Clinical trial authorisations: Making clinical trial submissions to the MHRA

From 1 November 2007, letters from the MHRA relating to clinical trial submissions will not be signed. The wording and format of letters from the MHRA relating to clinical trial submissions will also be modified from this date. This is in line with MHRA policy.

This page provides guidance on preparing and submitting electronic documents.

1. Types of submissions covered
The following types of clinical trial submissions are covered by this document

• Initial applications
• Substantial amendments
• Annual safety reports
• Responses to remarks in an acceptance letter
• Responses to letters giving ground for non-approval
• End of trial declarations

There are no changes to the way SUSARs are submitted.

2. Submissions
Applicants are required to submit electronic documents on disk with one PDF file for each document. In exceptional cases where the use of PDF files is not feasible, (for example, in the case of small, non-commercial clinical trials) electronic documents using Word are acceptable and will be processed to the same target timescales. Disks should be submitted with no subdirectory structure. The portal is not available for clinical trial submissions at this time. Updates on portal availability will be provided in due course.

3. Signatures
The signature page of the application form must be signed for inclusion on the disk. Either insert a signature image into the Word document (e.g. copy image “Paste Special>Picture (Windows metafile)”) prior to conversion to PDF, or print, sign, scan and then merge the signature page with the relevant PDF. Signatures are not required in the case of cover letters.
Please note that The MHRA do not currently accept digital signatures.

4. Disk formats
The following disk formats are acceptable:

• CD-ROM
• CD-R
• CD-RW
• DVD-R
• DVD-RW

The following formats are not acceptable:

• DVD-ROM
• DVD-RAM

5. Guidance on preparing PDF documents
As far as possible all data should originate from electronic files rather than from scanned data. There may be circumstances where the data is only available in paper format, please advise us in advance if this is the case by sending an e-mail to RIS.CT@mhra.gsi.gov.uk.

In order to process PDF documents efficiently MHRA assessors need to be able to easily navigate and manipulate the document (e.g. copy and pasting sections of the document or splitting a large document into multiple smaller documents). To facilitate this process the following points should be noted when creating PDF documents:

• All PDF documents should be created directly from Word or undergo Adobe Acrobat optical character recognition (OCR) at the time of creation. PDF document scanned images should not be provided as it is not possible to cut-and-paste data in this format.
• PDF documents should not be file protected as this prevents the printing and manipulation of the document.
• Fonts that are not supported by Microsoft Word should not be used on PDF documents.
• All PDF documents should be appropriately bookmarked to ensure that assessors can jump directly to the sections of interest. Only the simplest of PDF documents (e.g. a letter) should be submitted without bookmarks. All documents larger than 50 pages should be bookmarked (bookmarking to primary headings is sufficient). Documents less than 50 pages should be considered for bookmarking if they are particular complex and/or require frequent cross referencing within the document. In making this judgement consider whether bookmarking would help and assessor to work more efficiently.
• Supporting data and references should comply with the Vancouver convention where appropriate (http://www.icmje.org - external link).

If historical documents are not available electronically, a scanned image which has undergone OCR is acceptable. Applicants should ensure that the highest quality scan image is produced.

6. What to send
A request for a clinical trial authorization consists of:

• Covering letter
• The application form (signed PDF)
• Protocol
• IMPD or SmPC where relevant
• The specified particulars and documents (supporting data)
• The XML file of application form (complete data set)
• Applicable fee
  

The supporting data for substantial amendments will vary depending on the type of amendment being made but should include:

• Signed application form (PDF) with an updated XML file if the amendment affects the data previously submitted
• An extract of the modified documents, showing previous and new wording, where applicable
  or
• Where the changes are extensive and/or widespread, a revised version of the document clearly identified with version number and date
• Supporting information 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

Information on the pharmaceutical data required in a clinical trial submission is provided in EC document ‘Guideline on the Requirements to the Chemical and Pharmaceutical Quality Documentation concerning Investigational Medicinal Products in Clinical Trials’ (external link).

Information on the current fees and how to pay them can be found on the Fees for clinical trials section.

7. Where do I get the application forms?
The clinical trial application forms can be downloaded from EudraCT: European Clinical Trials Database (external link).

8. Which form do I use?

• To apply for authorisation to conduct a clinical trial (Initial Application), use the Clinical Trial Application Form (Annex 1) available through the EudraCT website (external link).
• To apply to make an amendment to a trial for which you already have approval, use the Notification of Amendment (Annex 2) form available through the EudraCT website (external link).
• To tell us that a trial has ended, use the Declaration of the end of a Clinical Trial form available through the EudraCT website (external link).

9. What is a EudraCT number?
A EudraCT number is a unique number used to identify the trial. One number is issued per protocol, irrespective of the number of trial sites or countries involved. The EudraCT number must be provided for all submissions to the MHRA.
A EudraCT number can be obtained from the EMEA’s EudraCT database (external link).

10. What is an XML file?
An XML file is the data format of the saved Clinical Trial Application Form information. It is created via the EMEA’s EudraCT database (external link). The XML file of the completed Clinical Trial Application Form information is required to enable us to enter the details of the trial into the EudraCT database, as we are obliged to do by the Clinical Trials Directive 2001/20/EC.

11. Structuring data on disk
All documents should be submitted in PDF format with one PDF file for each document, including:

• The appropriate application form.
• Supporting data files - named correctly as in the table in section 12 of this document.
• To support efficient processing of submissions the MHRA require that the relevant section numbers are prefixed to the file name of all submitted PDF files (see table at the end of this document).

Failure to label the files correctly may lead to the submission being rejected.

The disk itself should either be formatted into the full directory and sub-directory structure or submitted as a flat file with no directory structure.

12. Naming documents
It is important that the individual document filenames comply with the CTD convention (Attachment 2 of 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) and the naming structure outlined in the table below which shows only the files and filenames required for submissions to the MHRA. Please ensure the section numbers are prefixed to the file names as this allows our staff to quickly identify where the document should be indexed on our system.

Only one application should be submitted per disk.

Document Naming Convention for Electronic Documents In Support of a Clinical Trial Authorisation Application to the MHRA

Please note this table shows only the documents required for submissions to the MHRA.

 

	Information to be provided 1	PDF file name	Required for valid CTA application	XML file required	OCR PDF file required
1	General
1.1	Receipt of confirmation of EudraCT number	1-1-eudract-receipt	Yes	No	No
1.2	Covering letter	1-2-covering-letter	Yes	No	No
1.3	Application form	1-3-application-form	Yes	Yes	Yes
1.4	List of Competent Authorities within the Community which the application has been submitted and details of decisions	1-4-competent-authorities	Yes	No	No
1.5	Copy of Ethics Committee opinion in the MS concerned when available	1-5-ethics-committee-opinion	If available	No	No
1.6	Copy/summary of any scientific advice	1-6-scientific-advice	If applicable	No	No
1.7	If the applicant is not the sponsor, a letter of authorisation enabling the applicant to act on behalf of the sponsor2	1-7-applicant-authorisation	Yes	No	No
3	Protocol Related
3.1	Clinical trial protocol with all amendments to date	3-1-protocol	Yes	No	Yes
4	IMP Related
4.1	Investigator’s brochure	4-1-investigators-brochure	Yes	No	Yes
4.2	Investigational Medicinal product Dossier (IMPD)3	4-2-impd	If applicable	No	Yes
4.3	Simplified IMPD for known products3	4-3-simplified-impd	If applicable	No	Yes
4.4	Summary of Product Characteristics (SmPC) (for products with marketing authorisation within the EC)3	4-4-smpc	If applicable	No	Yes
4.5	Outline of all active trials with the same IMP	4-5-imp-active-trials	Yes	No	No
4.6	If IMP manufactured in EU and if no marketing authorisation in EU
4.6.1	Copy of the manufacturing authorization referred to in Art 13.1 of the Directive stating the scope of the authorisation	4-6-1-manufacturers-authorisation	Yes	No	No
4.7	If IMP not manufactured in EU and if no marketing authorisation in EU
4.7.1	Certification of the QP that the manufacturing site works in compliance with GMP at least equivalent to EU GMP, or that each production batch has undergone all relevant analyses, tests or checks necessary to confirm its quality	4-7-1-qp-declaration	Yes	No	No
4.7.2	Certification of GMP status of active biological substance	4-7-2-gmp-status-ai	Yes	No	No
4.7.3	Copy of the importers manufacturing authorization referred to in Art 13.1 of the Directive stating the scope of this authorization	4-7-3-importers-authorisation	Yes	No	No
4.8	Certificate of Analysis for test product in exceptional cases
4.8.1	Where impurities (not covered by the specification) are detected	4-8-1-test-product-c-of-a	Yes	No	No
4.9	Viral studies (where applicable)	4-9-viral-validation	Yes	No	No
4.10	Applicable authorisations to cover trials or products with special characteristics (if available) e.g. GMO, radiopharmaceuticals	4-10-special-characteristics-authorisation	Yes	No	No
4.11	TSE certificates (when applicable)	4-11-tse-certificate	Yes	No	No
4.12	Examples of the label in the national language	4-12-label	Yes	No	No

1 Attachment 1 - Detailed guidance for the request for authorisation of a clinical trial on a medicinal product for human use to the competent authorities, notification of substantial amendments and declaration of the end of the trial - October 2005 [ENTR/F2/BL D(2003)]
2 The letter of authorisation is required in all cases where the applicant is not the same legal entity as the sponsor
3 Where there is more than one IMPD, simplified IMPD or SmPC used in the trial, the files should be named “impd- < name-of-the-product> ”, “simplified impd- < name-of-the-product> ” or smpc- < name-of-the-product>

13. Why we need OCR PDF documents
PDF documents of the application form, protocol, investigator’s brochure, IMPD and SPC (where appropriate) should be created directly from Word or undergo Adobe Acrobat optical character recognition (OCR) at the time of creation. PDF document scanned images should not be provided as it is not possible to cut-and-paste data in this format. The OCR layer also supports text searching within the document and across the entire MHRA document store.

For further information on OCR files and how to make them, please see Special Mail 5: Frequently Asked Questions (insert link to PDF).

14. Labelling disks
Each disk should be labelled in the following manner:

• EudraCT number
• Description of contents
• • Initial Application
  • Response to Remarks from an Initial Application
  • Notification of a Substantial Amendment
  • Response to Remarks from a Substantial Amendment
  • Notification of End of Trial
  • Annual Safety Report
  • End of Study Report
  • SUSAR
• Company name
• Date sent

The disk may be printed or labelled with an adhesive paper label or a permanent marker pen.

15. Posting disks
All disks should be sent to the address below:

Information Processing Unit
Area 6
Medicines & Healthcare products Regulatory Agency
Market Towers
1 Nine Elms Lane
London
SW8 5NQ

16. Contacting us
All queries relating to electronic documents and submissions should be directed to: RIS.CT@mhra.gsi.gov.uk