Clinical trial authorisations: Safety reporting - SUSARS and ASRs

1 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 authorization, 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, or
(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 - April 2006 (external link)

2. What to report to the MHRA
A Sponsor shall ensure that all relevant information about a suspected unexpected serious adverse reaction (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 suspected unexpected serious adverse reaction (SUSAR) which is not fatal or life-threatening is reported as soon as possible, and in any event not later that 15 days after the Sponsor is first aware of the reaction.

3. 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.

4.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 suspected unexpected serious adverse reaction (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 suspected unexpected serious adverse reaction (SUSAR) which is not fatal or life-threatening is reported as soon as possible, and in any event not later that 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.

These reports or information may be provided on paper using the CIOMS form (external link).

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 - April 2006 (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).

5. How to report Suspected Unexpected Serious Adverse Reactions (SUSAR)
At present, a SUSAR should be reported using a CIOMS 1 form (external link).

When completing the CIOMS form, Sponsors should include the EudraCT number, CTA number (or DDX/CTX number), protocol number and study name.

6. What to include in a Suspected Unexpected Serious Adverse Reactions (SUSAR) report
The data elements expected in a SUSAR are listed in Annex 3 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 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.

7. How to send reports
SUSAR reports may be sent by fax, by email or as electronic documents on disk.

8. Where to send SUSAR reports

 i)  UK Clinical trial SUSAR reporting
Reports can be scanned as PDF documents and e-mailed to pharmacovigilance@mhra.gsi.gov.uk, clearly stating that the attachment is a UK clinical trial SUSAR.

Paper UK clinical trial SUSAR reports should be sent to our centralised scanning facility in Gloucester:
MHRA
PO Box 20
Mitcheldean
GL17 0WQ
These should be sent in accordance with the timelines stipulated for SUSAR reports in the 2004 Statutory Instrument (The Medicines for Human Use (Clinical Trials) Regulations 2004 – SI 2004/1031).

The existing fax facility for the reporting of UK SUSARs (020 7084 2443) can continue to be used but will be phased out. The date of its discontinuation will be provided once this has been confirmed.

ii) Non-UK clinical trial SUSAR reporting
SUSAR reports pertaining to non-UK clinical trials should continue to be sent to the MHRA’s Clinical Trials Unit at Market Towers. These can be scanned as PDF documents and sent on disk to by post/courier to:
Clinical Trials Unit
12-242
MHRA
Market Towers
1 Nine Elms Lane
LONDON
SW8 5NQ
Alternatively reports may be faxed on 020 7084 2443.

9. Annual Safety Reports (ASR)
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.

10. When is the Annual Safety Report (ASR) due?
Annual Safety Reports (ASR) 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 CTA approval for trials starting after 1 May. For trials with marketed products, the date is the first marketing authorisation granted in the EU.

11. What should the Annual Safety Report (ASR) 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 Annual Safety Report of a clinical trial should have three parts:
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)

12. Where to send the Annual Safety Report (ASR)
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, Market Towers, 1 Nine Elms Lane, Vauxhall, London SW8 5NQ.

13. 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 within 3 days.

Sponsors should phone the Clinical Trial Unit at the MHRA and discuss the issue with a medical assessor immediately. The sponsor must notify the MHRA and the Ethics Committee, in writing, of the measures taken and the reason for the measures within 3 days by submitting a substantial amendment. The substantial amendment should include a covering letter detailing the measures taken, the reason for them and the medical assessor contacted; a Notification of Amendment form; and supporting documentation.

The substantial amendment should be:

1. Faxed to the Clinical Trials Unit on 020 7084 2443 or sent by e-mail to clintrialhelpline@mhra.gsi.gov.uk) marked ‘Urgent Safety Measure’ and
2. Sent as PDF documents on disk to: Information Processing Unit, Area 6, Medicines and Healthcare products Regulatory Agency, Market Towers, 1 Nine Elms Lane, London. SW8 5NQ

14. 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 the reasons fopr 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, Market Towers, 1 Nine Elms Lane, London. SW8 5NQ.

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 and including a brief explanation of the reasons for ending the trial.

15. 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 Database (external link).

Information on the 'Declaration of the End of a Trial' is available in the European Commission document Detailed Guidance for the request for authorisation of a clinical trial product for human use to the Competent Authorities, notification of substantial amendments and declaration of the end of the trial (external link)

Forms should be sent as electronic documents on disk to:
Information Processing Unit
Area 6
Medicines & Healthcare products Regulatory Agency
Market Towers
1 Nine Elms Lane
London
SW8 5NQ

16 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.