In this section...
Preparing your application
During the course of a trial, it may be necessary to make changes to the protocol or to supporting documents submitted as part of the application. Such amendments can be categorised as substantial or non-substantial. The criteria to determine whether an amendment is substantial or not are contained in the 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) and are likely to have a significant impact on:
- the safety or physical or mental integrity of the subjects
- the scientific value of the trial
Please note: there is no longer a need to notify ‘for information only’ substantial amendments to the MHRA if the information is to be assessed only by the Ethics Committee.
All amendments made to the study documentation, or application form (annex I), which do not require notification to MHRA should be noted in the study documentation and subsequently submitted in the subsequent notification of a substantial amendment. In particular, the Clinical Trial Application Form should be updated in its entirety at the occasion of a substantial amendment. Details of non-substantial amendments should be clearly noted in the study documentation and differentiated from the substantial amendments being made.
Amendments as regards the IMPD
With regard to changes in the IMPD, guidance is contained in Chapter 8 of the Guideline on the requirements to the chemical and pharmaceutical quality documentation concerning investigational medicinal products in clinical trials (external link)
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 available on the EudraCT: European Clinical Trials (external link) 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.
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.
Further information is available in the section Safety reporting - SUSARs and ASRs
Amendments to the trial protocol
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.
Please also ensure that changes to the protocol and associated documentation are highlighted.
Amendments to the investigator’s brochure
Where an amendment is made to the investigators’ brochure, the following information should be provided in the submission:
- how the risk/benefit assessment of the study been affected
- how these changes impact the trial
- what alterations to the protocol are proposed to take account of these changes.
Annual updates to the investigator’s brochure which do not alter the benefit:risk assessment of the trial should not be submitted as substantial amendments.
Amendments Regarding Investigators Brochure (IB) Safety Updates
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.
Amendments to change the sponsor or sponsor name
Changing the sponsor or change the name of the sponsor of a clinical trial results in a new CTA number being issued for the trial. It is therefore important that the change of sponsor/sponsor name is the only amendment made at that time. Applications for a change in sponsor or sponsor name which include any other changes or documentation will be considered invalid.
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) signed by the new sponsor or person acting on the behalf of the sponsor.
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) signed by the new sponsor or person acting on the behalf of the sponsor
- a letter confirming the change from the old sponsor
- 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:
- a letter acknowledging receipt of the notification of amendment submission
- a letter confirming that the change has been registered and the old CTA number has been closed on our system
- a letter confirming the new CTA number which should be used on all future correspondence.
Amendments to change the contact person, or the contact details of the contact person
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 a change the person named as applicant.
Please note; changes to the contact person, or the contact details of the contact person are no longer considered as a substantial amendment but do require notification to MHRA.
Please see the Changes to the contact person or the contact details section of the website for further details
After submission
Validation
The substantial 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. A new application containing all the necessary components should be provided. Please note that we will not retain a copy of this submission. Invalid submissions will be confidentially destroyed.
Assessment
The assessment will be performed within 35 days. For the purposes of this calculation, the day of receipt of the valid application by the Clinical Trials Unit is day 0. Amendments for phase 1 studies will be assessed within 35 days, with an average of 14 days or less.
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 (usually requiring a resubmission of the amendment).
Acceptance of the request for a clinical trial authorisation subject to conditions
It is possible that the outcome of the assessment is acceptance of the request with conditions applied. Where the conditions are met, no further action is required by the sponsor. It is not necessary to confirm that the conditions are met.
Where the conditions are not met, the authorisation is not valid and the sponsor should submit a further substantial amendment supported by the relevant documentation to make the necessary changes.
Grounds for non-acceptance
Modifications to the original amendment required to address the grounds for non-acceptance (other than protocol changes) must be submitted as a new valid notice of amendment.
If your amendment relates only to changes to the protocol, you may make the amendment if you can modify the proposed amendment to meet all the concerns set out in the letter giving grounds for non-acceptance. However, you must give the Licensing Authority (and Ethics Committee) a minimum of 14 days notice if you intend to proceed with a modified amendment as per 25 (2) in the Medicines for Human Use (Clinical Trials) Regulations 2004 (as amended). The MHRA has 14 days from receiving a modified protocol amendment to assess the request.
At the end of the 14 day period, the applicant will be sent a letter informing them of:
- further grounds for non-acceptance of the revised protocol amendment, or
- acceptance of the revised amendment.
In order to submit a modified protocol amendment the following steps should be followed:
- the cover letter should identify that the submission is being made under the provision of regulation 25 (2) in the Medicines for Human Use (Clinical Trials) Regulations 2004 (as amended).
- the cover letter should identify the CTA number and data of submission of the amendment for which protocol grounds for non-acceptance were raised.
- The modified protocol amendment should be accompanied by a new Annex 2 form.
A template cover letter is provided to assist applicants to make such submissions.
Modified protocol amendments template 
(25Kb)
Modified protocol amendments, as detailed above, can be submitted to MHRA at any time following a GNA letter, provided that MHRA is given a minimum of 14 days notice.
