United Kingdom

Clinical trials

Legislation

Statutory Instrument 2004:1031 (1 May 2004)

Statutory Instrument 2006:1928 (29 August 2006)

The UK Clinical Trial Regulations were initially published as a Statutory Instrument (SI) - a UK law-making procedure - as SI 2004 No.1031 and came into force on 1 May 2004.
This regulations implemented, for the first time in UK law, European Directive 2001/20/EC relating to the implementation of good clinical practice (GCP) in the conduct of clinical trials on medicinal products for human use (often called 'the Clinical Tlials Directive').

It was necessary to amend the UK Clinical Trial Regulations in 2006, using SI 2006 No. 1928, in order to implement European Directive 2005/28/EC often called 'the GCP Directive. This laid down principles and detailed guidelines or GCP relating to investigational medicinal products for human use, as well as requirements for the authorisation of the manufacturing or importation of such products.

Other amendments - including the UK-specific requirement to report serious breaches of he protocol and GCP - were incorporated into the Regulations at this time.
A second amendment to the UK Clinical Trial Regulations was made in 2006 by SI 2006 No. 2984. This created an exception to the general rule that incapacitated adults cannot be included in a clinical trial, and established rules for he inclusion of these individuals.

In 2008, SI 2008 No. 941 further amended the UK Clinical Trial Regulations with respect to he function of ethics committees and pediatric trials. Each time that amendments to the Regulations were published, the SI provided details of how the principal regulation SI 2004 No. 1031 was to be amended. But unfortunately no official consolidated version exists

Guidelines

The UK use all the EU guidelines like the CT3 and Volume 9A. In addition they have published the “Purple Guide” which is a Good Pharmacovigilance Practice Guide. The guidelines for the post marketing part are expected to be substitute with the EU level guidelines which are scheduled to be released during 2012

Expedited Reporting

During the current development of EudraVigilance, clinical trial sponsors are required to report all UK-relevant suspected serious unexpected adverse reactions (SUSARs) to the MHRA, or alternatively  all SUSARs that would usually be submitted to EudraVigilance.

The Agency’s definition of 'UK-relevant' includes reports of the following:

- SUSARs originating in the UK

- SUSARs originating outside the UK where the sponsor has an ongoing trial in the UK involving the same investigational medicinal product.

All SUSARs should be reported electronically using the EudraVigilance Gateway, EVWEB or the MHRA’s eSUSAR website (http://esusar.mhra.gov.uk/). The eSUSAR website gives access to an electronic SUSAR (eSUSAR) form for submitting UK and third country SUSARs. The website can also be used to maintain a record of reports that have been submitted and there is pdf support for reporting to the Ethics Committee.

The MHRA only forwards UK and third country reports submitted via the MHRA’s eSUSAR website to the EVCTM.  eSUSAR reports originating in the UK should not be submitted to the EVCTM by the trial sponsor, so as to avoid duplication in the EVCTM

Sponsors reporting using either the EudraVigilance Gateway or EVWEB should dual report to both the MHRA and to the EVCTM.

Ethics committee reporting

 SUSARs must be notified to the main Research Ethics Committee but they only require reports for SUSARs occurring in the UK. There is no requirement to include reports of non-UK SUSARs, or of SUSARs occurring in other UK trials of the investigational medicinal products.

SUSAR reports should comply with ICH E2B guidance and be sent by e-mail accompanied by a covering form “Safety Report to Research Ethics Committee” available on the NRES web-site 

Periodic reports

Annual reports

In accordance with EU legislation the sponsor must supply the MHRA and main Research Ethics Committee with an annual safety report on the safety of subjects in all clinical trials of the product for which the sponsor is responsible,. This includes trials conducted UK or elsewhere in the word.

Annual safety reports are required to be in the format of Development Safety Update Reports (DSURs) as set out in the ICH E2F guideline. The DSUR is a summary of safety issues and includes all worldwide suspected serious adverse reaction (SSARs) in the reporting period both expected and unexpected.

The Development International Birth Date (DIBD) is used to determine the start of the annual period for the DSUR according to E2F. This is the date the sponsor received first authorisation 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 Development International Birth Date. The MHRA expects DSURs to be provided at yearly intervals from the date of the original clinical trial exemption. If it is a global trial a consolidated date, linked to the start of the authorisation of the first clinical trial is acceptable. For trials with marketed products, the date is the first marketing authorisation granted in the EU. DSURs should be provided to the MHRA as electronic documents on disk.

For ethics committees the DSURs should be submitted by e-mail or CD with a cover letter called “Safety Report to Research Ethics Committee”  which is available on the NRES web-site

Post marketing

Legislation

The legal basis is:

Statutory Instrument 1994:3144

Statutory Instrument 2008:3097
(Amending SI 1994 No 3144 and clarifies reporting obligations. Explicitly says that marketing authorisation holders should provide the MHRA with new information relating to the benefits and risks of a medicine. This includes information arising from clinical trials outside the licensed indication and information arising from third countries. It also addresses requirement for the marketing authorisation holder to have a Qualified Person for Pharmacovigilance. While deputy Qualified Person(s) must be nominated there is no national requirement to have a nominated individual in the UK with specific legal responsibilities for pharmacovigilance at the national level.

Under UK legislation it is a criminal offence to fail to report the relevant pharmacovigilance reports.

The post marketing regulation is currently being updated in the UK based on the Regulation No 1235/2010/EU amending Regulation (EC) No 726/2004  and Directive 2010/84/EU amending Directive 2001/83/EC

Reporting requirements

Expedited reports

The UK complies with European requirements relating to the expedited reporting of individual case safety reports. In addition to the standard European requirements the MHRA require to receive expedited reports for all suspected serious ADRs occurring in the EEA for marketing authorisations which are the subject of intensive safety monitoring: black triangle scheme

The MHRA require electronic reporting using the ICH-E2B electronic reporting standard sent via the EudraVigilance Gateway for all ICSRs (Individual Case Safety Reports).

The MHRA have produced a “Purple Guide” detailing Best Practice in Reporting of Individual Case Safety Reports (ICSRs). In addition to the standard EudraVigilance requirements the MHRA expect specific UK validation checks to be made. These additional validation requirements, information on testing procedures and Questions and Answers on E2B are available on the MHRA web-site: http://www.mhra.gov.uk/home/. Information regarding submission of production cases and receipt of automated acknowledgements This email address is being protected from spambots. You need JavaScript enabled to view it. may be cotacted. Contact regardingtesting of E2B submissions This email address is being protected from spambots. You need JavaScript enabled to view it. may be contacted.

All marketing authorisation holders may receive anonymised single patient reports (ASPRs) from the MHRA under certain circumstances:

• When the suspect drug is reported as a brand name only the MA holder that holds that licence(s) for that brand receives an ASPR/ICSR
• When the suspect drug is a multiconstituent product only MA holders that hold a licence for the same combination of actives receive an ASPR/ICSR
• When the suspect drug is reported as a single active substance, all MA holders that hold a licence for a product only containing the single active substance receive an ASPR/ICSR.

All ASPRs are sent out to MAHs electronically via E2B or as pdf documents

Periodic Reports

Periodic safety update reports (PSURs)

The UK follows the EU requirements regarding Periodic Safety Update Reports

PSURs may be submitted via the MHRA portal or on disc to the MHRA.

Company sponsored post-authorisation safety studies (PASS) 3

The UK follows European guidelines relating to company-sponsored post-authorisation safety studies.

Risk management

The UK complies with European requirements with respect to requirements for risk management.

The MHRA operates a system for the assessment of detailed descriptions of pharmacovigilance system (DDPS) in which the DDPS is held by the MHRA as a DDPS Master File. For national authorisations this will reduce the need to submit an unchanged approved DDPS for every marketing authorisation application. Guidance is available. Once an approved DDPS registration number has been issued, a template should be followed for all future marketing authorisation application.

Whenever any new or changing information becomes available which affects the risk-benefit analysis of a medicinal product which is licensed in the UK, the Post-Licensing Section of the MHRA should be contacted without delay. Consideration would need to be given as to whether a new or modified Risk Management Plan is required (MAIL 155] and whether the SmPC, patient information leaflet, advertising material, etc., should be changed

MHRA Guidance provides timeframes in which product information, which has been updated for safety-related reasons, shall be distributed and published. Distribution within the company, the updating of company-sponsored websites and submission to external publications e.g., the British National Formulary (BNF) should all take place within 10 working days of approval of the new information. Stock with the new packaging components must be introduced for release to the market within three to six months. These timeframes are considered as maximum recommendations for 'routine' safety updates. Immediate communication to concerned parties may be necessary in the event of Urgent Safety Restrictions

Inspections

The Agency is responsible for conducting inspections to ensure compliance with Good Pharmacovigilance Practice. Inspections are conducted on a regular basis but any specific concerns and issues may trigger ad hoc inspections.

All UK marketing authorisation holders are required to submit a Compliance Report. A risk assessment is undertaken based on the Report and other information about the organisation. The resulting risk assessment is a ranking based on a score assigned to the organisation’s control of their risk subtracted from a score assigned to the risk. The result is provided to the organisation. Priority inspections are given to companies with the highest risk assessment scores.

Once the risk assessment has been determined and an inspection scheduled, the organisation will be requested to provide a Summary of Pharmacovigilance Systems (SPS) document. Critical findings from an inspection are referred to a multidisciplinary MHRA advisory committee, the Inspection Action Group (IAG).

The MHRA web-site provides further information in the form of Questions and Answers and inspection metrics reports.