordinating investigators, and sponsor and co-sponsors, can work together in platform trials.

2.12 If the applicant is CRO or a third party, does regulatory authority need any authorization or transfer of obligations from the sponsor? Does the authorization letter need to be notarized and/or apostilled? 

Whilst there is no one-size-fits-all for the management of trials, there is a clear requirement in the regulations that the sponsor retains all responsibility for the conduct and reporting of clinical trials (SI 2004/1031 Regulation 3).

If a sponsor(s) of a CTIMP is not established in the UK or on an approved country list (which initially includes EU / European Economic Area (EEA) countries), it is a statutory requirement to appoint a legal representative based in the UK or a country on the approved country list for the purposes of the trial. Details of the legal representative should be entered in the ‘legal representative’ section of IRAS.

Therefore, it is imperative that the sponsor has systems and procedures in place to ensure adequate oversight of the management of clinical trials both conducted in-house and those outsourced to vendors. It is important that the delegation of duties is clearly documented and there are no gaps or ambiguities which may lead to non-adherence with regulatory requirements.

Sponsor oversight is not just the initial vendor assessment process, it should be demonstrated throughout the trial. A risk-based approach to vendor selection and management is recommended and this should be identified within your QMS. Identify those key areas where you want to concentrate your oversight activities and ensure the activities are commensurate to the risk associated with the vendor (for example, consider how much is gained from conducting TMF/ISF audits only and think about when investigator site audits/ monitoring visits may be necessary). Most importantly, ensure sponsor oversight activities are clearly defined within your QMS and retain documentation and evidence of oversight in the TMF. Further guidance is available in Chapter 1 of the MHRA GCP Guide. Sponsor Oversight Blog by MHRA is also available.

2.13 Is there a requirement to register clinical trials on a local registry or database?

Yes, the ISCRTN registry in the UK is the minimum requirement. 

From January 2022, HRA will automatically be registering clinical trials as part of their Make it Public strategy. It is a condition of a Research Ethics Committee (REC) favorable opinion that a clinical trial is registered. 

Sponsors should register their trial before the first participant is recruited and no later than six weeks after. (If your trial is already registered when you complete your IRAS application, you should include your registration number. If you register after submitting your IRAS application, then you should email the REC with your registration number to be added to the study records. You should ensure you keep the record in the registry up to date. If you make amendments to your study, update the record in the registry, as needed.)

A ‘public registry’ is any registry on the WHO list of primary registries or the ICMJE list of registries.

Recognized registries include:

• International Standard Randomized Controlled Trial Number (ISRCTN) Registry which accepts prospective and retrospective registration of all clinical research studies. ISRCTN Registry is the preferred partner of the Department of Health and Social Care.
• ClinicalTrials.gov which accepts prospective and retrospective registration of medical studies in human volunteers.
• EU Clinical Trials Register which consists of information from the EU Clinical Trial Database, EudraCT. It accepts interventional clinical trials that are conducted in the European Union (EU) and the European Economic Area (EEA) as well as clinical trials conducted outside the EU / EEA that are linked to European pediatric-medicine development. For clinical trials (other than adult Phase 1 studies) involving both UK and EU sites, a record in the EU Clinical Trials Register will satisfy the REC favorable opinion condition for registration.

2.14 What is the local requirement for clinical study documents archival; minimum of years for the archival, specific format followed (electronic/paper and/or both)?

Archiving is a legal requirement that is relevant to all trials. It is part of the ‘trial close-out phase’ group of stations in the UK.

Art. 31A of the Clinical Trial Regulation 2004 indicates the following: 

(7) “Sponsors and chief investigator shall ensure that the documents contained, or which has been contained, in the trial master file are retained for at least 5 years after the conclusion of trial and that during that period are:

1. Readily available to the licensing authority on request, and
2. Complete and legible.

(8) The sponsor and chief investigator shall ensure that the medical files of trial subjects are retained for at least 5 years after the conclusion of the trial.

The sponsor/someone on behalf of the sponsor should consider whether the results of a trial will or may be included in a marketing authorization application and should take the necessary steps to ensure appropriate retention of the essential documents. Consideration of site-specific archiving requirements, as detailed by each R&D Department, is essential as these may differ from those outlined below.

Trials that are NOT to be used in regulatory submissions

Essential documents of the sponsor/trial organizers and investigators, from trials that are not to be used in regulatory submissions, should be retained for at least five years after the completion of the trial. These documents should be retained for a longer period if required by the applicable regulatory requirement(s), the sponsor, or the funder of the trial.

Trials to be included in regulatory submissions

• The sponsor-specific essential documents should be retained until at least two years after the last approval of a marketing application in the EU. (Caveat: these documents should be retained for a longer period if required by the applicable regulatory requirement(s) or if needed by the sponsor).
• The Clinical Trials Regulations and specifically Regulation 31A of the Medicines for Human Use (Clinical Trials) Amendment Regulations 2006 define the archiving requirements for Clinical Trials of Investigational Medicinal Products (CTIMPs).
• All essential documents should be archived, and this includes essential documents held by investigators, sponsors, and others involved in the conduct of a clinical trial (including services departments such as pharmacy, laboratories, and radiology).
• The Joint Project Notes on Archiving give further information on the storage (and destruction) of essential documents and the duration/timelines appropriate for archiving. Funders, journals, sponsors, and host organizations will also have local policies/procedures covering archive requirements, which must also be followed. Consideration should be given to the archive of both paper and electronic data (such as databases).

2.15 Requirements around periodic safety reporting and timelines on SAEs/AEs/ADRs/SUSARs/DSURs.

The procedures for safety reporting will vary depending on the type of study.

Urgent safety measures (all studies)

A sponsor or investigator may take appropriate urgent safety measures in order to protect research participants against any immediate hazard to their health or safety, without prior authorization from a regulatory body.

For studies not submitted via combined review

The research ethics committee (REC) must be notified by email within three days. The notice should set out that such measures have been taken and the reasons why. Where an urgent safety measure (USM) requires an amendment to study documents, this should be submitted as a substantial amendment as soon as possible. The amendment should be marked as being in response to urgent safety measures and a copy of the USM notification should be submitted with the amendment.

Copies of the information should be provided to the REC that approved the study using the appropriate REC safety reporting cover sheet (see below).

For CTIMPs submitted via combined review

An urgent safety measure (USM) notification should be submitted in IRAS. No additional notification is required to the REC. Where an urgent safety measure (USM) requires an amendment to study documents, this should be submitted as a substantial amendment as soon as possible. The amendment should be marked as being in response to urgent safety measures.

Safety reporting for clinical trials of investigational medicinal products (CTIMPs): 

For CTIMPs not submitted via combined review

The REC should be notified by using the CTIMPs Safety Report form which is a standard cover sheet. A single CTIMP Safety Report form may be used for the submission of multiple safety reports for the same trial. The CTIMP Safety Report form should not normally cover more than one trial, though this may be permitted by the REC where two trials are very closely connected (e.g., a main study and an extension study with the same treatment regime).

Sponsors will receive an acknowledgment receipt of all safety reports, by email or a signed copy of the covering letter, within 30 days. Reports sent without the CTIMP safety report form cover sheet will not be acknowledged.

For CTIMPs submitted via combined review

Development safety update reports (DSURs) should be submitted in IRAS where at least one of the trials was submitted through combined review.

Suspected unexpected serious adverse reactions (SUSARs) should be submitted to the MHRA as per the guidance on the MHRA website. There is no need to submit a separate notification to the REC, the MHRA will liaise with the REC if deemed appropriate.

Note that the information in the table below applies to clinical trial studies with investigational medicinal products submitted under the combined process (i.e. submission to MHRA and REC via the IRAS website).

Procedural table – Safety and Progress Reports

2.16 Requirement on any periodic clinical study update, specific template, and its frequency (e.g., interim or annual progress report and final report, etc.)? 

Effective from the 01^st of June 2024, only studies reviewed by a REC in Scotland or Northern Ireland require a progress report to be submitted to the REC which gave the favorable opinion 12 months after the date on which the favorable opinion was given.

However, progress reports are not required in the following instances:

• If the study is expected to run for less than two years in duration.
• If the study received a proportionate review.
• If the study received a favorable ethics opinion from a REC in England or Wales.

If the study was given a favorable ethics opinion by a REC in Scotland or Northern Ireland, there are separate forms for submitting progress reports, depending on the type of research. Please consult the HRA's “Progress Reports” page to access the required and most up-to-date version of the template.

Available forms must be completed in typescript. They will need to be authorized by the Chief Investigator or the sponsor/sponsor representative.

An electronic copy should be emailed to the REC within 30 days of the end of the reporting period.

Annual progress report form for clinical trials of investigational medicinal products (CTIMPs)

For research with HRA and HCRW Approval which were not required to be reviewed by a REC, progress reports are not required.

2.17 Does the local regulation require notification of “serious breaches” of GCP or the trial protocol? 

Yes, sponsors must notify MHRA of serious breaches of GCP or the trial protocol.

• See Guidance for the notification of serious breaches of GCP or the trial protocol.
• Sponsors must complete the notification of serious breaches of GCP or the trial protocol form and send it to GCP.SeriousBreaches@mhra.gov.uk.
• The Notification of a Serious Breach form and associated guidance have been updated, with the aim of improving the completeness and quality of information being received for review and assessment of the breach.

The most common queries MHRA has when reviewing serious breach reports are actually general ones requiring further information and justification of decisions, such as impact assessments and root cause analysis. Therefore, MHRA has added further details of what they expect to receive.

The initial notification must be submitted within 7 days of first awareness. MHRA expects that details and information may be incomplete at that point; however, follow-up reports should strive to provide complete information.

Please note CTR consultation is underway in the UK and under new sanctions and corrective measures, these include permitting regulators to take into account serious and ongoing non-compliance when considering new studies and enabling regulatory action to be taken against specific parts of a trial rather than the whole trial.

Common questions

• What impact assessment has been done? What methodology was used and what was the outcome?
• Has this issue happened at other sites/on other trials? How do you know if this is an issue only at one particular site if you have not checked across sites?
• What root cause assessments have been undertaken, how was this done, what was found and how does this link to the CAPA provided?
• How has the issue been documented in the Trial Master File/s (TMF/s) across all organizations involved?
• Have you ensured this incident is transparently reported in the Clinical Study Report/s?

The updated form and guidance aim to address these questions. However, the quality and completeness of the information also depend on the organization filling in the form. If sponsors have questions, they are advised to contact the MHRA GCP Inspectorate.

2.18 Does RA/CA require insurance and indemnity to cover the sponsor and investigator’s potential liability?

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 Medicines for Human Use (Clinical Trials) Regulations 2004 does not ascribe responsibility to the sponsor or his/her designated representative to obtain insurance and indemnity. However, 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. The sponsor or his/her designated representative must ensure that the research covered by the National Health Service (NHS)'s indemnity policy is in place for each publicly funded participating study site.

• See “Clinical Trial Compensation Guidelines” developed by the Association for the British Pharmaceutical Industry (ABPI) which include information on the insurance compensation arrangements for clinical trials in the UK.
• It is a requirement that “proof of insurance” is submitted for commercially initiated clinical research.