Clinical trial authorisations: Maintaining a clinical trial authorisation - Amendments and trial conclusion

1. What are my responsibilities as a sponsor?

• Obtain an authorisation from the MHRA.
• Obtain a positive opinion from the Ethics Committee.
• Make arrangements to conduct the trial in accordance with the principles of Good Clinical Practice (GCP)
• Comply with the requirements to report serious unexpected adverse reactions (SUSARs) to the MHRA and relevant Ethics Committee within the required time limits.
• Provide the MHRA and relevant Ethics Committee with an annual safety report (ASR).
• Allow inspection of any trial premises by MHRA inspectors as appropriate.

2. Can I make changes after receiving an authorisation?
If the sponsor wants to make a substantial amendment (a change to the terms of the request for authorisation of the trial or the particulars or documents that accompanied that request), then a request has to be made to the MHRA.

Information on substantial amendments 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).

A sponsor can make amendments, other than substantial amendments, at any time but must keep records of these amendments.

3. What does a request for a substantial amendment contain?

• The Notification of Amendment (Annex 2) form (PDF)
• An updated XML and PDF file of the Clinical Trial Application Form (Annex 1) if the amendment affects the information previously submitted
• Description of the amendment
• Reasons for the proposed amendment
• Copy of the proposed changes to the protocol or any other documents, showing previous and new wording, where applicable
• Supporting data for the amendment, including as applicable
• • summaries of data
  • updated overall risk benefit assessment
  • possible consequences for subjects already in the trial
  • possible consequences for the evaluation of results.
• Fees

If you refer to previously authorised amendments in your application, please quote the EudraCT number, CTA number, protocol code and product name.

One copy of the Notification of Amendment form (available from EudraCT: European Clinical Trials Database - external link) and supporting data should be provided. Documents should be provided in an electronic format on disk.

Further information on the fees payable for substantial amendments is provided on our Fees section.

4. Amendments to the trial protocol and investigator’s brochure
Where an amendment is made to the trial protocol, the following information should be provided in the submission:

• Has the risk:benefit assessment of the study been affected?
• If the risk:benefit has been affected, how do the changes impact the trial?
• What alterations to the protocol are proposed to counter these changes?
  

Please also ensure that changes to the protocol and associated documentation are highlighted.

Amendments do not need to be submitted for changes to the investigator’s brochure which do not alter the benefit:risk assessment of the study.

5. Amendments to change the sponsor or sponsor name
Amendments to change the sponsor or change the name of the sponsor of a clinical trial are administrative changes that result in a new CTA number being issued for the trial. It is therefore important that the change of sponsor is the only amendment made at that time.

Where the amendment is to change of sponsor name/ company name (ie. the name is changed but the legal entity remains the same), the following information should be provided in the submission:

• A cover letter
• A signed Notification of Amendment (Annex 2) form (PDF)
• An updated PDF and XML file of the Clinical Trial Application Form (Annex 1)

If the sponsor is changed ie. the legal responsibility for the trial is transferred from one legal entity to another, the following information should be provided in the submission:

• A cover letter that includes the date of transfer of responsibilities
• A signed Notification of Amendment (Annex 2) form (PDF)
• An updated PDF and XML file of the Clinical Trial Application Form (Annex 1)
• A letter of authorisation from the new sponsor
• A letter confirming the change from the old sponsor
• Include an explanation of how emergency contact details provided to the trial volunteers/patients will be managed
  

The previous sponsor will receive a letter acknowledging receipt of the amendment, and subsequently, a letter stating that the change of sponsor has been recorded, resulting in a change of CTA number for the trial and that the original CTA number has now been closed.

The new sponsor will receive a letter stating that the change has been recorded resulting in a new CTA number for the trial and providing the new CTA number which should be quoted on all further correspondence associated with the trial.

As the amendment is processed, the applicant will receive:

1. A letter acknowledging receipt of the notification of amendment submission.
2. A letter informing you that the change has been registered and the old CTA number has been closed on our system.
3. A letter informing you of the new CTA number which should be used on all future correspondence.

6. Amendments to change the person named as applicant
We are only able to respond to the person named in Section C1 of the Clinical Trial Application Form submitted for the initial clinical trial authorisation unless we are notified of an amendment to change the person named as applicant.

Amendments to change the applicant should be made as substantial amendments and be accompanied by:

• A signed Notification of Amendment (Annex 2) form (PDF)
• An updated PDF and XML file of the Clinical Trial Application Form (Annex 1) as the amendment affects the information previously submitted
• A revised letter of authorisation enabling the applicant to act on behalf of the sponsor (required where the applicant is changed and the applicant is not the same legal entity as the sponsor).

7. Amendments to change the coordinating or principal investigator(s)
Amendments to change the coordinating or principal investigator(s) for a clinical trial authorisation should be made as substantial amendments and be accompanied by:

• A signed Notification of Amendment (Annex 2) form
• An updated PDF and XML file of the Clinical Trial Application Form (Annex 1) as the amendment affects the information previously submitted

The Notification of Amendment form need does not need to provide full addresses of coordinating or principal investigator(s) but should state what changes are being made ie which investigators are being added or removed. Full address details of the coordinating or principal investigator(s) should be provided in the updated PDF and XML file of the Clinical Trial Application Form. This is treated by the Agency as an administrative amendment and an acknowledgement letter is sent.

8. To add a new investigational site
The addition of a new investigational site is a substantial amendment. A completed Notification of Amendment (Annex 2) form should be submitted to the MHRA. The front of this form should show that it is being submitted for information only. This is treated by the Agency as an administrative amendment and an acknowledgement letter is sent.

The Notification of Amendment form need does not need to provide full addresses of coordinating or principal investigator(s) but should state what changes are being made ie which sites are being added or removed. Full address details of the new site should be provided in the updated PDF and XML file of the Clinical Trial Application Form.

9. Amendments or end of trial declarations for clinical trials that were originally CTX/DDX applications
As limited information was required at the time of application for Clinical Trial Exemption (CTX) and Doctor and Dentist Exemption (DDX) studies, we have been unable to process amendments or end of trial notifications to such studies electronically, resulting in delays to assessment and responses to sponsors. In order to remedy this situation and to ensure efficient processing of amendments to such trials, we ask that applicants fill out CT Form UK 1, provided below, and submit the completed form, with a completed Notification of Amendment form or Declaration of the end of a Clinical Trial form with the relevant data.
› CT Form UK 1 (61Kb) 

Applicants only need to fill out CT Form UK 1 once for each trial (for the first amendment application made after 1 October 2007 or the end of trial declaration).

10. 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 & Healthcare products Regulatory Agency, Market Towers, 1 Nine Elms Lane, London. SW8 5NQ

11. 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 (for example 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 & 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.

12. What happens when we receive an amendment application?
The amendment will be validated on receipt and an acknowledgement letter will be sent to the person submitting the application. This is the person named in Section C of the Clinical Trial Application Form. If the application is valid then the assessment period will begin. This starts from the date of receipt of a valid application. If the application is not valid then the person making the application will be told of the deficiencies. Nothing will happen to the application until the missing components are provided.

13. What is the timeframe for amendments?
The assessment of amendments will be performed within 35 days. For the purposes of this calculation, the day of receipt of the amendment by the Information Processing Unit is day 0. Amendments referring to phase 1 healthy volunteer trials will be assessed within 35 days, with an average of 14 days. Further information on the timescales and possible outcomes of applications can be found at Timescales and Outcomes - Amendments.

14. What are the possible outcomes?
When the amendment has been assessed (within 35 days) the applicant will be sent a letter informing them of:

1. Acceptance of the amendment OR
2. Acceptance of the amendment subject to conditions OR
3. Grounds for non-acceptance of the amendment.

Further information on the timescales and possible outcomes of amendments can be found in our Timescales and outcomes - Amendments section

15. What happens when the trial ends?
A Declaration of the end of a Clinical Trial form should be sent to the MHRA by the sponsor within 90 days of it the trial conclusion. 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) The MHRA will acknowledge receipt of the End of Trial Declaration.

The sponsor must subsequently submit an end of trial study report to the MHRA within one year of the end of the trial.

If a trial is terminated before the specified date for its conclusion then the sponsor should notify the Licensing Authority and the Ethics Committee within 15 days of the date of termination.

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, contact: clintrialhelpline@mhra.gsi.gov.uk