Clinical trials for medicines: Safety reporting - SUSARs and DSURs

The requirements for safety reporting can be found in Part 5 (Regs 32, 33, 34 and 35) of The Medicines for Human Use (Clinical Trials) Regulations 2004: SI 2004/1031.

Nurse reporting safety problem on a computer


ESUSAR banner


MHRA eSUSAR website launches

  • Electronic reporting of SUSARs by non-commercial sponsors (and SMEs).
  • Facilitates electronic reporting of all UK-relevant SUSARs.
  • Sponsors reporting via EudraVigilance Gateway and EVWEB to dual report from 1 August 2010.
  • Full transition to electronic reporting by all trial sponsors by 1 September 2010.

 

What to report to the MHRA
The requirements for safety reporting can be found in Part 5 (Regs 32, 33, 34 and 35) of The Medicines for Human Use (Clinical Trials) Regulations 2004: SI 2004/1031.

The MHRA would like to see and analyse all UK-relevant suspected unexpected serious adverse reaction (SUSAR) reports in order that it can fulfill its obligation to monitor the safety of the UK Clinical Trial population. Therefore, during ongoing development of EudraVigilance and its associated medicinal product dictionary and data warehouse, the MHRA requests that Clinical Trial Sponsors report all UK-relevant 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 IMP.

The MHRA only forwards UK and third country* reports submitted via the MHRA’s eSUSAR website to the European Medicines Agency's (EMA's) EudraVigilance Clinical Trial Module (EVCTM) (external link) (see below for further information on the MHRA’s eSUSAR website).

SUSAR 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 arrange to dual report to both the MHRA and to the EVCTM. Please note that spontaneous reports are unaffected by this change and will continue to be forwarded to EudraVigilance.

 *Third countries are defined as those being outside the EEA.

Reporting timelines
A sponsor shall ensure that all relevant information about a SUSAR which occurs during the course of a clinical trial in the United Kingdom and is fatal or life-threatening is reported as soon as possible to the MHRA, the competent authorities of any EEA State, other than the United Kingdom, in which the trial is being conducted, and the relevant Ethics Committee.

This needs to be done not later than seven days after the sponsor was first aware of the reaction. Any additional relevant information should be sent within eight days of the report.

A sponsor shall ensure that a SUSAR which is not fatal or life-threatening is reported as soon as possible and in any event not later than 15 days after the sponsor is first aware of the reaction.
 

Terminology
Adverse event (or adverse experience): any untoward medical occurrence in a subject to whom a medicinal product has been administered, including occurrences which are not necessarily caused by or related to that product.

Adverse drug reaction (ADR): any untoward and unintended response in a subject to an investigational medicinal product which is related to any dose administered to that subject.

Unexpected adverse reaction: an adverse reaction the nature and severity of which is not consistent with the information about the medicinal product in question set out:

(a) in the case of a product with a marketing authorisation, in the summary of product characteristics for that product

(b) in the case of any other investigational medicinal product, in the investigator's brochure relating to the trial in question.

Serious adverse event or serious adverse drug reaction or unexpected serious adverse reaction: any adverse event, adverse reaction or unexpected adverse reaction, respectively, that:

(a) results in death

(b) is life-threatening

(c) requires hospitalisation or prolongation of existing hospitalisation

(d) results in persistent or significant disability or incapacity

(e) consists of a congenital anomaly or birth defect.

Important medical events that may not be immediately life-threatening or result in death or hospitalisation but may jeopardise the patient or may require intervention to prevent one of the other outcomes listed in the definition above should also be considered serious.

Further guidance on safety reporting can be found in Detailed guidance on the collection, verification and presentation of adverse reaction reports arising from clinical trials on medicinal products for human use – June 2011 (external link)

 

Investigator responsibilities
The investigator shall report any serious adverse event (SAE) which occurs in a subject immediately to the sponsor.

The immediate report may be made orally or in writing and shall be followed by a detailed written report on the event. Where the event reported consists of, or results in, the death of a subject, the investigator shall supply the sponsor with any additional information requested by the sponsor. Where the death has been reported to the relevant ethics committee, the investigator shall supply any additional information requested by that committee.


Sponsor responsibilities

The sponsor shall keep detailed records of all adverse events relating to a clinical trial which are reported to him by the investigators for that trial. The Licensing Authority may require the sponsor to send those records, or copies of such records, to the authority.

A sponsor shall ensure that all relevant information about a SUSAR which occurs during the course of a clinical trial in the United Kingdom and is fatal or life-threatening is reported as soon as possible to the MHRA, the competent authorities of any EEA State, other than the United Kingdom, in which the trial is being conducted, and the relevant ethics committee.

This needs to be done not later than seven days after the sponsor was first aware of the reaction. Any additional relevant information should be sent within eight days of the report.

A sponsor shall ensure that a SUSAR which is not fatal or life-threatening is reported as soon as possible, and in any event not later than 15 days after the sponsor is first aware of the reaction, to the MHRA, the competent authorities of any EEA State, other than the United Kingdom, in which the trial is being conducted and the relevant ethics committee.

Further information is available in the following European Commission document: Detailed guidance on the collection, verification and presentation of adverse reaction reports arising from clinical trials on medicinal products for human use -2011 (external link)

The key points relating to pharmacovigilance are included in Part 5 of The Medicines for Human Use (Clinical Trials) Regulations 2004: SI 2004/1031 (external link).


What to include in a SUSAR report
The data elements expected in a SUSAR report are listed in Detailed guidance on the collection, verification and presentation of adverse reaction reports arising from clinical trials on medicinal products for human use – June 2011(external link).

Where incomplete information is available at the time of initial reporting, all the appropriate information for an adequate analysis of causality should be provided as follow-up reports as it becomes available.


How to report a SUSAR
All SUSAR reports should now be reported electronically.


Electronic reporting
Electronic reporting is achievable using the MHRA’s eSUSAR website (external link), the EudraVigilance Gateway or EVWEB.

MHRA eSUSAR website: This form is available for use by all Clinical Trial Sponsors and aims to provide an easy to use method of electronic submission of UK and Third Country SUSAR reports to the MHRA and, subsequently, on to the EVCTM. The eSUSAR website may also be used to report SUSARs originating in other EEA Member States to the MHRA.

However, reporting to other EEA Member State Competent Authorities must be carried out in accordance with each individual Member State’s requirements.

In addition to this, the website can be used to maintain a record of reports that have been submitted for each of the Institution’s clinical trials and a PDF output can be used to report to the Ethics Committee. Further information can be found on the eSUSAR website (external link).

Before using the eSUSAR website for the first time, Institutions will need to register their details with the MHRA. This process registers the Institution and a representative of the institution as an Administrator.

In order to commence the registration process, the representative should complete the:

eSUSAR Registration Form Word file (opens in new window) (45Kb)

and email it to esusar@mhra.gsi.gov.uk with the subject line eSUSAR Registration.

EudraVigilance Gateway: Sponsors wishing to submit SUSAR reports to the MHRA, in E2B format via the EudraVigilance Gateway, are required to successfully test electronic transmission with the MHRA prior to switching to E2B reporting.

Further information on E2B reporting with the MHRA can be found in the safety information section of the website.

EVWEB: Alternatively, sponsors can use the EMA EVWEB tool to submit SUSAR reports electronically. Further details of this can be found on the EMA website (external link).


Development Update Safety Reports (DSURs)

The Development Safety Update Report (DSUR) Guidance (ICH E2F) (external link)  was published in the EU in September 2010 and has been implemented in September 2011 and the one year transition period agreed by the Commission has now ended.  

In addition to the expedited reporting required for SUSAR, sponsors are required to submit a safety report to the MHRA and the Ethics Committee, once a year throughout the clinical trial or on request. The annual safety report should take into account all new available safety information received during the reporting period.

When is the DSUR due?
DSURs should be provided at yearly intervals from the date of the original exemption, for trials ongoing on 1 May 2004, or the date of the first CTA approval for trials starting after 1 May. For trials with marketed products, the date is the first marketing authorisation granted in the EU.

What should the DSUR include?
The aim of the annual safety report is to describe concisely all new safety information relevant for one or several clinical trial(s) and to assess the safety of subjects included in these studies.

The DSUR should include the following:

Part 1: Analysis of the subjects’ safety in the concerned clinical trial(s) with an appraisal of its ongoing risk:benefit

Part 2: A line listing of all suspected serious adverse reactions (including all SUSARs) that occurred in the concerned trial(s), including all serious adverse reactions from third countries

Part 3: An aggregate summary tabulation of suspected serious adverse reactions that occurred in the concerned trial(s).

Full details of what to include in an annual safety report can be found in Section 5.2 of Detailed guidance on the collection, verification and presentation of adverse reaction reports arising from clinical trials on medicinal products for human use - April 2006 (external link)

Where to send the Development Update Safety Report (DSUR)
Annual safety reports should be provided as electronic documents on disk and be sent to:

Information Processing Unit
Area 6
Medicines & Healthcare products Regulatory Agency
151 Buckingham Palace Road
Victoria
London
SW1W 9SZ

Frequently asked questions regarding the Development Safety Update Report (DSUR) (external link)

Annual Investigators Brochure (IB) Update
The Reference Safety Information (RSI) for any Investigational Medicinal Products (IMPs) involved in a clinical trial must stay consistent during each reporting period. At the end of the reporting period the sponsor may assess the new safety information that has been generated and submit any proposed safety changes to the IB or reference safety information as a substantial amendment. This amendment should be supported by the ASR/DSUR and approved before the RSI is changed.

Changes to the reference safety information include the downgrading of reactions form unexpected to expected. Until the amendment justifying the downgrading has been approved the events must be treated as unexpected.


Reference Safety Information (RSI) for a Clinical Trial

For new clinical trial applications:

When submitting a clinical trial application the reference safety information (RSI) should be, when applicable, within the Summary of Product Characteristics (SmPC) or within the Investigators Brochure (IB).
If the RSI is within IB it should be a clearly identified separate section. This section should include a list of expected adverse reactions, e.g. in the form of a table, where all related adverse events (i.e. adverse reactions) are listed by nature and severity including frequency (see CT1 section 2.3. (32.), CT3 section 7.2.3.2. (51 to 53)). If different indications are being investigated for the investigational medicinal product (IMP), separate tables of expected adverse reactions by indication might be applicable to avoid misinterpretation, e.g. oncologic indications and immune mediated diseases.

If RSI is within the SmPC, the list of expected adverse reactions is contained in section 4.8 Undesirable Effects. Please note that relevant safety information may also be contained in other sections, for further details please see Volume 2C. (external link)

If the IMP has a marketing authorization (MA) in several Member States concerned with different SmPCs, the sponsor should justify its selection of the most appropriate SmPC, with reference to subject safety, as the RSI (see CT3 section 7.2.3.2. (54).

In cases where the IB is used as the RSI (rather than the SmPC) for IMPs with MA any differences between the list of expected adverse reactions in the IB and the SmPC should be highlighted and justified.

Please indicate in your cover letter where the RSI is located.

For ongoing clinical trials:

If the RSI is within the IB for an investigational medicinal product and there is not yet a clearly identified separate section to this effect, where all related adverse events (i.e. adverse reactions) are included e.g. in the form of a table (see above), we expect this to be implemented within your next (regular) IB update.

Please indicate in your cover letter where the RSI is located.

Changes during a clinical trial – (Substantial) Amendment to a clinical trial:

While submitting a (substantial) amendment to an ongoing clinical trial, e.g. an IB update, please indicate in your cover letter if the RSI is updated. Where changes are proposed these should be clearly indicated using a Track Changes table.

Any change to an RSI is considered a substantial amendment and it requires to be justified with supportive data. It is recommended  to update the RSI, if necessary, in alignment with the annual period for a development safety update report (DSUR). If the date of RSI update is aligned this way the DSUR can act in part as justification for the RSI changes. In case your RSI is updated prior to the end of the reporting period of the DSUR a detailed justification by data is expected.

Coming into effect one month after posting.


Urgent safety measures

The sponsor and investigator may take appropriate urgent safety measure to protect clinical trial subjects from any immediate hazard to their health and safety (Reg 30). The measures should be taken immediately. You do not need to wait for Licensing Authority approval before implementing urgent safety measures; however, you must inform the MHRA in writing in the form of a substantial amendment within three days.

Sponsors should phone the Clinical Trial Unit at the MHRA and discuss the issue with a safety scientist immediately. Should further clarification be required the sponsor will be contact by a medical assessor.

The sponsor must notify the MHRA and the Ethics Committee, in writing, of the measures taken and the reason for the measures within three days. This notification should include a covering letter detailing the measures taken, the reason for them, an Annex II substantial amendment form and any supporting documentation.

The amendment should be sent as PDF documents on disk to:

Information Processing Unit
Area 6
Medicines and Healthcare products Regulatory Agency
151 Buckingham Palace Road
Victoria
London
SW1W 9SZ


Temporary halt of a trial
When a sponsor halts a trial temporarily, he should notify the MHRA and Ethics Committees immediately and at least within 15 days from when the trial is temporarily halted. The notification should be made as a substantial amendment using the notification of amendment form and clearly explain what has been halted (eg. stopping recruitment and/or interrupting treatment of subjects already included) and the reasons for the temporary halt.)

Substantial amendments relating to temporary halts should be submitted as PDF documents on disk to:

Information Processing Unit
Area 6
Medicines and Healthcare products Regulatory Agency
151 Buckingham Palace Road
Victoria
London
SW1W 9SZ

To restart a trial that has been temporarily halted, the sponsor should make the request as a substantial amendment using the notification of amendment form and providing evidence that it is safe to restart the trial.

If a sponsor decides not to recommence a temporarily halted trial, the MHRA and Ethics Committees should be notified within 15 days of his decision, using the End of Trial Declaration form available from the EudraCT: European Clinical Trials website (external link) and including a brief explanation of the reasons for ending the trial.


Premature trial closure
If a trial is terminated before the date specified for its conclusion (in the application), the sponsor should notify the Licensing Authority and the Ethics Committee within 15 days of the date of termination by submitting a declaration of the end of a clinical trial form.

The declaration of the end of a clinical trial form is available from EudraCT: European Clinical Trials website (external link).

Information on the 'Declaration of the End of a Trial' is available in the European Commission document Detailed guidance on the request to the competent authorities for authorisation of a clinical trial on a medicinal product for human use, the notification of substantial amendments and the declaration of the end of trial (CT-1) (external link)

Forms should be sent as electronic documents on disk to:

Information Processing Unit
Area 6
Medicines and Healthcare products Regulatory Agency
151 Buckingham Palace Road
Victoria
London
SW1W 9SZ


Powers of the Licensing Authority
The Licensing Authority may make amendments to a clinical trial authorisation, suspend or terminate a trial in certain circumstances, for example if there are doubts over the safety or scientific validity of the trial.


Contact for further information
All queries relating to electronic documents and submissions should be directed to: RIS.CT@mhra.gsi.gov.uk

For queries relating to the legislation: clintrialhelpline@mhra.gsi.gov.uk


Page last modified: 04 September 2013