SPECIAL MAIL 5

FREQUENTLY ASKED QUESTIONS

Document Version : 2.1 Publication Date : 08 June 2009

i

Special MAIL 5 Submission Guidelines

Frequently Asked Questions

The MHRA has recently completed a major redevelopment of its Information Management systems under its “Sentinel” programme. The introduction of the Sentinel system affects all areas of the MHRA’s work and introduces an entirely electronic working environment. The introduction of the Sentinel system was accompanied by a major business reorganisation which included the creation of an MHRA Information Processing Unit (IPU). The role of the IPU is to ensure that all submissions are quickly and accurately entered onto the Sentinel system and made available for specialist assessment. Our aim to provide a fast and efficient service to our customers is critically dependent of the standard of submissions received by the IPU. Processing poor quality submissions requires significant additional resource which leads to delays in processing subsequent submissions. Special MAIL 5 (SM5) defines a standard approach to sending submissions to the MHRA which supports quick and efficient processing of submissions through to specialist assessment.

We have received many requests for clarification or more information on the requirements detailed in Special MAIL 5. This document lists the most common queries and provides expanded guidance in these areas.

This is a “living” document; it will be updated as required. It is advisable to regularly check the MHRA website to ensure that you have the latest version.

http://www.mhra.gov.uk/mhra/SpecialMail5

The “Submissions in non-XML eCTD format” document describing our then new ability to handle these Non-eCTD electronic Submissions (NeeS) is largely replaced by the EU guidance (see below).

The guidance in Special MAIL 5 includes that for submitting new MA applications, MA variations and Clinical Trial applications. For MA applications and variations, it is expected that this guidance will remain in place until companies move to providing these submissions using the eCTD standard. It uses the ICH M4 guidelines for CTD organisation to provide the granularity of files for non-eCTD electronic submissions. Special MAIL 5 does not provide any guidance on submitting eCTDs. If you require any advice or information on preparing and submitting eCTDs then please contact Dr David Wheeler (david.wheeler@mhra.gsi.gov.uk) or look at the new EU eCTDguidance. http://esubmission.emea.europa.eu/doc/eCTD%20Guidance%20Document%201.0%20FINAL%20FOR%20PUBLICATION.pdf In issuing the guidance in Special MAIL 5, our primary objective is to reduce delays in the current system. These delays are a source of considerable concern for the Industry and the MHRA and we need to work together to address the root causes. One of the root causes is poor quality submissions. We do not intend this guidance to be unnecessarily burdensome and it is our intention to enforce the guidance in a reasonable and pragmatic manner. It should be borne in mind that the overall goal of the exercise is to ensure that submissions reach the assessors electronically in the best practicable format to allow for easy access to and review of the data Submissions that do not comply with the guidance in a minor way will not be pedantically rejected if the non-compliance does not significantly affect our ability to efficiently process the data. However, poor quality submissions lead to significant and unpredictable delays for everyone and will be returned to the applicant. If there is any doubt about a submission’s compliance with the guidelines, it is advisable to contact the Information Processing Unit before sending the data. All submissions are screened before entry onto the Sentinel system. Please note that the guidance in Special MAIL 5 applies to submissions concerning medicines only. The guidance does not apply to submissions concerning medical devices. In particular, the guidance on Clinical Trial applications applies to Clinical Trials for medicinal products (not clinical investigations of medical devices) and the guidance on Notified Bodies Consultations concerns medical devices incorporating one or more ancillary medicinal substances. Further updates of these FAQs are unlikely, as the MHRA accepts the EU NeeS interim standard, or, more and more, full eCTD submissions. http://esubmission.emea.europa.eu/doc/eGuidance_Document_1.4.pdf

ii

iii

INDEX

Page Introduction & Index i - iii Questions relating to:

Links to major, important or useful changes ....................................................................................................... iv 1. CTD document names & file structures…........................................................................................................1 2. Bookmarking….................................................................................................................................................6 3. CTD Module 1 and Annexes… ........................................................................................................................8 4. Labeling of Submissions, sending submissions and structuring of disks….....................................................9 5. Paper submissions and text-searchability requirements…............................................................................10 6. Submitting SmPCs, PILs, labels & Variations… ............................................................................................13 7. Change of Ownership….................................................................................................................................16 8. Active Substance (Drug) Master Files…........................................................................................................17 9. Renewals and PSURs…................................................................................................................................19 10. Clinical Trials… ............................................................................................................................................21 11. Responses to RFIs…...................................................................................................................................23 12. Rejections and the Portal… .........................................................................................................................25 13. Withdrawals and Cancellations… - NEW.....................................................................................................27 14. Parallel Import Applications… - NEW ..........................................................................................................29 15. Information Updates (Add/Amends)… - NEW .............................................................................................31 Annex A – List of CTD file names – UPDATED.................................................................................................32 Annex B – Module 1.2 Annex Documents .........................................................................................................39 Annex C – CTA Document Naming Conventions - UPDATED..........................................................................40 Annex D – Guidance on Text Searchable Documents for MHRA Submissions - NEW ....................................42 Annex E – List of PLPI file names - NEW..........................................................................................................44 Annex F – List of documents required for different PLPI variations – NEW......................................................46 Annex G – Updated submission route summary - NEW....................................................................................48

REVISION HISTORY

Document Version : 1.0 Publication Date : 24 November 2006 Document Version : 2.0 Publication Date : 21 December 2007

Notes: This version contains amendments to the SM5 FAQs v1.0. The approach taken is to add, in addition to the previous section bookmarks, a list of major, important or useful changes, also bookmarked. All updated questions are marked as such, and question numbers in each section are now prefixed with the section number for ease of reference.

Several points for clarification have been raised via telephone conversations with the

MHRA, emailed requests for further details, conferences and meetings with Industry. This constructive feedback is appreciated, and we hope it continues.

A significant evolution is the addition of a new section on text-searchability of documents,

compiled by the ABPI – this is included in the list of major amendments below. We have also included a substantial section on PLPI submissions, a revision of the CT

section, and an up to date summary of submission routes.

Document Version : 2.1 Publication Date : 08 June 2009 Notes: This version contains minor amendments to the SM5 FAQs v2.0.

The minor amendments have been highlighted in pink, to distinguish them from the highlights in yellow and green (updated or added as NEW in v2.0). The most significant changes are the new “Guidelines on Submission of Labels and Patient Information Leaflets (October 2008)”, which came into force 1 April 2009, the change in scanning provider, resulting in all applications coming to Market Towers as of 23 February 2009, and the update to the application form (m1-2) Annexes from 6 to 5. There are unlikely to be further updates to these FAQs, as the UK accepts the EU NeeS standard, and, more and more, full eCTDs are received. http://esubmission.emea.europa.eu/doc/eGuidance_Document_1.4.pdf We also now ask that submissions to IPU for changes to labels and leaflets arenow made to Area 9, not Area 6 - PIU. This reflects a change in processing (thesame team had previously processed CT and PIU submissions).

iv

v

Links to major, important or useful changes in v2.0 Acceptance of NeeS as “Submissions in non-XML eCTD format” 25 MB size limit preference on PDF files M1 DTD v1.2.1 documents in NeeS Clarification of file-naming in bulk submissions Letter.Access@MHRA.gsi.gov.uk emailbox PSUR updated guidance Responses to RFIs additional guidance Basic Portal tips 10. Clinical Trials… - UPDATED v2.1 13. Withdrawals and Cancellations… – NEW, & Withdraw.Cancel@MHRA.gsi.gov.uk emailbox 14. Parallel Import Applications… - NEW 15. Information Updates (Add/Amends)… - NEW Annex A – List of CTD file names – m131 update - for text-searchability - see Annex D Annex C – CTA Document Naming Conventions - UPDATED Annex D – Guidance on Text Searchable Documents for MHRA Submissions - NEW Annex E – List of PLPI file names - NEW Annex F – List of documents required for different PLPI variations - NEW Annex G – Updated submission route summary - UPDATED v2.1 Links to additional minor amendments in v2.1 5. Paper submissions and text-searchability requirements… 6. Submitting SmPCs, PILs, labels & Variations... 11. Responses to RFIs... 13. Withdrawals and Cancellations... - NEW (new in v2.0) Annex B – Module 1.2 Annex Documents - UPDATED v2.1

1

1. CTD document names & file structures…

**New MHRA Flat Folder Utility now rolled out into IPU. We can now accept eCTDs without the xml backbone**

See – “Submissions in non-XML eCTD format” document on NeeS at:

http://www.mhra.gov.uk/mhra/SpecialMail5

Q1-1. Why do you require one document for each CTD section? Can I provide more than one document for a CTD section? - UPDATED A1-1. The CTD structure is the foundation of the Sentinel system. All documents associated with a submission are indexed into the appropriate CTD directory on Sentinel which allows assessors to rapidly locate documents during the assessment process. If documents are not submitted at this lowest level of granularity (closely in line with ICH M4 document “Organisation of the Common Technical Document for the Registration of Pharmaceuticals for Human Use” issued in the EU as CPMP/ICH/2887/99 – please refer to this for guidance), the MHRA needs to manually split the documents to this level. This is a time consuming task which leads to significant processing delays and knock-on delays in the assessment of the submission. Compliance with the guidelines (see Annex A) will allow the MHRA to process submissions as efficiently as possible. Multiple PDF documents for a single CTD section can be provided rather than a single PDF if the applicant judges that this would aid the MHRA in processing or assessing the submission or if it would improve the maintainability of the applicant’s document set. We would also ask that documents are preferably kept below 25 MB to allow efficient and trouble-free upload into our Sentinel database (see Q1-13) NOTE: To aid rapid processing, please only send the documents required to support the submission. Sending extra documents that do not add to the assessment of the submission increases MHRA processing times If you are unsure of what documents to send, please contact the MHRA Regulatory Information Service for guidance. Version 1.4 PDFs, produced by various PDF software applications, are preferred, but for the most part, any is accepted (see Section 12 for exception re: Portal forms) Q1-2. Why do you require the CTD section number to be prefixed to the relevant document name? - UPDATED A1-2. All documents are indexed against the CTD structure on Sentinel. Including the CTD section code in the document name allows our staff to quickly identify where the document should be indexed on our system. In the absence of the CTD section number the document may need to be opened by data entry staff to identify it. The cumulative effect of these small delays can quickly become significant. (But, see link above for the publication “Submissions in non-XML eCTD format” on the new MHRA Flat Folder Utility which allows submission of non-xml eCTDs in folders) Q1-3. The disk is formatted using the CTD folder structure, do the individual files still have to have the section prefix? - UPDATED A1-3. No, the applicant can now make use of this NeeS format. It should be noted, however, that NeeS currently can't be submitted complete via the Portal, and need to be submitted on CD/DVD (see link above for the publication “Submissions in non-XML eCTD format”). For Portal submissions, to make use of this option, you will need to send just the form through the Portal, with a ticket number generated, and then submit a CD/DVD with the folder-structured submission, also carrying the form, and with the ticket number quoted on the disk and the cover letter. The MHRA cannot currently accept any submission via the Portal in a folder structure except full xml eCTDs, as it presents a large processing overhead to “drill” into the subfolders and manually index documents. Special MAIL 5 does not refer to eCTD submissions. If you are able to submit eCTDs or require any advice or information on preparing and submitting eCTDs then please contact Dr David Wheeler (david.wheeler@mhra.gsi.gov.uk).

2

Q1-4. We are planning to submit our new national application on CD-ROM, however we are not sure how to organise the disk. - UPDATED A1-4. The disk can either be formatted into the full CTD folder structure or the data can be submitted as a flat folder structure. If a full CTD structure is used it is no longer essential to name the individual files according to Special Mail 5 and prefix the CTD section number (see Q1-3, and Table 1, below). Individual files must, of course, still be named according to CTD standards. Only one new application should be submitted per disk. For variations, it is acceptable to submit multiple separate variations on a disk. In these circumstances the files supporting each variation (or bulk set) should be in their own folder named using the PL number of the licence being varied (or the lead for a bulk set). Each directory should constitute a “stand-alone” variation, or set of bulk variations (i.e. common files should be duplicated in the relevant folders for variations that are NOT part of a bulk submission). Submitting variations of different types (e.g. Type IA and Type II) on one disk is not permitted as they pass through different Sentinel workflows. Table 1 Folder structure Filenames Submission

CTD in SM5 format Flat (ie. no) folder structure SM5 filenames 1) Portal or 2) CD/DVD NeeS with folder

structures (including MHRA Non-XML eCTD

format)

CTD folder structure CTD filenames 1) CD/DVD or 2) CD/DVD + form via Portal

eCTD CTD folder structure CTD filenames

1) CD/DVD or 2) CD/DVD + form via Portal or 3) all through

Portal up to 100 MB total submission size

[N.B. Portal form required for reduced fee]

Q1-5. The MHRA’s naming convention and file requirements differ from the ICH guidelines. Is it possible for you to publish a complete file structure of how you would want the folders named, would naming our folders in line with ICH guidelines comply with your requirements? - UPDATED A1-5. Yes, see question 1-3, above. For submissions that do not meet the requirements in the publication “Submissions in non-XML eCTD format”, the MHRA have endeavoured to remain as close to the CTD standard as practical in defining the submission requirements in Special MAIL 5. The exception is the requirement to prefix the CTD section number to the individual file names (see Q1-2). The complete CTD structure and the associated MHRA file names can be found in Annex A of this document. The need for standard file names and the prefix of the CTD section number is driven by our requirement to be able to quickly identify and index the individual documents in the submission (see Qs1-1 & 1-2). Assuming that the CTD section number is correctly prefixed and that the document name is clear, we are unlikely to reject a submission on the basis of small variations in document naming (we are aware, for instance that there may be technical limitations on some very long file names and sensible abbreviations are acceptable). Q1-6. We are not yet in a position to submit a full eCTD application however we are regularly submitting electronic CTD applications to other EU authorities. Our internal procedures and file structures as set-up to meet as many of the ICH eCTD requirements as possible particularly for the naming of the folders. The naming convention you mention in Special MAIL 5 is actually different to that specified by eCTD standard – UPDATED (see note on flat folder utility and NeeS) A1-6. The naming conventions used in the guidance for new applications and variations are designed to comply with the CTD structure which has been a mandatory requirement for all “non eCTD” (paper and electronic) submissions since 1 July 2003. The processing areas of the Sentinel system are designed with the CTD standard in mind. The CTD structure does differ from the eCTD definitions (the standards have become more aligned with the release of version 1.2.1 of Module M1). We are able to receive full eCTD submissions, non-xml eCTD submissions (NeeS), and submissions in the CTD format detailed in the Special Mail 5 guidance (see Table 1, above).

3

Q1-7. The example you give in Special MAIL 5 is for a Module 2.3 document describing the Description and Composition of the Drug Product. According to your document this should be named M2-3-P-1 however according to CPMP/ICH/1840/01 (the eCTD standard) the folder for this would be called “23-qos” and we would submit one PDF file for the entire QOS bookmarking each section. - UPDATED A1-7. The eCTD standard does differ from the CTD standard (see Q1-6) and, for consistency, if not formatted as non-xml eCTD submissions, we do require non-eCTD “electronic” submissions to be in the CTD format detailed in the Special Mail 5 guidance. We have reviewed our original guidance in this area and we will accept other levels of granularity in this area if they are consistent with ICH M4 (see Q1-1). For example, in the QOS section, submitting single PDFs for the M2-3-P, M2-3-S, M2-3-A and M2-3-R sections respectively is acceptable. We will also accept a single PDF for the entire QOS section if the document is bookmarked. Please see Annex A for more detail in this area. Q1-8. Special MAIL 5 states that "failure to label the files correctly may lead to the submission being rejected". Is there any contact with the validation team and possibility to re-submit prior to rejection? Which are the deviations to the rule tolerated and recommendations in case older files do not strictly comply with the guideline? A1-8. If a submission is rejected we will make it clear by e-mail the reason for the rejection and ask that you resend the entire submission correctly formatted. Submissions are rejected at an initial screening step where all submissions are checked. No details on the submission will be entered on the Sentinel system and no fee levied. If you feel that the submission has been wrongly rejected, please contact the Information Processing Unit to discuss. We do not specify any tolerated deviations, beyond sensible, clear file names abbreviations (see Q1-5, above, and Annex A) and “volumising” references (see Q2-3). It is our intention to enforce the guidance in a reasonable and pragmatic manner. Submissions that do not comply with the guidance in a minor way will not be pedantically rejected if the non-compliance does not significantly affect our ability to efficiently process the data. However, poor quality submissions lead to significant and unpredictable delays for everyone and will be returned to the applicant. If in doubt, please contact us before sending the submission. Q1-9. With regard to study reports, Special MAIL 5 states that, for example, "Study Reports on Primary Pharmacodynamics should be submitted as a single PDF file named as M4-2-1-1 Primary Pharmacodynamics". Does this apply even if we have more than one study under this section? This would apply to all CTD sections that contain studies, such as M5-3-5-1? A1-9. We are happy to receive multiple PDF files for a given CTD section if there is more than one study, in line with the ICH M4 guidelines. The important requirement in this area is that the individual study names are descriptive and, hence, support an assessor in rapidly locating a particular study.

For example, in Module 5.3.5.1 “Study Reports of Controlled Clinical Studies Pertinent to the Claimed Indication” an acceptable naming convention would be: m5-3-5-1-cont-clin-2001-ocd.pdf m5-3-5-1-cont-clin-2003-depression.pdf If unique study identifiers are used consistently throughout the submission including in overviews and summaries then they may be used. For example: m5-3-5-1-study SA12345.pdf Non informative names would be rejected. For example, the following is not acceptable: m5-3-5-1-study-report-1.pdf m5-3-5-1-study-report-2.pdf If the study reports are submitted in a single PDF, it is essential that the PDF is bookmarked. Bookmarked headings should indicate the study in each section using a meaningful title and prefixing the CTD section number. Q1-10. With regard to appendices of study reports, for section 5.3.5.1 do we need to create one PDF file that contains all appendixes of the study reports? Can we create this PDF file for each study separately? This applies to all CTD sections that contain appendices.

4

A1-10. We are happy to receive multiple PDFs for the appendices (see Q1-9). The important requirement in this area is that the individual appendices names are descriptive and, hence, support an assessor in rapidly locating the data. For example, in Module 5.3.5.1 an acceptable naming convention would be: m5-3-5-1-cont-clin-2001-ocd-append-1.pdf m5-3-5-1-cont-clin-2003-depression-append-1.pdf If unique study identifiers are used consistently throughout the submission including in overviews and summaries then they may be used. For example: m5-3-5-1-study SA12345 appendix 1.pdf If the appendices are submitted in a single PDF, it is essential that the PDF is bookmarked. Bookmarked headings should indicate the appendices in each section using a meaningful title.

Q1-11. With regard to files and pagination, in some cases the study report are made of several documents - appendices generally - which are assembled and published to result in several PDF files numbered vol. 1 to vol. n .PDF. Would it be appropriate to submit the study report as a collection of files (one for each appendix) knowing that there won't be any consecutive pagination from the first to the last page of the report, or would the MHRA prefer a single file named "study XXX".pdf ? How should they be named? - UPDATED A1-11. We are happy to receive the report in volumes if the files names are descriptive and, hence, would support an assessor rapidly locating the data For example, an acceptable naming convention would be: m5-3-1-1-bioavailability-vol-1.pdf m5-3-1-1-bioavailability-vol-2.pdf etc. or m5-3-1-1-bioavailability.pdf and m5-3-1-1-bioavailability-appendix-1.pdf m5-3-1-1-bioavailability-appendix-2.pdf etc. If the CTD section document can be submitted as a single merged PDF of reasonable size (less than 50 pages, and preferably less than 25MB, see Q1-13, below) we would prefer to receive the data in this format. It is essential that each PDF file is bookmarked to allow easy navigation between sections in the document (see section 2 on bookmarking). Q1-12. How should individual reports such as a validation report be presented? A1-12. Validation reports should be named in accordance with the file naming conventions in Annex A (see Q1-5). Q1-13. Does the MHRA impose a size limit on PDF files? - UPDATED A1-13. The MHRA has now found it necessary to advise a preferred limit. Large files (in excess of 25 MB) are difficult to handle so please “volumise” these files and 100MB is the absolute ICH limit. The Sentinel Product Licensing case folder will not allow us to efficiently import larger files, so these should not be submitted if avoidable. Please condider this when building your dossier. As pdfs are downloaded complete from Documentum to be viewed by assessors (not viewed page by page, as is often the case e.g. over the Internet) large files introduce delays in assessment whilst the download occurs.

5

In addition, owing to a limit on upload of documents via a third party, any individual item sent via the Portal should not be over 15 MB, or you may have problems uploading the documents. For zipped objects, this limit also applies, so you may need to create more than one zip file for large Portal submissions, but do not submit zip files within zip files. Q1-14. To prepare ourselves for future EU eCTD submissions, we have adopted the ICH eCTD specification directory and filename convention for EU e-Submissions. As the Sentinel system is designed to support eCTD would this format be acceptable to the MHRA? - UPDATED A1-14. We can now accept a CTD submission using eCTD file names and folder structures on disk, see Q1-3, above. Q1-15. How should I denote that a file is an addendum, rather than a replacement, or for review only? - NEW A1-15. We suggest a suffix, as below. To make it very clear, we suggest this is best in CAPITALS*, and would much prefer this, so as not to be confused with an abbreviation that is part of the file name, but lower case will suffice if this presents difficulties with applicants naming systems already in place. In this case, something in the TOC or cover letter to clarify what the status of said documents is, is always useful. Examples would be: Addendum = ADM or adm

m2-5-clinical-overview-ADM.pdf [or m2-5-clinical-overview-adm.pdf] For Review = REV or rev

m3-2-p-5-1-specifications-REV.pdf

[or m3-2-p-5-1-specifications-rev.pdf]

*[this would seem reasonable, as it is a stand in for the eCTD operators, which appear in capitals in the index.xml displays, and not part of the ICH defined file names, which of course should be lower case]

6

2. Bookmarking… Q2-1. Are you able to provide us with any guidance on the use of bookmarks in our PDF files? Will application forms require bookmarking? A2-1. All documents larger than 50 pages should be bookmarked to section headings (will happen automatically if headed documents are converted from MS Word). Bookmarking to primary headings is sufficient. Short documents should be considered for bookmarking if they are particularly complex and/or require frequent cross referencing within the document. In making this judgement please consider whether bookmarking would help an assessor to work more efficiently. When submitting “m1-2-form.pdf” including annexes, or “m1-2-annexes.pdf”, bookmark to each annex, to allow the use of the bookmark tab in Adobe Acrobat. Q2-2. Do you always require files at the lowest level of CTD granularity when bookmarking larger files is an option? For example, we have module 3.2.S in one PDF file with all sub-sections fully bookmarked and therefore easily searchable. Will this be accepted or do we have to break down the PDF file into its individual sub-sections? A2-2. In order that we can efficiently process the submission we do require the submission to be in the CTD format detailed in the guidance (see questions in section 1 and the full CTD listing in Annex A). Q2-3. How should I submit literature references? A2-3. Literature references can be submitted in one of two ways, either “volumised”, for example: m3-3-lit-ref-a-m.pdf m3-3-lit-ref-n-z.pdf With the PDF bookmarked to individual references. Or by individual author, for example: m3-3-arthur-2001.pdf m3-3-goater-2005.pdf m3-3-maxwell-1999.pdf Either way should allow an assessor to efficiently locate a study. References should be provided in either the Vancouver or ChemAbs naming conventions Q2-4. Concerning bookmarks and hyperlinks, my understanding is that, due to the MHRA uploading process, all external bookmark and hyperlinks are broken, and are therefore not required or used. Please can you confirm this, as there is additional hyperlinking that could be provided to aid reviewer navigation of our submissions. Currently we provide no hyperlinking in MHRA submissions unless it is required elsewhere. We would consider a degree of hyperlinking to support review if it were utilised. A2-4. Bookmarking within a document is preserved when we load documents onto the Sentinel system and we require that documents are bookmarked (see Q2-1). Due to a technical issue with third party software, hyperlinks are not currently supported within the Sentinel system. However, this issue is still outstanding, but we do still strongly encourage the use of hyperlinking within the submission (however, unlike bookmarks, we will not reject a submission on the basis of the absence of hyperlinks). Q2-5. In converting a submission to the MHRA’s file naming requirements we are aware that the existing hyperlinks in the document will no longer function. Will the submission be accepted? - UPDATED A2-5. Yes, we will accept files under these circumstances at present.

7

Q2-6. Are there any specific requirements on PDF Document Information Field values? A2-6. The Document Information Field values are used infrequently by assessors and it is not, therefore, a mandatory requirement. However, we recognise that it has value in searching for documents. If you are completing these areas please continue to do so.

8

3. CTD Module 1 and Annexes… UPDATED v2.1 Q3-1. Do we have to include a cover letter for simple applications? - UPDATED A3-1. Yes, please include an electronic cover letter and ensure that it includes the submission type. If you are not including a Table of Contents, please also include a list of the documents included in the submission. This allows us to quickly ascertain the nature of your submission and to double check that all the documents are present. The cover letter need not be signed. To help with the rare occurrence of corrupt CDs, include a contact email address written or printed on the actual disk, or on a copy of the cover letter printed to accompany the submission. If you are using the MHRA Portal intelligent form, a cover letter also allows you to provide us with a second communication route (e.g. a telephone number) which can allow us to quickly contact you if we have any initial queries. Please do not use a generic cover letter, as this can cause confusion. For a bulk submission, a single copy of a cover letter referring to all PLs is required. For each individual submission, a brief cover letter outlining what you are sending is most helpful. For Portal updates, please include a list of new documents (see Q12-3) Q3-2. Module 1.2 Application form has 22 annexes. How should the files for these be labelled? - UPDATED v2.1 A3-2. They may be merged with the form [NOT with the Portal form though], or submitted as a separate “m1-2-annexes.pdf” document if using our intelligent form for Portal submissions (see Annex A, and Annex B which comprises a list of the 22 annexes). We will also accept individual annex pdfs, as e.g. m1-2-5-1-proof-of-payment.pdf. Other regional documents belong in Module 1 additional, for example:

m1-additional-guidelines.pdf or m1-guidelines.pdf (as an abbreviation) However, as not all applicants are using the eCTD ICH M1 DTD v1.2.1 either for eCTDs, or for file-naming as SM5 submissions, and so need a location for documents with no home in the M1 DTD 1.1 naming convention, the MHRA allow the m1-[variable] option, to help applicants. (See Annex A for both M1 DTD v1.1 and 1.2.1 naming conventions) Q3-3. I cannot find the new PDF Application Forms (mentioned in Section 3.2 of Special MAIL 5) on the website. Where can these forms be found? Are these new PDF forms compatible with Adobe Acrobat v5 (PDF v1.4)? Are these PDF forms mandatory? We intend to continue to use the Word-based forms available via the MHRA website for the time being. A3-3. The PDF forms are on the MHRA electronic Portal. For non-Portal customers, the PDF form is created from completing our Word format forms and then converting to PDF. PDF forms are mandatory with the exception of the submission of the Summary of Product Characteristics text where the use of the MHRA SmPC Word templates is mandatory for the “clean” version (see Q6-10). Q3-4. Version 1.2.1 of the eCTD Module 1 contains sections that were not covered in Annex A. How should the files for these be labelled? - NEW v2.0 - UPDATED v2.1 A3-4. Annex A has been updated. They should be named as for other documents to be included in Module 1additional, and the principle followed for any further DTD updates, for example: m1-data-market-exclusivity.pdf or in line with DTD 1.2.1, as e.g. m1-5-3-data-market-exclusivity.pdf

9

4. Labeling of Submissions, sending submissions and structuring of disks… Applicants now have 2 electronic submission options, besides eCTD submission: either i) submit using SM5 prefixes, or ii) submit in a folder structure for the MHRA to pass through our “flat folder utility” (see Section 1, including Table 1). Option i) is more efficient for the MHRA. To take advantage of option ii) and use the Portal, submit a Portal form with a ticket number generated, and send CD/DVDs through the post, also including a copy of the “ticketed” form. Q4-1. Can I include submissions for a mixture of variation types in a single disk?

A4-1. Please do not include a mixture of variation types in a single disk. Submit Type IA, IB and II variations on separate disks. Similarly MR variations should be kept separate from National variations. All these submission are processed in different work streams and keeping them separate will help us to deal with them efficiently. Q4-2. How exactly should we label our CDs? To avoid including a paper covering letter with a CD, what could we include on the label? A4-2. Remember to always label the actual disk not the case – the two can become separated. Please label the disk in accordance with Special MAIL 5 (section 6). In addition, including a contact e-mail address on the label will help us to quickly contact you if the disk is unreadable. Q4-3. With reference to section 4.10 of Special MAIL 5 (submitting responses to RFIs), please can you advise me how you would like to see the disc labelled in case multiple RFIs pertaining to different products are sent on one single disc? A4-3. All relevant PL numbers, including the 4 digit case numbers, should be on the CD label. Q4-4. Please would you clarify whether the same convention for naming files etc., should also be applied to e-submissions through the MHRA portal? - UPDATED A4-4. Use the same naming convention for Portal documents as for submissions on CD (see questions in section 1 and the full CTD listing in Annex A). eCTD submissions via the Portal must use the naming conventions defined in the eCTD standard. The eCTD standard and eCTD submission are not in the scope of Special MAIL 5 or this document. The MHRA will be issuing separate guidance in this area. NOTE: for submissions through the Portal, no folder structure should be used, as it will delay processing, and so may result in rejection. Q4-5. I will be submitting 4 renewals for products that vary only in one small area. The documents prepared are done such that they cover all 4 products. If the application forms are placed in their own directory in the CD correctly identified with the PL number etc. can the supporting information be put in a separate file for all four renewals rather than duplicating the information in each product directory. A4-5. We require that each PL numbered product directory constitutes a stand alone directory, so all common supporting documentation will need to be duplicated in the relevant directories. Q4-6. Can I submit multiple applications through the Portal? - UPDATED

A4-6. Please do not submit multiple individual applications in a Portal submission. You may submit a bulk submission on one form, and the UK accepts this for MR variations. Only one application form per submission can be processed, so multiple applications are automatically treated by the system as one application. This requires significant manual manipulation to correct and leads to delays, so may result in rejection (see also section 12) Q4-7. We are ready to send a submission to you and, after reading Special MAIL 5, we are not really sure if we should submit paper copies of the dossier in combination with a CD-ROM or if a CD-ROM is sufficient? A4-7. Please only send the data on CD, formatted according to the requirements in Special MAIL 5. A duplicate paper copy is not required and will simply be securely disposed of – a waste of your and our resources.

10

5. Paper submissions and text-searchability requirements…- UPDATED v2.1

See Annex D Q5-1. Why do the MHRA require that all scanned PDF CTD and CTA documents undergo Optical Character Recognition (OCR)? - UPDATED A5-1. The MHRA’s Sentinel system provides a fully searchable electronic document store of all MHRA documents and supports fully electronic assessment of submissions. Text-searchable PDFs allow assessors to cut-and-paste and otherwise manipulate the documents in support of their assessment which speeds up the assessment process. Crucially the OCR layer added to scanned PDFs also supports text searching within the document and across the entire MHRA document store. This ability to locate any documents on our system allows us to respond efficiently to any public health issues that may arise. As a measure of how important we consider this requirement, over 14 million pages of historical paper data was scanned and loaded onto the Sentinel system prior to “go live” and we ensured that every page underwent OCR. However, it should be noted that Special MAIL 5 was ambiguous in this regard. It is certainly not a requirement that all of the documents are printed and OCR’d. In fact, wherever possible, we would prefer that the PDF files are created from original electronic source text, by converting the electronic text into a PDF which is searchable and can be manipulated. Please see Q5-2 and Annex D for a full listing of the types of documents which we would like to receive for each element of the CTD structure. Q5-2. Can you clarify which of the PDF CTD and CTA documents you require to be created electronically from the original text and which are acceptable as scanned images which have undergone OCR? - UPDATED A5-2. Annex D indicates whether we require the individual PDF document to be created from the electronically held source text (ensuring highly accurate text searching) or whether a scanned image which has undergone OCR is acceptable (accepting that the OCR layer may not be perfect, for example if the image is of low quality). Where we require the individual PDF document to be created from the electronically held source text, you should save the electronic source text as a PDF document that is searchable and able to be manipulated. Some software packages allow you to output an electronic file to PDF format as an “image” that can not be searched or manipulated. This option should not be used. Where a scanned image which has undergone OCR is acceptable, companies should still make every effort to, ideally, source the original electronic copy of the document. If this is not possible, ensure that the scanned image is produced of at least 300dpi. If we have asked for a particular PDF document to be created from the original text and this is not possible, please contact us to discuss this before submission. In these situations, an OCR'd and scanned image of at least 300dpi may be acceptable. Similarly, if we have asked for a document to be OCR’d and this is not possible (for example, where an old document is only available as a scanned image), please contact us to discuss. Any submission with very poor quality images may be rejected if the documents are considered to be unreadable by the staff reviewing them. Q5-3. Can I use the OCR system in my scanner? How do I OCR an image using Abode Acrobat? A5-3. You should preferably use the OCR facility in Adobe Acrobat (or another suitable piece of software) to OCR files, not any OCR functionality built into your scanning system. To create a searchable PDF document (in Adobe Acrobat 6.0 Professional) 1. Open up the pdf document produced from scanning a printed document 2. Go to the toolbar and click on ‘Document’ 3. Click on ‘Paper Capture’ and a side drop folder will appear 4. Click on ‘Start Capture’ 5. A grey screen will appear 6. Click in the circle next to ‘All Pages’

11

7. Click on ‘Edit’ 8. Another screen will appear. Click into the field next to the title ‘PDF Output Style’ and choose ‘Searchable Image (Exact)’ * click ‘OK’ 9. Click into the field next to the title ‘Primary OCR Language’ and choose English (UK) click ‘OK’ 10. Click on ‘Primary OCR English (UK)’ 11. Click on ‘OK’ *MHRA recommended setting The process will begin to configure each page. This can be used on any scanned image PDF produced by you or sent to you - it can be done retrospectively. A 100% quality check on the resulting OCR by the applicant is not required. Q5-4. There are also certain documents that are provided to us by a third party that arrive in PDF format. It is not known if these documents have been scanned or converted from electronic files. A5-4. If there is any doubt as to whether the PDF has undergone OCR, then the procedure in Q5-3 (using Adobe Acrobat as an example) should be followed. Third party documents provided in paper format must be scanned into PDF format and undergo OCR. Please note that you should carry out the OCR prior to merging any documents, as otherwise OCR may not perform correctly. For example in Adobe Acrobat an error concerning “renderable text” occurs if part of the document is already fully electronic text. We would advise that third parties providing documents that are to be part of a submission are made aware of the requirements of Special MAIL 5. The minimum resolution requirement in Adobe Acrobat to perform OCR is 200dpi. We would recommend applicants work to a minimum of 300dpi. Higher resolution will produce consequently larger files. Q5-5. We plan to submit an application for a new drug via the paper route. In light of Special MAIL 5, can you outline the implications of this approach in contrast to providing the submission electronically. How quickly are paper submissions processed? - UPDATED A5-5. We would strongly advise to that the application is submitted via the MHRA Portal, or on CD/DVD. Electronic applications structured in line with Special MAIL 5 are relatively straightforward for us to handle. In contrast, paper applications require significantly more work to get onto the Sentinel system. We cannot commit to any timescale to process paper applications as it is a question of priority rather than absolute timelines. We will prioritise work on electronic applications over paper applications. The time to process a paper application will, therefore, be dependent on the overall workload of other applications in the Information Processing Unit at that time, and this, of course, fluctuates. Q5-6. Please can you clarify the statement in the MHRA Special MAIL 5 issue that states "The MHRA will accept paper submissions but can not guarantee that they will be processed to the same target timescales as submissions received via the MHRA portal or on disk"? Does this mean the MRP or DCP fixed timeline requirements indicated in relevant EU guidance documents will not be adhered to? A5-6. Please see Q5-5 for information on the processing of paper applications in general. As European applications are subject to timelines outside of our control, we endeavour to process all such applications to the relevant targets even if the submission is provided on paper. We would, however, strongly encourage electronic submissions. Q5-7. Do I send my paper application to the Information Processing Unit? - UPDATED v2.1 A5-7. We would ask that you do not make paper submissions. However, as the MHRA’s scanning provider has changed,(as of 23 February 2009) if you must make a submission on paper, it should be sent to the MHRA, as for e-submissions. We will contact you on receipt of any paper to discuss electronic submission, and request an e-copy is sent. If the paper must be scanned, this, along with the subsequent OCR, document splitting and re-naming, may introduce unavoidabledelays. Paper will thereafter be disposed of securely, as we do not have storage capacity.

12F

For further information on IPU addresses, please see the summary in Annex G. Q5-8. Special MAIL 5 stated PDF documents should originate from electronic files rather than scanned documents. I normally submit everything on a CD and would normally submit a scanned signed covering letter and also scanned signature pages of the Application Form. Should I continue? Does the covering letter really need a signature or is this not really necessary? - UPDATED A5-8. The signature page of the application form may be signed for inclusion on the disk, although the MHRA does not require this. Please print, sign, scan and then merge the signature page with the relevant PDF. A separate signature page can be included if merging presents difficulties for applicants. The MHRA would expect to see the signature requirement for the QOS, Non-clinical and Clinical Overviews met with a separate signature page in Module 1.4. Signatures are not required in the case of cover letters. Please note that The MHRA do not currently accept digital signatures. NOTE: please see specific Clinical Trials requirements in Section 10 A note on highlighting for paper submissions to be scanned: Dark highlighting will come out dark grey or black when scanned, so obscuring the writing beneath. This should be avoided. Anything submitted for scanning should be on a plain white background if possible.

13

6. Submitting SmPCs, PILs, labels & Variations… - UPDATED v2.1

See http://www.mhra.gov.uk/mhra/SpecialMail5 for the new guidance on CTD Module 1.3 Q6-1. I am not sure which posting area to send this Patient Information Update to could you please indicate. It is not part of another variation. - UPDATED v2.1 A6-1. Please now send the update to Area 9 (see Annex G). Please note that the guidelines in Special MAIL 5 applying to variations also apply to PIU submissions (see Q6-3). Q6-2. We are submitting a variation to a licence that will update from a data sheet to a SmPC. Do I submit SmPC fragments or do I submit as a new SmPC using the MHRA template? - UPDATED A6-2. We require the SmPC to be submitted using the MHRA SmPC Word template. If you have never previously submitted an SmPC in this format, then you should submit the entire SmPC as: m1-3-1-full-spc.doc and make this clear in the cover letter If you have previously submitted the SmPC using the Word template then only submit the sections of the SmPC that are changing using the appropriate MHRA SmPC Word fragment template (see Annex A for the fragment naming conventions). See “SmPC template” and “SmPC fragments” at: http://www.mhra.gov.uk/home/idcplg?IdcService=SS_GET_PAGE&nodeId=109 Q6-3. Do you have any information how the PIL and Labels should be submitted? - UPDATED v2.1 A6-3. The PIL and label should be submitted in PDF format (see Qs5-2 and 5-3, and Annex D for text-searchability requirements). Please use the correct new naming convention, in force from 1 April 2009. Q6-4. Does the information regarding using the MHRA Word template for submitting SmPCs apply to harmonised SmPC or is it only for National SmPC? A6-4. The information regarding the SmPC refers to all versions of the SmPC and is relevant to the harmonised version of the SmPC as well as the national SmPC. Q6-5. We are amalgamating individual SmPCs into one common to all products. This involved changes to the format rather than the information. Would you require individual word templates for all sections that have proposed changes? Would this be required for each product or if necessary would one copy be acceptable to cover all? A6-5. Any change to a SmPC fragment must use the correct fragment template. This includes changes in format. For these SmPC changes, as in all variations, each folder on the disk must constitute a stand alone application (which may be a bulk National submission), so each folder would need the relevant SmPC fragments. Q6-6. I have a similar template to the MHRA SmPC template which has identical headings but there are additional headers and footers and a front page. Is this acceptable or will the contents have to be moved onto the MHRA template? A6-6. The MHRA Word template is designed to support the automatic uploading of SmPC data into the Sentinel system. It is essential, therefore, that it is not altered in any way beyond insertion of information. Any alterations will cause an upload failure and delay the processing of the submission. We will, therefore, reject submissions with non standard templates for the clean/proposed versions.

14

Q6-7. I am about to submit a renewal, will the SmPC need to be submitted in the MHRA Microsoft Word template? A6-7. Yes, the MHRA SmPC Word template must be used and the file names as per the naming conventions in Annex A (see Q6-2). Q6-8. Can you confirm the naming convention for SmPC fragments? A6-8. Please see Annex A. Note that the SmPC fragments are already named when downloaded from the MHRA website, e.g. "04-8-undesirable effects". These names should be kept, and should then be prefixed by the CTD module number and name, giving e.g. "m1-3-1-04-8-undesirable-effects.doc" (see Q6-2, above). Q6-9. How should I name components of the labelling such as the carton and blister labels? - UPDATED v2.1

A6-9. “m1-3-1-label-painese.pdf” and “m1-3-1-leaflet-painese.pdf” are examples for a hypothetical product "painese".The descriptive part can be prefixed by m1-3-2 if preferred, and m1-3-1 used for any text versions (e.g. track changes).Labelling components (e.g. blister, carton, foil, label) must all be consolidated into one document.See Guidelines on Submission of Labels and Patient Information Leaflets (October 2008)Q6-10. When we are submitting a bulk variation for a large SmPC update that affects a number of products how would we name these? Do you require marked and clean versions of the SmPC fragments? - UPDATED A6-10. The requirement to send clean and marked copies of the SmPC with a variation application still applies (see guidance on variations applications & using the form), this is a requirement of the procedure. The “marked” SmPC can be in either Word or PDF format and the changes should be in a different colour text and/or highlighted, or marked using “Track Changes”, for ease of assessment. This can come as a single SmPC document, and need not be fragmented for review. The only requirements we have for formatting are that the new proposed unmarked (clean) SmPC fragment is in the MHRA SmPC Word template and named correctly (see Annex A). As described in Special MAIL 5, several separate variations may be submitted on one CD. The supporting files should be in PL numbered directories, with a flat folder structure (no subdirectories). Each folder must constitute a stand-alone application (where a bulk variation is one application to the MHRA) with common files duplicated into the relevant folders for separate applications (i.e. common documents DO NOT need duplicating within a bulk submission). The marked copy is for the assessors reference and use in the procedure. Use the m1-3-1 prefix and section name and the description "marked" or "clean" as appropriate to allow correct and efficient electronic filing. Multiple variations to the same licence if sent on a single disk should be marked with letter suffix on the folder name. Where documents differ in content between members of a bulk, but would otherwise carry the same file name, add in the PL number. For example, two bulk variations on a single CD including PL 99000/0001, and one (“a”) including a Summary of Clinical Efficacy that is actually different in content between the PLs 99000/0001 and 0002. For variation “b”, the SmPC content is the same, i.e. the fragment is common to all PLs, and supplied only once: D:/ PL 99000-0001a / m1-0-cover.pdf

m1-2-form.pdf m2-7-3-sum-clin-eff-99000-0001

m2-7-3-sum-clin-eff-99000-0002

PL 99000-0001b / m1-0-cover.pdf m1-2-form.pdf m1-3-1-full-spc-marked.pdf m1-3-1-04-5-interactions-clean.doc (if for variation labelled “PL 99000-0001a”, there was a Summary of Clinical Efficacy common to both both PLs, a single document m2-7-3-sum-clin-eff.pdf with no PL suffix would be included.)

Q6-11. Can you confirm that for SmPC only clean proposed needs to be fragments? – NEW A6-11. Yes. Any highlighted copy for review can be sent as a single highlighted PDF, or track-changes Word document. It is easier to process and review that way. Q6-12. Can you provide more detail on the new Label and Leaflet guidance, perhaps with an example? – NEW v2.1 A6-12. Please see the example below. The most common query we have received is around what to include in each of the consolidated "label" documents. You should submit a separate set of documentation for each PL. A separate PDF must be submitted for each brand, generic or OLS (own label supplier), and this must contain all the relevant pieces of artwork which will be registered for all marketed pack sizes and presentations when the application is approved. It should only contain one version of each section, and this should be the new (proposed) clean version if any given part is being amended. Please bookmark to changed sections.

Please do not include any highlights, comments or track changes - these, as previously, should be separate documents, and, as they are simply for assessor review, can be just the parts being changed, and not the whole document.

Please do not include both present and proposed for a given section. It will contain present (unchanged) and proposed (changed) parts in the document, but each part (e.g. a 100 pack bottle label) will only be represented once.

If only the PIL or only the packaging is changing, we do not need the other document - as for all submissions, one should only ever include supporting documentation in relation to the changes being made.

This applies to all submission types (variations, label and leaflet changes, renewals, MAAs) and for both National and MRP or DCPs. It also applies to NeeS and eCTD submissions, with naming as in the guidance.

Each document contains all packsizes and presentations - clean versions only.

If just the label for the 100 pack changes for a single PL (12345/0002, 200mg here), just submit thedocument below, named appropriately, and the new part bookmarked

blister pack

carton 14 pk

blister pack

carton 28 pk

blister foil 14 pk

blister foil 28 pk

bottle carton 50

pk

bottle carton 100 pk

bottle label 50

pk

new clean proposed 100 pk

bottle label

named m1-3-1-label-ibuprofen-200mg.pdfor m1-3-1-label-ibuprofen-pl-12345-0002.pdf

plus the required marked versions separately

For a bulk submission changing the PIL for all packsizes and the 100 pack label for two PLs,then we require

blister pack

carton 14 pk

blister pack

carton 28 pk

blister foil 14 pk

blister foil 28 pk

bottle carton 50

pk

bottle carton 100 pk

bottle label 50

pk

new clean proposed 100 pk

bottle label

m1-3-1-leaflet-ibuprofen-100mg.pdf m1-3-1-label-ibuprofen-100mg.pdfor m1-3-1-leaflet-ibuprofen-pl-12345-0001.pdf m1-3-1-label-ibuprofen-pl-12345-0001.pdf

blister pack

carton 14 pk

blister pack

carton 28 pk

blister foil 14 pk

blister foil 28 pk

bottle carton 50

pk

bottle carton 100 pk

bottle label 50

pk

new clean proposed 100 pk

bottle label

m1-3-1-leaflet-ibuprofen-200mg.pdf m1-3-1-label-ibuprofen-200mg.pdfor m1-3-1-leaflet-ibuprofen-pl-12345-0002.pdf m1-3-1-label-ibuprofen-pl-12345-0002.pdf

plus the required marked versions separately

200mg LABEL PL 12345/0002

200mg LABEL PL 12345/0002

100mg LABEL PL 12345/0001

200 mg PIL

14, 28, 50 & 100 packs

100 mg PIL

14, 28, 50 & 100 packs

15

16

7. Change of Ownership…

Q7-1. In order to submit a change of ownership I have the following documents for submission: 1. Covering Letter 2. Cashier Letter 3. Change of ownership form 4. Copy of current licence 5. Artworks Could you please indicate what numbering system I should use in order for these not to be rejected, as they do not fit into any numbering system mentioned in the Special MAIL 5. Additionally, please clarify which posting area to use for change of ownerships. - UPDATED A7-1. Please send Change of Ownerships to Area 1 in the Information Processing Unit Only CTD files and files associated with Clinical Trial applications require a number prefix. The names above are clear and unambiguous and, therefore, perfectly acceptable as PDF file names. Preferably though, CTD file names should be used, e.g. m1-0-cover m1-2-form m1-2-annexes (including annex 6.1 proof of payment) m1-3-1-label m1-current-licence etc. All files should be submitted in PDF format. See Annex D and Section 5. In general, the PDF files should be created from the electronically held source text, you should save the electronic source text as a PDF document that is searchable and able to be manipulated. Some software packages allow you to output a electronic file to PDF format as an “image” that can not be searched or manipulated. This option should not be used. If an electronic copy of the original text is not available, a scanned image which has undergone OCR is acceptable, ensuring that the scan image is produced is at least 300dpi and can be properly read by someone reviewing the electronic document.

17

8. Active Substance (Drug) Master Files… Q8-1. Please clarify what is required here in submitting a DMF. Special MAIL 5 states: “one PDF file for each document” and that “ the applicant’s part, restricted part and quality overall summary should be submitted as a number of individual PDF documents as defined in the relevant sub-sections of the CTD” Does this mean that a single PDF document containing all of the applicant’s part is acceptable? This would be bookmarked and section numbered as appropriate, but not broken down into all of the CTD sections as separate documents? Alternatively, should each document (e.g. applicant’s part) be broken down into the individual defined CTD sections? - UPDATED A8-1. Please submit the documentation broken down into the individual CTD sections. Annex A details the level of granularity required. On the CD, please put the Restricted (closed) part and the Applicant’s (open) part into labelled folders.

Refer to Annex A for file names and Annex D for the requirements on text-searchablility (see Qs5-2 and 5-3). Q8-2. What documentation should I provide in submitting a DMF? - UPDATED A8-2. In submitting a DMF, the following documents should be provided:

• Covering letter with a clear indication of the DMF’s current edition and the MHRA’s DMF number, and whether the active substance is currently approved for manufacture of a medicine marketed in the EU (if known). Please also clearly state the name and address of the Master File Holder, and of the Manufacturing Site, as there are often several address involved, and this will clarify matters and aid processing. If the MHRA DMF number (format MFD-[company number]-1 or 2-[substance number]-[version] e.g. MFD-99000-1-12345-0001) is not known, then the 5 digit company number should be quoted (99000 in this example above) m1-0-cover • Expert report, Closed Part and Open Part in CTD format (see Q8-1). • GMP and TSE declarations • Letter of Access m1-2-annexes (including: 6.9 statement/GMP; 6.10 Letter of Access and 6.12 TSE – BOOKMARKED) • Quality overall summary in CTD format, i.e. m2-3-qos-introduction m2-3-s-drug-substance m2-3-p-drug-product m2-3-a-appendices m2-3-r-regional-information

All documents should be in PDF format. Refer to Annex A for file names and Annex D for the requirements on text-searchability (see Qs5-2 and 5-3). Q8-3. We have been sending Letters of Access on paper, but note that this is no longer acceptable. To avoid sending for scanning, what should we do? - UPDATED A8-3. Please either save the unsigned letters in PDF format from the electronically held source text or scan and OCR the letters (see Q5-2 and 5-3) then send on CD to Area 7 of the Information Processing Unit, or email to Letter.Access@MHRA.gsi.gov.uk This can also be used for small DMF submissions if they are required to be sent urgently

18

In the subject line you must include the following submission information: • Submission Type (abbreviated - LOA, DMF, DMF RP, DMF AP, DMF QOS) • The MFD number(s) (if known) • Any related PL numbers • substance/product for reference • Company name • Any other relevant information

For example: Subject: | LOA – MFD-99000-1-12345 – PL 99000/1234 – Dihydrogen oxide – Pharmalabs Inc., UK Or Subject: | DMF RP – MFD-99000-1-12345 – version 3 June 2007 - Dihydrogen oxide – Pharmalabs Inc., UK The maximum size of e-mail attachments (which may be zipped) should be 1MB and a maximum of 5 attached documents. Failure to adhere to these limits will result in delays. Please note that e-mail is not a secure method of data transfer – it is used at the applicants own risk. Q8-4. We request further clarification on the submission process of the restricted part of the DMF when we submit via the portal. - UPDATED A8-4. The DMF holder would not have access to the portal hence would submit the restricted part by CD, as part of a submission of the complete new DMF or update. To tie the PL Submission and the restricted part of the DMF together once it reached the MHRA, it should be made clear in their covering letters that the submissions are related. For DC/MR procedures where some Member States request the DMF to be submitted some time before the actual MA submission, the applicant should already have requested a PL number from the MHRA, and this should be quoted in the Letter of Access, along with the MR or DC procedure number, if known. The MHRA does not want DMF submissions without a related PL submission. For DMF updates and associated variations, the same would apply. Both applicant and DMF holder should supply all the information requested in the cover letter in Q8-2, above.

19

9. Renewals and PSURs… - UPDATED v2.1 Q9-1. Please clarify if it is acceptable to submit more than one renewal on the same CD providing they are in separate folders? A9-1. Yes, we will accept more than one renewal application on the same disk. Each of the applications should be structured in line with section 4.7 of Special MAIL 5 and should be in its own folder with the PL number as the folder name. The disk should then be sent to Area 4 of the Information Processing Unit (see address in Special MAIL 5 section 5). Q9-2. Special MAIL 5 does not mention if it is possible to send small files by e-mail. We have a PSUR submission which is only a few MBs (or less). Generally speaking, is it possible to send files by e-mail and if so, is there a special format or address to send to? - UPDATED A9-2. Do not send PSUR files via e-mail unless, under exceptional circumstances, we request submission by e-mail. They can be very large, so e-mail would often not be appropriate. In addition, it is important to note that e-mail is NOT a secure method of data transfer – it is used at the applicants own risk. PSURs may be submitted via the portal. To submit a PSUR via the portal please use the General PL Submissions form. Please indicate clearly on the form if the PSUR has been submitted as part of the PSUR synchronisation scheme. Q9-3. Guidance is requested on the naming convention for PSURs as the details in Special MAIL 5 are not consistent between Renewals and PSURs. - UPDATED A9-3. The PSUR should be named as m5-3-6-reports-of-postmarketing-experience regardless of whether it is part of a renewal package, a new license PSUR or a three-yearly PSUR. For the latter two cases, the covering letter should state the nature of the submission. See Annex A for additions to the PSUR (m5-3-6) file name for individual reports. PLEASE NOTE: the documents below should all be sent, if applicable, even if not mentioned in section 4.1 of the Portal Adobe Renewal form. Renewals should include: m1-2-form m1-0-cover*

*(Please clearly state on the cover letter if the PSUR submitted with the renewal is being submitted under the PSUR synchronisation scheme)

m1-post-authorisation-submissions-since-last-authorisation-renewal-list e.g. as m1-post-auth-subs m1-follow-up-measures-specific-obligations

e.g. as m1-follow-up-meas-spec-oblig m1-2-6-9-statement-or-gmp m1-3-1-full-spc*

*(If changes are proposed the updated fragments should be supplied.) e.g. "m1-3-1-label-painese" e.g. "m1-3-1-leaflet-painese" m2-3-qos-introduction m2-3-s-drug-substance m2-3-p-drug-product m2-3-a-appendices

20

m2-3-r-regional-information m2-5-clinical-overview m5-3-6-reports-of-postmarketing-experience

e.g. as

m5-3-6-rep-p-m-exp-psur-01-jul-31-dec-07 m5-3-6-rep-p-m-exp-psur-01-jan-30-jun-06

NOTE: For Portal submissions, to allow processing as a collection, send all Intralinks Publication IDs for individual submissions to Submissions.Centre@MHRA.gsi.gov.uk

21

10. Clinical Trials… - UPDATED v2.1

Q10-1. Special MAIL 5 requires all documents to be submitted in PDF format with one PDF file for each document. Additionally, the PDF document should not be scanned images. How should the following documents be submitted: 1. signed application forms 2. legacy documents that had no "Word" file - UPDATED A10-1. In Clinical Trial applications we require the individual PDF documents to be created from the electronically held source text if at all possible, with the electronic source text saved as a PDF document that is searchable and able to be manipulated (see Qs5-2 and 5-3 for information on this area). However, if historical documents are not available electronically, a scanned image which has undergone OCR is acceptable (see Section 5). Applicants should ensure that the highest quality scan image is produced. File names should follow the naming convention in Annex C. With Clinical Trial applications, signatures are a legal requirement. In these cases, then a separate signature page as an image can be sent, or a signature page merged with the relevant electronic document Q10-2. Is it necessary / helpful to provide an electronic Table of Contents (TOC) with hyperlinks to the PDF documents on the disk in addition to the list contained in the cover letter and section J checklist? - UPDATED A10-2. This is not mandatory but any additional tools to aid navigation are always helpful. Guidance regarding Bookmarking (see Q2-1) is applicable for large documents. Q10-3. Is a hard copy of the documentation required to accompany the disk? - UPDATED A10-3. Please do not submit hard copy when submitting an electronic copy of the submission on disk. Q10-4. Special MAIL 5 stated PDF documents should originate from electronic files rather than scanned documents. I normally submit everything on a CD and would normally submit a scanned signed covering letter and also scanned signature pages of the Application Form and Protocol. Should I continue? Does the covering letter really need a signature or is this not really necessary? - UPDATED A10-4. The signature page(s) of the covering letter and application form must be signed and scanned for inclusion on the disk. Either merge the signature page with the relevant PDF, or submit as separate PDFs without OCR with the relevant descriptive names and prefixed by the section number from Special MAIL 5 Annex A, reprinted and amended here as Annex C. Q10-5. Special MAIL 5 states that all files submitted on disk must be PDF format (with the exception of the MHRA SmPC Word Template). Does this mean you no longer require the XML version of the Application Form (Item 1.3) to be burnt on to CD-ROM? - UPDATED v2.1 A10-5. If you are submitting the application on disk the full application including the xml file should be included on the CD. If you are submitting the application on paper to the MHRA (which should be avoided), the electronic copy of the xml file should also be sent to the Information Processing Unit – Area 6 - CT (see Annex G). Q10-6. Some of our IMP related documents (e.g. Investigator’s Brochure, Manufacturers Authorisation, TSE statements) have been supplied to us as PDF files. Do we need to ensure that these are supplied in a text-searchable format? - UPDATED A10-6. If there is any doubt as to whether a scanned PDF has undergone OCR, and so is text-searchable, then the procedure in Q5-3 of this document, should be followed (using Adobe Acrobat as an example).

22

Q10-7. In Special MAIL 5 you request that all PDF documents are appropriately bookmarked. With a CTA application does this essentially only applies to the Clinical Protocol and the IMPD files? Given that we supply all appendices to these documents as separate PDF files (itemised & named accordingly) will it be acceptable to only bookmark primary headings in these documents? A10-7. 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 please consider whether bookmarking would help and assessor to work more efficiently. Q10-8. Should CTA submission file names start with the section numbers from Special MAIL 5 Annex A? - UPDATED A10-8. Yes the section numbers should prefix the CTA file names, this will impose order on the files (see Annex C). Q10-9. When do we need to provide the xml file with a substantial amendment? - NEW A10-9. Article 10(a) of the Directive allows amendments to be made to the conduct of a clinical trial after its commencement. It does not require notification of non-substantial amendments (that is those that do not meet the criteria of substantial set out in 4.2.3.1 of ENTR/F2/BL D(2003) CT-04-EN Revision 2); only amendments that are substantial must be notified to the Competent Authority and ethics committee concerned. The sponsor should inform the Competent Authority of any substantial amendment to information for which only the ethics committee is responsible (e.g. facilities for the trial). To provide this information the applicant should provide the notification of amendment form (Annex 2) once the decision on the amendment has taken place, indicating in Section A.4 that it is “for information only”. NOTE: 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>” – see Annex C

23

11. Responses to RFIs… - UPDATED v2.1 Q11-1. What documentation should I provide in a response to an RFI? - UPDATED A11-1. In responding to an RFI, the following documents should be provided: • Covering letter • Discussion document which includes specific answers to the points raised in the RFI and an explanation of the

consequential changes made to documents in the dossier (e.g. “response-discussion-01-nov-06.pdf” – use date submitted, or in line with M1 DTD v1.2.1, as “m1-responses-01-nov-06.pdf” - see Annex A)

• Listing of the changed documents provided (including version control information, name e.g. “list-of-changed-documents-01-nov-06.pdf” – use date submitted, or an approximation, to help with version control of associated documents)

• A complete set of changed documents (see Q11-4) For Module 1 documentation (e.g. SmPC, Label, Patient Information leaflet, MAA form, etc.), a separated marked-up version showing the changes should also be provided (see Q6-10). Documents should be supplied in PDF format except for SmPC and SmPC fragments where the MHRA SmPC Word template should be used (see Q6-2). Refer to Annex D for the requirements as to whether the PDF files should be created from the electronically held source text, which is searchable and able to be manipulated, or whether a scanned image which has undergone OCR is acceptable (see Q5-2 and 5-3). Q11-2. Should I send responses to RFIs direct to the assessor? - UPDATED

A11-2. No. Please send all submissions and responses to RFIs to the appropriate area of the Information Processing Unit (see Special MAIL 5, section 5, and Annex G here). The IPU will ensure that the response is uploaded onto the Sentinel system and that the assessor is made aware of its receipt. Sending disks to other areas of the Agency introduces unpredictable delays as the disk is routed to the IPU. Small responses to RFIs can be e-mailed to RFI.Responses@MHRA.gsi.gov.uk (see Q11-3) We recognise that there may be exceptional circumstances – for example where a particularly fast turnaround is needed - where a response needs to be routed directly for the assessors attention. In these circumstances a copy of the response should be sent to the IPU by Ccing the the above address in the same single email communication. In this way, the IPU can liaise with the assessor to agree who will upload into Sentinel, and avoid duplication

Please note that e-mail is not a secure method of data transfer – it is used at the applicants own risk.

A better approach therefore, is to join the free MHRA Portal (see Q12-8). Portal customers should email the Intralinks Portal receipt (or the 8 digit reference number) to the assessor to allow them to forward this to IPU, if an RFI submitted as an update to a pending publication needs to be expedited. Q11-3. Will you accept small responses to RFIs via e-mail? - corrected v2.1 A11-3. We have set up a mail box to handle very small RFI submissions via e-mail: RFI.Responses@MHRA.gsi.gov.uk In the subject line you must include the following submission information: • Submission Type (use abbreviation from Table 2) • The PL, PLPI, NB and procedure number(s) (if applicable) • substance/product for reference • Any other relevant information

24

For example: Subject: | DCP RFI - PL 99000/1234 - UK/H/0123/01/DC – Dihydrogen oxide – Day 105 Response Table 2 Abbreviation to include at start of

Subject line for e-mailed RFI

MAA RFI Area 1

Responses to RFIs concerned with New National Market Authorisation Application and COAs

MRP RFI or DCP RFI Area 2

Responses to RFIs concerned with New MR & DCP Procedures Applications

NAT VAR RFI or MR VAR RFI Area 3

Reponses to RFIs concerned with variation Applications (National & MR)

MR REN RFI or NAT REN RFI or PSUR RFI

Area 4

Reponses to RFIs concerned with MA Renewals (National & MR), PSURs & Cancellations

PLPI RFI or HOMEO RFI or NB RFI

Area 5

Reponses to RFIs concerned with PLPI, Homeopathic and Notified Body Applications

MF RFI Area 7

Reponses to RFIs concerned with Active Substance (Drug)Master Files

PIU RFI Area 9

Reponses to RFIs concerned with PIU - Patient Info Updates

The maximum total size of all e-mail attachments (which may be zipped) should be 1MB and a maximum of 5 attached documents. Failure to adhere to these limits will result in delays. Please note that e-mail is not a secure method of data transfer – it is used at the applicants own risk. Q11-4. I'm preparing to submit a response to an RFI. Should I structure the data in several files or can I use one file with bookmarks in the discussion document to the different parts? If I use different files should I name them like a CTD section (even if they are only a part of the relevant section e.g.: M3-2-P-7 CoA of Aluminium foil?) or can I use "annex 5 - CoA of aluminium foil"? - UPDATED A11-4. If the response to the RFI includes a major revision and replacement of a CTD section, a discussion document should be provided, plus the whole CTD section as a single PDF file, in line with ICH M4, (see Qs5-2 and 5-3 and Annex D concerning text-searchability) and named as in Annex A. In this case: response-discussion-01-nov-06 [use the date of submission] m3-2-p-7-container-closure-system

Documents that are not part of the CTD structure should be given descriptive, and so useful, file names and the covering letter should state clearly that this is done as they are non-CTD documents. If they belong in Module 1 additional, you should prefix with m1-, as in Annex A. Q11-5. I am submitting a response to a bulk variation on the Portal, and have one publication hook*. Do you need all documents repeated for each PL number? – NEW *(see Section 12 for definition) A11-5. No, only one copy is required if the response is common to all PLs in the bulk variation. The documents will be uploaded into a shared location for the collection of cases, and then indexed to all members. Q11-6. My response is to questions raised during an MRP. If I wish to email this, should it go to IPU on the RFI.Responses emailbox, or to MR-DCprocedures for attention of the European Support Unit? - NEW A11-6. All MRP and DCP responses during the procedure can be sent securely using Eudralink to MR-DCprocedures@MHRA.gsi.gov.uk, quoting the MRP or DCP number, and the PL number. You should contact the EMEA for details on Eudralink. No European procedure response should be sent by duplicate routes, so if it goes by Eudralink or to MR-DCprocedures, IPU do not require a copy. Data sent on CDs to Area 2 or Area 3 will be made available to the ESU.

25

12. Rejections and the Portal…

Q12-1. Our MRP submission has been rejected for processing. Can we resubmit using the same MRP number? A12-1. Yes, please resubmit to the MHRA using the same MRP number. Q12-2. I have to resubmit a Portal application. Should I use the same publication hook? - UPDATED A12-2. No. The original application is moved into a rejected area in the Sentinel system. Please delete this publication hook* and start a new publication. This original hook is now a “dead end”. *[this is the whole submission in your intralinks work space, called a ‘hook’ as documents are hung on there. Any communications back to you are sent back to this location for retrieval, and an email alert sent] Equally, if you wish to stop a submission being processed that has not yet been processed into Sentinel (having checked with us that this is the case), deleting from your workspace only deletes your copy, not ours, so you must request that we also delete it at this end. Q12-3. The submission I have made has formatting errors, so was rejected for processing, can I just e-mail corrections, or, with a Portal submission, send through an update? - UPDATED A12-3. Please resend the complete submission. Rejected applications are moved out of Sentinel work queues, and bringing several parts of a submission together can cause problems and may result in the incorrect documents being processed. For Portal submissions, the publication hook is now a “dead end” in the MHRA staging area (See Q12-2, above). Please note that any Portal update should always carry a cover letter, even if the update is made very soon after the original submission, with the PL number (plus case number if known) and original submission date to allow it to be linked with its initial submission. A list of changed documents in the cover letter is extremely useful, and naming them e.g. “m1-3-1-label-5-updated-01-june-07.pdf” is very helpful, so we can distinguish new from old documents. Q12-4. My Patient Information Update was rejected for file naming, but these do not seem to be mentioned in Special MAIL 5? A12-4. They were considered to be to fall under the variations requirement. The submission should comply with the CTD file naming convention to allow us to process the submission efficiently (see Annex A). Q12-5. My PLPI submission was rejected for non-compliant file naming, but these do not seem to be mentioned in Special MAIL 5? - UPDATED A12-5. Please stick to CTD file names. Please see Section 14 on PLPIs, and Annexes E & F Q12-6. I keep receiving paper letters for Portal submissions, why is this? - NEW A12-6. If any errors or important omissions are made in the data entry on Intelligent forms, or the forms are manipulated or compressed, they may cause case-creation errors, which can include failure for Sentinel to set up the communication channel back to your publication hook. The most common error is not actually using e.g. the “Add MA” button in section 2.2 of the Change of MA form to drop the PL into the “List of Marketing Authorisations” box. The PL is in the search box, but not on the list, and correct Sentinel case-creation will fail. Further guidance is available from your MHRA Portal Manager, and your eSubs workspace. The MHRA is continuously looking at how to best help applicants to make full and proper use of the Portal and the associated Adobe forms, and how we can feedback issues that arise

26

IMPORTANT NOTE: In order to ensure that we process efficiently and provide the service applicants require, it may be necessary to reject for processing submissions made with incorrect or incomplete Portal forms. Q12-7. What PDF versions can be submitted to the MHRA? - NEW A12-7. Version 1.4, produced by various PDF software applications, is preferred, but for the most part, any is accepted for supporting data. For the completion of the Portal Adobe (Intelligent) forms, you must use only Adobe Reader 7.05 to 8.1.0 (see your eSubs workspace for further information) Q12-8. I want to make a submission for several PL numbers. Should I upload all the Adobe forms to the same Portal publication hook? Should I still include a copy of the Word form converted to PDF? - NEW A12-8. No. Each Portal submission must only contain one Adobe Portal form. If more than one form is uploaded, the validation of the submission will fail, and so case creation will have to be carried out manually, and the communication method will default to paper (see also Q4-6). For variations, you should add all the PLs (see Q12-6, above). For Renewals, it is currently one form per PL. Please mention in the cover letter that they can be processed as a collection, and let us have the 8 digit number Portal references from the submission receipts. Please do not send both types of application form (the old Word form converted to PDF and new Adobe form). In the worst case, if we receive a submission on CD without any indication that it is the data to accompany a Portal submission, and it has its own form, we will create a case. For a new MAA, this could result in the use of the PL number on a case without electronic communication. For an eCTD submission, we will have lost the chance to Auto-Index the dossier, and so the chance to feedback on this to the applicant.

For further information on the free MHRA Portal, please contact Portal.Manager@MHRA.gsi.gov.uk

Or visit http://www.mhra.gov.uk/home/idcplg?IdcService=SS_GET_PAGE&nodeId=936

This is the preferred submission route to the MHRA, and offers benefits including secure electronic document transmission, fast receipt of electronic Approval letters and other communications, including Requests for Further

Information, and also rapid and secure upload of responses

General notes on the Portal:

• If you do not get an emailed Intralinks receipt, we have not received your submission • Owing to a limit on upload of documents via the third party, any individual item sent through the Portal

should not be over 15 MB, or you may have problems uploading the documents. For zipped objects, this limit also applies, so you may need to create more than one zip file for large Portal submissions

• Deleting the publication on your workspace does not delete it at the MHRA end – you must contact the Portal Managers if you need to delete a publication

• The General PL Submission form Information Update is not for RFI response submission, or for making enquiries (use the RIS) – it creates an External Information update casefolder for your Product Licence. Use this for e.g. corrections, to inform us that you are removing a CMS from and MRP licence

• Please do not use any special characters when completing the Adobe forms, this may cause form validation failure, and resulting paper communications. To avoid this, limit copy and paste to simple text, or type directly into the forms. Use e.g. (C) not ©, which may mean reversing (or turning off) Auto-correct functions

• The MHRA cannot currently accept any submission via the Portal in a folder structure except eCTDs (full xml), as it presents a large processing overhead to “drill” into the subfolders and manually index documents.

27

13. Withdrawals and Cancellations… - NEW v2.0

Q13-1. Could you clarify the use of the terms “withdrawal“ and “cancellation“? A13-1. There are a few aspects to this. Any pending submission can be withdrawn by an applicant, and they will be entitled to a refund proportional to the work not yet carried out. Please contact the RIS for more information. Marketing Authorisation Holders can remove a product from the market place (“halt sales”), but may subsequently wish to start selling it again. Once the product is gone from all the sales areas, and no longer available to any consumer, the MAH has the option of cancelling the licence.

Q13-2. We wish to remove a product from the market place at present, but not cancel our licence. How should we inform the MHRA? Can you please provide information on complete cancellation of our MA once all product is off the shelves? A13-2. Portal customers can update their publication, including all relevant information, for any withdrawal of a pending submission. It may be helpful, as it is more visible, to email as below, even if it is just to mention the Portal submission, referencing the 8 digit publication ID. Non-Portal customers should send a letter by CD to the IPU Area number used for the original submission (see Annex G), or via email (see below).

For removal from the market place (“halt in sales”) they should contact the MHRA Information Centre.

Portal customers should send a Cancellation request for their MA using the General Product License Application Form. Non-Portal customers should send the request on CD to IPU, Area 4.

We cannot action any withdrawal or cancellation without an electronic document to place on Sentinel as a record. To assist with this requirement, we have set up the following mailbox: Withdraw.Cancel@MHRA.gsi.gov.uk In the subject line you must include the following submission information: • Submission Type (use abbreviation from Table 1) • The PL, PLPI, NB and procedure number(s) (if applicable) • substance/product for reference • Any other relevant information

For example: Subject: | DCP SUB W/DRAW - PL 99000/1234 - UK/H/0123/01/DC – Dihydrogen oxide

28

Table 3 Abbreviation to include at start of

Subject line for e-mailed withdrawals & cancellations

MAA SUB W/DRAW or COA W/DRAW or MAA W/DRAW FROM

MARKET Area 1 New National Market Authorisation Application and

COAs

MRP SUB W/DRAW or DCP SUB W/DRAW Area 2 New MR & DCP Procedures Applications

NAT VAR SUB W/DRAW or MR VAR SUB W/DRAW Area 3 Variation Applications

(National & MR) NAT REN SUB W/DRAW or MR

REN SUB W/DRAW or PSUR SUB W/DRAW or MAA CANC

Area 4 MA Renewals (National & MR), PSURs & Cancellations

PLPI SUB W/DRAW or HOMEO SUB W/DRAW or NB SUB W/DRAW

or PLPI CANC or NB CANC or HOMEO CANC

Area 5 PLPI, Homeopathic and Notified Body Applications

MF SUB W/DRAW or MF CANC Area 7 Active Substance (Drug)

Master Files

PIU W/DRAW Area 9 PIU - Patient Info Updates

The maximum size of e-mail attachments (which may be zipped) should be 1MB and a maximum of 5 attached documents. Failure to adhere to these limits will result in delays. Please note that e-mail is not a secure method of data transfer – it is used at the applicants own risk.

29

14. Parallel Import Applications… - NEW v2.0

Why is the Parallel Import Unit making these changes?

The PLPI Unit have recently completed a review of its working practices in order to improve its efficiency. The efficiency of the application process is critically impacted by the format and quality of the data submitted by parallel import companies. The purpose of this document is to ensure that a standard approach is defined for sending submissions to the MHRA and to assist companies in preparing submissions in a manner that ensures that the MHRA can process their submission as efficiently and as quickly as possible. This document outlines the approach all parallel import companies should adopt in order to ensure this aim is achieved. Q14-1. I have a number of labelling components to submit such as carton, blister label, Braille and text over labels. How should the files for these be submitted and named? A14-1. They should be merged together into one PDF document and should not be submitted as separate documents. Labelling components should also be merged for different product names and pack sizes. Please ensure they are merged in a systematic manner to make it easier for the assessor to assess them (e.g. merge all labelling components for the generic product name together within the PDF). File names listed in Annex E should be used to label the files. Q14-2. Why do you require one PDF document for all labels and leaflets? Why can’t I split PDF documents for label and leaflets with a different product name or pack size? A14-2. Quite often Parallel Import companies wish to market their product under different names and pack sizes. It can be very time consuming for the Information Processing Unit and the assessor if they have to merge documents afterwards. Furthermore, when documents are being merged the risk of omitting pages or merging the wrong pages is high if a large number of documents are involved. We wish to minimise this risk.

Q14-3. You request that any changes should be highlighted for amended documents. How do I highlight changes?

A14-3. Changes may be highlighted in the document by using a different colour for the text that has been amended or changes/amendments made could be listed in the cover letter. This is important so as to alert the assessor to any changes that have been made and greatly speeds up the assessment time. Sometimes changes are made which the assessor has not requested. These changes need to be brought to the attention of the assessor in order to avoid mistakes slipping through. Q14-4. Depending on the variation, I am not always sure what documentation I should provide when making a submission? A14-4. When submitting a variation, different documents are required depending on the type of variation. Annex F explains the different types of variation applications that can be made with the appropriate fee category that is associated with them. In addition, suggested wording for the reason for the variation has been provided with an indication of the documents that will need to accompany the application. Please understand that this list is not exhaustive and other variations are possible and you should use this list as a guide only. You should seek advice from the appropriate source if further guidance is required when preparing your variation application Q14-5. Sometimes I find it difficult to decide whether a separate variation is necessary or whether it is a consequential change? A14-5. Consequential changes are those that happen as a result/consequence of varying a particular part of the licence. Examples of consequential changes are given in Annex F. Often consequential changes affect the PIL and labels. In such cases, only the consequential changes to these documents are permitted. No other changes are allowed in this variation application. If such changes are made, they will not be assessed and not approved and you will be required to submit a separate variation for them.

30

Q14-6. Why should I provide the date in the document name for a response to an RFI? A14-6. This is to ensure that responses are handled in chronological order and to avoid responses submitted on different dates for the same application being mixed up. Q14-7. Should I generate a ticket number on my Adobe Portal form to accompany my samples? A14-7. No, please do not do this. The ticket number indicates to IPU that they should wait for a CD/DVD submission carrying extra data. If you generate a ticket number, and do not send a disk, the submission will be on hold waiting for the data, so will be delayed. We may not consider the complete submission received until we either have the expected data, or confirmation it will not be coming. Q14-8. I have a very large collection (bulk) variation, can I just send it all as one submission? A14-8. No, for efficient processing, the MHRA has always limited the size of collections. Please send a maximum of 50 per submission. To allow for only a single full fee, we will require the whole collection to be received at once, and a summary list of all licences that comprise the larger complete collection to be sent, both with the submission, and by email prior to despatch to Submissions.Centre@MHRA.gsi.gov.uk

31

15. Information Updates (Add/Amends)… - NEW v2.0 Q15-1. I need to send a request to make an amendment to data held by the MHRA, as I have noticed an error. How should I do this, and where should this be sent? A15-1. If the error is minor, such as a typo in a SmPC fragment, this is most simply addressed as part of your next variation submission. The “present and proposed” for this amendment should be clear, and labelled separately from the variation documentation. More complex corrections that are applicant errors (so the submission was determined based on the information submitted to the MHRA) will need to be handled as a separate variation. If there are substantial changes needed, and the MHRA has made the error, then a separate submission to make the amendment should be sent as an Information Update. This can go either on the General PL Submission Portal form, or on CD to Information Processing Unit, Area 10 (see Annex G). Please contact the RIS (MHRA Regulatory Information Service) if you have any queries in this area. NOTE: this form creates a new case folder on Sentinel, and should not be used for requesting information. It is also incorrect to attach a new submission of any other type (e.g. a PLPI submission on a Word form) to a Information Updates. Such submissions will not be processed.

Special Mail 5 FAQs – Annex A

32

Annex A – List of CTD file names – UPDATED v2.0 and v2.1 Please note – for text-searchability requirements, please see Section 5 and Annex D CTD Specification Sections PDF Document Name

1) sensible, clear abbreviations are perfectly acceptable 2) we must ALWAYS receive a complete revised whole CTD document to update the dossier held (in line with ICH M4)

m1 1.0 Cover Letter m1-0-cover or m1-0-cover-co-ref-123 (where co-ref-123 is a short company reference) 1.1 Comprehensive Table of Contents m1-1-comprehensive-table-of-contents or m1-1-toc 1.2 Application Form** m1-2-form 1.2 Annexes 6.1 - 6.22 (see Annex B)** m1-2-annexes (**Portal; forms must never be scanned or compressed.

For non-Portal forms, annexes may be merged with m1-2-form)or included separately as e.g. m1-2-6-1-proof-of-payment

1.3 Product Information 1.3.1 SPC*, Labelling and Package

Leaflets m1-3-1-full-spc

* Must use MHRA SmPC Template m1-3-1-01-name m1-3-1-02-qualitative-and-quantitative m1-3-1-03-pharmaceutical-form m1-3-1-04-1-therapeutic-indications m1-3-1-04-2-posology-and administration m1-3-1-04-3-contra-indications m1-3-1-04-4-special-warnings m1-3-1-04-5-interactions m1-3-1-04-6-pregnancy-and-lactation m1-3-1-04-7-driving-and-machines m1-3-1-04-8-undesirable-effects m1-3-1-04-9-emergency-procedures m1-3-1-05-1-pharmacodynamics m1-3-1-05-2-pharmacokinetics m1-3-1-05-3-preclinical-safety m1-3-1-06-1-excipients m1-3-1-06-2-incompatibilities m1-3-1-06-3-shelf-life m1-3-1-06-4-special-storage-precautions m1-3-1-06-5-container m1-3-1-06-6-special-disposal-precautions m1-3-1-07-ma-holder m1-3-1-08-ma-number m1-3-1-09-first-authorisation-date m1-3-1-10-revision-date m1-3-1-11-dosimetry m1-3-1-12-radiopharmaceuticals-preparation

Special Mail 5 FAQs – Annex A

33

CTD Specification Sections PDF Document Name For review please include marked-up

documents if applicable, e.g. m1-3-1-04-8-undesir-eff-track-changes.doc or e.g. m1-3-1-full-spc-highlighted.pdf If any documents differ between members

of a single bulk submission, append the PL numbers, e.g. m1-3-1-04-8-undesir-eff-99000-0001

or e.g. m1-3-1-04-8-undesir-eff-99000-0002 e.g. for a hypothetical product "Painese" m1-3-1-label-and-leaflet-painese [containing all labelling components] m1-3-1-label-painese m1-3-1-leaflet-painese

1.3.2 Mock-up m1-3-2-[descriptive parts as above]

See "Guidelines on Submission of Labels and Patient Information Leaflets (October 2008)" m1-3-1 can be used for text versions e.g. track changes and m1-3-2 for the colour mockups 1.3.3 Specimen m1-3-3-specimen 1.3.4 Consult. with Target Patient Groups m1-3-4-consult-with-target-patient-groups or m1-3-4

readability 1.3.5 Prod Info already approved in MS m1-3-5-prod-info-already-approved-in-ms 1.3.6 Braille m1-3-6-braille 1.4 Information about the Experts 1.4.1 Quality m1-4-1-quality 1.4.2 Non-Clinical m1-4-2-non-clinical 1.4.3 Clinical m1-4-3-clinical 1.5 Specific Requirements for Differ … 1.5.1 Info. For Bibliographical Applic. m1-5-1-bibliographic 1.5.2 Info. For Generic, ‘Hybrid’ or Bio-sim. m1-5-2-generic-hybrid-biosimilar 1.5.3 (Extended) Data/Market Exclusivity m1-5-3-data-market-exclusivity 1.5.4 Exceptional Circumstances m1-5-4-exceptional-circumstances 1.5.5 Conditional Marketing Authorisation m1-5-5-conditional-ma 1.6 Environmental Risk Assessment 1.6.1 Non-GMO m1-6-1-non-gmo 1.6.2 GMO m1-6-2-gmo 1.7 Information relating to Orphan… 1.7.1 Similarity m1-7-1-similarity 1.7.2 Market Exclusivity m1-7-2-exclusivity 1.8 Information relating to Pharmaco… 1.8.1 Pharmacovigilance System m1-8-1-pharmacovigilance-system 1.8.2 Risk-Management System m1-8-2-risk-management-system 1.9 Info. Relating to Clinical Trials m1-9-clinical-trials Responses to Questions (add date

submitted) response-discussion-01-nov-06.pdf

or m1-responses-01-nov-06.pdf list-of-changed-documents-01-nov-06.pdf or m1-responses-list-of-changed-docs-01-nov-06.pdf Additional Data m1-additional Usefully, e.g. m1-guidelines

Special Mail 5 FAQs – Annex A

34

CTD Specification Sections PDF Document Name m2 2.1 CTD Table of Contents (Module 2.5) m2-1-ctd-table-of-contents-module-2 or m2-1-toc 2.2 CTD Introduction m2-2-introduction 2.3 QUALITY OVERALL SUMMARY** m2-3-qos-introduction [**a single m2-3-qos is acceptable] 2.3.s DRUG SUBSTANCE m2-3-s-drug-substance 2.3.p DRUG PRODUCT m2-3-p-drug-product 2.3.a APPENDICES m2-3-a-appendices 2.3.r REGIONAL INFORMATION m2-3-r-regional-information 2.4 NON.CLINICAL OVERVIEW m2-4-nonclinical-overview 2.5 CLINICAL OVERVIEW m2-5-clinical-overview 2.6 NON-CLINICAL SUMMARY 2.6.1 Introduction m2-6-1-nonclin-sum-introduction 2.6.2 PHARMACOLOGY WRITTEN

SUMMARY m2-6-2-pharmacology-written-summary

2.6.3 PHARMACOLOGY TABULATED SUMMARY

m2-6-3-pharmacology-tabulated-summary

2.6.4 PHARMACOKINETICS WRITTEN SUMMARY

m2-6-4-pharmacokinetics-written-summary

2.6.5 PHARMACOKINETICS TABULATED SUMMARY

m2-6-5-pharmacokinetics-tabulated-summary

2.6.6 TOXICOLOGY WRITTEN SUMMARY

m2-6-6-toxicology-written-summary

2.6.7 TOXICOLOGY TABULATED SUMMARY

m2-6-7-toxicology-tabulated-summary

2.7 CLINICAL SUMMARY 2.7.1 Summary of Biopharmaceutic

Studies and Associated…. m2-7-1-summary-of-biopharmaceutic-studies

2.7.2 Summary of Clinical Pharmacology Studies

m2-7-2-summary-of-clinical-pharmacology-studies

2.7.3 Summary of Clinical Efficacy m2-7-3-summary-of-clinical-efficacy for multiple indications, add useful

descriptive part to name, e.g.m2-7-3-sum-clin-eff-ocd

Or e.g. m2-7-3-sum-clin-eff-depression 2.7.4 Summary of Clinical Safety m2-7-4-summary-of-clinical-safety 2.7.5 Literature References m2-7-5-literature-references 2.7.6 Synopses of Individual Studies m2-7-6-synopses-of-individual-studies m3 3.1 Table of Contents of Module 3 m3-1-table-of-contents-of-module-3 or m3-1-toc 3.2 Body of Data 3.2.s DRUG SUBSTANCE 3.2.s.1.1 Nomenclature m3-2-s-1-1-nomenclature 3.2.s.1.2 Structure m3-2-s-1-2-structure 3.2.s.1.3 General Properties m3-2-s-1-3-general-properties 3.2.s.2.1 Manufacturer m3-2-s-2-1-manufacturer For more than one active, all 3.2.s

documents must be supplied for each, in line with ICH M4, use active name, e.g.

m3-2-s-2-1-manufacturer-paracetamol

m3-2-s-2-1-manufacturer-codeine

Special Mail 5 FAQs – Annex A

35

CTD Specification Sections PDF Document Name 3.2.s.2.2 Desc. of Manuf. Process and

Process Controls m3-2-s-2-2-description-of-manufacturing-process-and-process-controls

3.2.s.2.3 Control of Materials m3-2-s-2-3-control-of-materials 3.2.s.2.4 Control of Critical Steps and

Intermediates m3-2-s-2-4-controls-of-critical-steps-and-intermediates

3.2.s.2.5 Process Validation and/or Evaluation

m3-2-s-2-5-process-validation-and-or-evaluation

3.2.s.2.6 Manufacturing Process Development

m3-2-s-2-6-manufacturing-process-development

3.2.s.3.1 Elucidation of Structure and other Characteristics

m3-2-s-3-1-elucidation-of-structure-and-other-characteristics

3.2.s.3.2 Impurities m3-2-s-3-2-impurities 3.2.s.4.1 Specification m3-2-s-4-1-specification 3.2.s.4.2 Analytical Procedures m3-2-s-4-2-analytical-procedures 3.2.s.4.3 Validation of Analytical

Procedures m3-2-s-4-3-validation-of-analytical-procedures

3.2.s.4.4 Batch Analyses m3-2-s-4-4-batch-analyses 3.2.s.4.5 Justification of Specification m3-2-s-4-5-justification-of-specification 3.2.s.5 Reference Standards or materials m3-2-s-5-reference-standards-or-materials 3.2.s.6 Container Closure System m3-2-s-6-container-closure-system 3.2.s.7.1 Stability Summary and

Conclusions m3-2-s-7-1-stability-summary-and-conclusions

3.2.s.7.2 Post Appr. Stab. Protocol and Stab. Commitment

m3-2-s-7-2-post-approval-stability-protocol-and-commitment

3.2.s.7.3 Stability Data m3-2-s-7-3-stability-data 3.2.p DRUG PRODUCT 3.2.p.1 Desc. and Comp. of the Drug

Product m3-2-p-1-description-and-composition

3.2.p.2 Pharmaceutical Development m3-2-p-2-pharmaceutical-development 3.2.p.3.1 Manufacturer(s) m3-2-p-3-1-manufacturers 3.2.p.3.2 Batch Formula m3-2-p-3-2-batch-formula 3.2.p.3.3 Desc. of Manuf. Process and

Process Controls m3-2-p-3-3-manufacturing-process-and-controls

3.2.p.3.4 Controls of Critical Steps and Intermediates

m3-2-p-3-4-controls-of-critical-steps-and-intermediates

3.2.p.3.5 Process Validation and/or Evaluation

m3-2-p-3-5-process-validation-and-or-evaluation

3.2.p.4.1 Specifications m3-2-p-4-1-specifications 3.2.p.4.2 Analytical Procedures m3-2-p-4-2-analytical-procedures 3.2.p.4.3 Validation of Analytical

Procedures m3-2-p-4-3-validation-of-analytical-procedures

3.2.p.4.4 Justification of Specifications m3-2-p-4-4-justification-of-specifications 3.2.p.4.5 Excipients of Human or Animal

Origin m3-2-p-4-5-excipients-of-human-or-animal-origin

3.2.p.4.6 Novel Excipients m3-2-p-4-6-novel-excipients 3.2.p.5.1 Specification(s) m3-2-p-5-1-specifications 3.2.p.5.2 Analytical Procedures m3-2-p-5-2-analytical-procedures 3.2.p.5.3 Validation of Analytical

Procedures m3-2-p-5-3-analytical-procedures-validation

3.2.p.5.4 Batch Analyses m3-2-p-5-4-batch-analyses 3.2.p.5.5 Characterisation of Impurities m3-2-p-5-5-characterisation-of-impurities

Special Mail 5 FAQs – Annex A

36

CTD Specification Sections PDF Document Name 3.2.p.5.6 Justification of Specification(s) m3-2-p-5-6-justification-of-specifications 3.2.p.6 Reference Standards or materials m3-2-p-6-reference-standards-or-materials 3.2.p.7 Container Closure System m3-2-p-7-container-closure-system 3.2.p.8.1 Stability Summary and

Conclusion m3-2-p-8-1-stability-summary-and-conclusion

3.2.p.8.2 Post. Appr. Stability Protocol and Commitment

m3-2-p-8-2-post-approval-stability-protocol-and-stability-commitment

3.2.p.8.3 Stability Data m3-2-p-8-3-stability-data 3.2.a APPENDICES 3.2.a.1 Facilities and Equipment m3-2-a-1-facilities-and-equipment-report 3.2.a.2 Adventitious Agents Safety

Evaluation m3-2-a-2-adventitious-agents-safety-evaluation

3.2.a.3 Excipients m3-2-a-3-excipients 3.2.r Regional Information m3-2-r-regional-information 3.3 Literature References m3-3-literature-references e.g. volumised and BOOKMARKED m3-3-lit-ref-a-m.pdf m3-3-lit-ref-n-z.pdf or individual reference pdfs m3-3-arthur-2001.pdf m3-3-goater-2005.pdf m3-3-maxwell-1999.pdf m4 4.1 Table of Contents of Module 4 m4-1-table-of-contents-of-module-4 or m4-1-toc 4.2 STUDY REPORTS

Study reports in these categories carrying module prefix, descriptively, and so usefully, named, or using company reference as file name, as referred to in dossier. Multiple files can be submitted under

each section, in line with ICH M4. To include a short company reference, place at the end

4.2.1.1 Primary Pharmacodynamics m4-2-1-1-primary-pharmacodynamics e.g. m4-2-1-1-prim-pharm-vol-1-co-ref-123 m4-2-1-1-prim-pharm-vol-2-co-ref-456 m4-2-1-1-prim-pharm-appendices-co-ref-789 4.2.1.2 Secondary Pharmacodynamics m4-2-1-2-secondary-pharmacodynamics 4.2.1.3 Safety Pharmacology m4-2-1-3-safety-pharmacology 4.2.1.4 Pharmacodynamic Drug

Interactions m4-2-1-4-pharmacodynamic-drug-interactions

4.2.2.1 Analytical Methods and Validation Reports

m4-2-2-1-analytical-methods-and-validation-reports

4.2.2.2 Absorption m4-2-2-2-absorption 4.2.2.3 Distribution m4-2-2-3-distribution 4.2.2.4 Metabolism m4-2-2-4-metabolism 4.2.2.5 Excretion m4-2-2-5-excretion 4.2.2.6 Pharmacokinetic Drug Interactions

(non-clin) m4-2-2-6-pharmacokinetic-drug-interactions

4.2.2.7 Other Pharmacokinetic Studies m4-2-2-7-other-pharmacokinetic-studies 4.2.3.1 Single Dose Toxicity m4-2-3-1-single-dose-toxicity 4.2.3.2 Repeat-Dose Toxicity m4-2-3-2-repeat-dose-toxicity 4.2.3.3.1 In vitro m4-2-3-3-1-in-vitro 4.2.3.3.2 In vivo m4-2-3-3-2-in-vivo 4.2.3.4.1 Long-term studies m4-2-3-4-1-long-term-studies

Special Mail 5 FAQs – Annex A

37

CTD Specification Sections PDF Document Name 4.2.3.4.2 Short- or medium-term studies m4-2-3-4-2-short-or-medium-term-studies 4.2.3.4.3 Other studies m4-2-3-4-3-other-studies 4.2.3.5.1 Fertility and Early Embryonic

Development m4-2-3-5-1-fertility-and-early-embryonic-development

4.2.3.5.2 Embryo-fetal development m4-2-3-5-2-embryo-fetal-development 4.2.3.5.3 Prenatal and postnatal

development m4-2-3-5-3-prenatal-and-postnatal-development

4.2.3.5.4 Studies in which the offspring (juvenile) are dosed

m4-2-3-5-4-offspring-juvenile-animals-studies

4.2.3.6 Local Tolerance m4-2-3-6-local-tolerance 4.2.3.7.1 Antigenicity m4-2-3-7-1-antigenicity 4.2.3.7.2 Immunotoxicity m4-2-3-7-2-immunotoxicity 4.2.3.7.3 Mechanistic studies m4-2-3-7-3-mechanistic-studies 4.2.3.7.4 Dependence m4-2-3-7-4-dependence 4.2.3.7.5 Metabolites m4-2-3-7-5-metabolites 4.2.3.7.6 Impurities m4-2-3-7-6-impurities 4.2.3.7.7 Other m4-2-3-7-7-other 4.3 LITERATURE REFERENCES m4-3-literature-references e.g. volumised and BOOKMARKED m4-3-lit-ref-a-m.pdf m4-3-lit-ref-n-z.pdf or individual reference pdfs m4-3-arthur-2001.pdf m4-3-goater-2005.pdf m4-3-maxwell-1999.pdf m5 5.1 Table of Contents of Module 5 m5-1-table-of-contents-of-module-5 or m5-1-toc 5.2 TABULAR LISTING OF ALL

CLINICAL STUDIES m5-2-tabular-listing-of-all-clinical-studies

5.3 CLINICAL STUDY REPORTS Clinical study reports in these categories carrying module prefix, descriptively, and so usefully,

named, or using company reference as file name, as referred to in dossier. Multiple files can be submitted under each section, in line with ICH M4. To include a short company reference, place at the

end 5.3.1.1 Bioavailability (BA) Study Reports m5-3-1-1-bioavailability-study-reports 5.3.1.2 Comparative BA and

Bioequivalence Study Reports m5-3-1-2-comparative-ba-and-bioequivalence-study-reports

5.3.1.3 In vitro-In vivo Correlation Study Reports

m5-3-1-3-in-vitro-in-vivo-correlation-study-reports

5.3.1.4 Reports of Bioanalytical and Analytical methods…

m5-3-1-4-reports-of-bioanalytical-and-analytical-methods-for-human-studies

5.3.2.1 Plasma Protein Binding Study Reports

m5-3-2-1-plasma-protein-binding-study-reports

5.3.2.2 Reports of Hepatic metabolism and Drug Int. Studies

m5-3-2-2-reports-of-hepatic-metabolism-and-drug-interaction-studies

5.3.2.3 Reports of Studies Using Human Biomaterials

m5-3-2-3-reports-of-studies-using-other-human-biomaterials

5.3.3.1 Healthy Subject PK and Initial Tolerability Study Rep.

m5-3-3-1-healthy-subject-pk-and-initial-tolerability-study-reports

5.3.3.2 Patient PK and Initial Tolerability Study Reports

m5-3-3-2-patient-pk-and-initial-tolerability-study-reports

5.3.3.3 Intrinsic Factor PK Study Reports m5-3-3-3-intrinsic-factor-pk-study-reports 5.3.3.4 Extrinsic Factor PK Study Reports m5-3-3-4-extrinsic-factor-pk-study-reports 5.3.3.5 Population PK Study Reports m5-3-3-5-population-pk-study-reports

Special Mail 5 FAQs – Annex A

38

CTD Specification Sections PDF Document Name 5.3.4.1 Healthy Subject PD and PK/PD

Study Reports m5-3-4-1-healthy-subject-pd-and-pk-pd-study-reports

5.3.4.2 Patient PD and PK/PD Study Reports

m5-3-4-2-patient-pd-and-pk-pd-study-reports

5.3.5.1 Study Reports of Controlled Clinical Studies….

m5-3-5-1-controlled-clinical-studies-pertinent-to-the-claimed-indication

for multiple indications, add useful

descriptive part to name, e.g.m5-3-5-1-cont-clin-2001-ocd

m5-3-5-1-cont-clin-2003-depression 5.3.5.2 Study Reports of Uncontrolled

Clinical Studies m5-3-5-2-study-reports-of-uncontrolled-clinical-studies

5.3.5.3 Reports of Analyses of Data from more than One Study

m5-3-5-3-reports-of-analyses-of-data-from-more-than-one-study

5.3.5.4 Other Clinical Study Reports m5-3-5-4-other-study-reports 5.3.6 Reports of Post-Marketing

Experience m5-3-6-reports-of-postmarketing-experience

for PSUR reports, add date to name, e.g. m5-3-6-rep-postmarket-exp-psur-01-jul-31-dec-07 m5-3-6-rep-postmarket-exp-psur-01-jan-30-jun-06 5.3.7 Case Report Forms and Individual

Patient Listings m5-3-7-case-report-forms-and-individual-patient-listings

5.4 LITERATURE REFERENCES m5-4-literature-references e.g. volumised and BOOKMARKED m5-4-lit-ref-a-m.pdf m5-4-lit-ref-n-z.pdf or individual reference pdfs m5-4-arthur-2001.pdf m5-4-goater-2005.pdf m5-4-maxwell-1999.pdf

NOTE: For Addendum or Review documents, follow this procedure, as in Q1-15 Addendum = ADM or adm

m2-5-clinical-overview-ADM.pdf [or m2-5-clinical-overview-adm.pdf] For Review = REV or rev

m3-2-p-5-1-specifications-REV.pdf [or m3-2-p-5-1-specifications-rev.pdf]

Special Mail 5 FAQs – Annex B

39

Annex B – Module 1.2 Annex Documents - UPDATED v2.1 to "Annex 5" from "6"m1-2 5 (include where appropriate) If included, documents may be merged with application form itself, or collected as a separate document "m1-2 annexes.pdf" if using our intelligent form, with bookmarks, or as separate annexes, e.g. m1-2-6-1-proof-of-payment.pdf 5.1 Proof of payment

5.2 Informed consent letter of marketing authorisation holder of authorised medicinal product.

5.3 Proof of establishment of the applicant in the EEA. 5.4 Letter of authorisation for communication on behalf of the applicant/MAH 5.5 Curriculum Vitae of the Qualified Person for Pharmacovigilance

5.6 5

Manufacturing Authorisation required under Article 40 of Directive 2001/83/EC (or equivalent, outside of the EEA where MRA or other Community arrangements apply). A reference to EudraGMP will suffice when available.

.7 Justification for more than one manufacturer responsible for batch release in the EEA

5.8

Flow-chart indicating all sites involved in the manufacturing process of the medicinal product or active substance (including sites involved in sampling and testing for batch release of products manufactured in third countries). Note: All manufacturing and control sites mentioned throughout the whole dossier must be consistent regarding their names, detailed addresses and activities.

5.9

Statement (or GMP Certificate issued by an EEA inspectorate, when available) from the competent authority which carried out the inspection of the manufacturing site(s) (not older than 3 years). References to EudraGMP will suffice when available. Where applicable a summary of other GMP inspections performed in the last 2 years

5.10 Letter(s) of access to Active Substance Master File(s) or copy of Ph. Eur. Certificate(s) of suitability

5.11 5

Copy of written confirmation from the manufacturer of the active substance to inform the applicant in case of modification of the manufacturing process or specifications according to Annex I of Directive 2001/83/EC.

.12 Ph. Eur. Certificate(s) of suitability for TSE

5.13 5

Written consent(s) of the competent authorities regarding GMO release in the environment.

.14 Scientific Advice given by CHMP

5.15 5

Copy of Marketing Authorization(s) required under Article 8(j)-(L) of Directive 2001/83/EC in the EEA and the equivalent in third countries on request (a photocopy of the pages which give the marketing authorization number, the date of authorisation and the page which has been signed by the authorizing competent authority will suffice).

.16 Correspondence with European Commission regarding multiple applications.

5.175

List of Mock-ups or Samples/specimens sent with the application, as appropriate (see Notice to Applicants, volume 2A, chapter 7)

.18 Copy of the Orphan Designation Decision.

5.195

List of proposed (invented) names and marketing authorisation holders in the concerned member states

.20 5

Copy of EMEA certificate for a Vaccine Antigen Master File (VAMF) .21 Copy of EMEA certificate for a Plasma Master File (PMF)

5.22

For each active substance, attach a declaration from the Qualified Person of the manufacturing authorisation holder in Section 2.5.1 and from the Qualified Person of each of the manufacturing authorisation holders (i.e. located in EEA) listed in Section 2.5.2 where the active substance is used as a starting material that the active substance manufacturer(s) referred to in Section 2.5.3 operate in compliance with the detailed guidelines on good manufacturing practice for starting materials. This does not apply to Blood or blood components.

Special Mail 5 FAQs – Annex C

40

Annex C – CTA Document Naming Conventions - UPDATED v2.0Document Naming Convention for Electronic Clinical Trial Authorisation Applications to the MHRA Information to be Provided* PDF File Name Required for

valid CTA application

1 General 1.1 Receipt of confirmation of EudraCT number 1-1-eudract-receipt Yes 1.2 Covering letter 1-2-covering-letter Yes 1.3 Application form 1-3-application-form 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

1.5 Copy of ethics committee opinion in the MS concerned when available

1-5-ethics-committee-opinion When available

1.6 Copy/summary of any scientific advice 1-6-scientific-advice If applicable 1.7 If the applicant is not the sponsor, a letter of authorisation

enabling the applicant to act on behalf of the sponsor 1-7-applicant-authorisation Yes

3 Protocol related 3.1 Clinical trial protocol with all current amendments 3-1-protocol Yes 4 IMP related 4.1 Investigator’s brochure 4-1-investigators-brochure Yes 4.2 Investigational Medicinal Product Dossier (IMPD)** 4-2-impd If applicable 4.3 Simplified IMPD for known products (see table 1)** 4-3-simplified-impd If applicable 4.4 Summary of Product Characteristics (SmPC) (for products

with marketing authorisation in the Community)** 4-4-smpc If applicable

4.5 Outline of all active trials with the same IMP 4-5-imp-active-trials Yes 4.6 If IMP manufactured in E.U. and if no marketing

authorisation in E.U:

4.6.1 Copy of the manufacturing authorization referred to in Art.13.1. of the Directive stating the scope of this authorization

4-6-1-manufacturers-authorisation

Yes

4.7 If IMP not manufactured in E.U. 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

4.7.2 Certification of GMP status of active biological substance 4-7-2-gmp-status-ai Yes 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

4.8 Certificate of analysis for test product in exceptional cases

4.8.1 Where impurities (not covered by specification) are detected

4-8-1-test-product-c-of-a Yes

4.9 Viral studies when applicable 4-9-viral-validation Yes 4.10 Applicable authorisations to cover trials or products with

special characteristics (if available) e.g. GMOs, radiopharmaceuticals

4-10-special-characteristics-authorisation

Yes

4.11 TSE Certificate when applicable 4-11-tse-certificate Yes 4.12 Examples of the label in the national language 4-12-label Yes

Special Mail 5 FAQs – Annex C

41

Information to be Provided* PDF File Name Required for valid CTA application

5 Facilities & staff related 5.1 Facilities for the trial 5-1-trial-facilities No

5.2 CV of the coordinating investigator in the MS concerned (for multicentre trials)

5-2-cv-coordinating-investigator No

5.3 CV of each investigator responsible for the conduct of a trial in a site in the MS concerned (principal investigator) 5-3-cv-principle-investigators No

5.4 Information about supporting staff 5-4-supporting-staff No 6 Finance related

6.1 Provision for indemnity or compensation in the event of injury or death attributable to the clinical trial 6-1-indemnity No

6.2 Any insurance or indemnity to cover the liability of the sponsor or investigator

6-2-indemnity-sponsor-or-investigator No

6.3 Compensation to investigators 6-3-compensation-investigator No

6.4 Compensation to subjects 6-4-compensation-subject No 6.5 Agreement between the sponsor and the trial site 6-5-sponsor-site-agreement No

6.6 Agreement between the investigators and the trial sites 6-6-investigator-site-agreement No

6.7 Certificate of agreement between sponsor and investigator when not in the protocol 6-7-certificate-of-agreement No

* 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)]

**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>

Special Mail 5 FAQs – Annex D

42

Annex D – Guidance on Text Searchable Documents for MHRA Submissions - NEW v2.0

1. General Applicants are requested to ensure that all submissions contain the maximum amount of text searchable content. Documents with searchable text will aid the assessor, or any other user, in searching for specific terms and also in copying and pasting information into another document, such as an assessment report.

The MHRA recognize that not all documents need to be text searchable. This short document provides some guidance about what must be text searchable and the ways to ensure that files are created appropriately.

1.1 Creating Text Searchable Files PDF files with searchable text can be created by all PDF tools from a source file in a text format (e.g. MS Word, SAS, MS PowerPoint, Rich Text Files, etc.). When created in this way, the file will usually be the smallest in size (measured in kilobytes or megabytes) that they can be.

If the only version of a document available is in paper, then scanning to PDF and using an Optical Character Recognition (OCR) routine is the only way to create searchable text. PDF files created in this way tend to be much larger in size, for the same number of pages (from 10 to 100 times as large), and the quality of the text that is created will almost certainly not be a 100% match to the original text. It is noted that tools for checking and correcting this text tend to be somewhat cumbersome. For these reasons, applicants are recommended to use OCR only as a last resort.

Applicants are reminded that the text produced by the OCR routine should be “hidden” behind the image of the original page so that the user can refer to the picture of the page and the text on it as final verification of the data. As a result, the applicant should ensure that, as a minimum, the text on the scanned image is legible to the user. Poor quality images should not be provided and you should note that these can only inevitably lead to poor quality OCR text.

2. Documents that must always be text searchable (i.e. the PDF should be produced wherever possible from a text source, such as MS Word, but if sourced from a scanned original then they must be OCR’d.)

• Key administrative documents in Module 1 including, the cover letter, application form, labelling documents o Applicants are reminded that the MHRA considers the sign in process to Sentinel as sufficient to

establish a users identity and do not require signatures on Cover Letters and Application Forms submitted through the portal

o This also covers similar documents provided in non-MAA submissions. • Any document in Module 2 of the MAA (QOS, Preclinical Overview and Summaries, Clinical Overview and

Summaries). o This also covers similar documents provided in non-MAA submissions.

• The main body of text and main tables in any preclinical or clinical report required to support the main claim of the application.

o This also covers similar documents provided in non-MAA submissions. • The main body of text in any reports, methods, analytical procedures, etc. supplied in Module 3 of the MAA

o This also covers similar documents provided in non-MAA submissions. • The main body of text of Periodic Safety Update Reports (PSURs) • The main body of text of Risk Management Plans • Any English translation of a document originally written in a foreign language (see also below)

3. Documents that do not need to be text searchable (i.e. the PDF should be produced wherever possible from a text source, such as MS Word, but if sourced from a scanned original then there is no need for OCR.)

Special Mail 5 FAQs – Annex D

43

• Any original GMP certificate • Any original certificate of analysis • Any manufacturer’s licences • Any certificates of suitability • Any Manufacturing Authorisation • Any document written in a foreign language where a translation is provided in English (however, the

translation should be text searchable, see above) • Any literature references sourced from journals, periodicals and books (except when these are used in a

bibliographic application so support the main claims of the application). • The blank CRF in a Clinical Study Report • Patient data listings (when supplied) • CRFs (when supplied) • Any page with a signature that does not contain other information key to the understanding of the

submission o Applicants should consider providing signatures on separate pages from key text in reports,

overviews, etc.

4. Further Information If applicants are uncertain whether or not a particular document should be text searchable, they should contact:

Shaun.Fiddes@MHRA.gsi.gov.uk

Lindsay.Goater@MHRA.gsi.gov.uk

Special Mail 5 FAQs – Annex E

44

Annex E – List of PLPI file names - NEW v2.0 Information to be Provided* Document Naming Convention for

Parallel Import Applications to the MHRA

1. New PLPI applications (initials) Covering letter (dated appropriately with date of submission).

m1-0-cover-dd-mm-yyyy

Application form (Initial, renewal or MLA forms).

m1-2-form

Labels (full colour image of all components e.g. Carton label, bottle label, blister label, carton mock-ups & Braille labels – all components should be combined into one file even if a number of different product names and pack sizes are to be used)

m1-3-1-label

Leaflet (A leaflet is a full colour image of a document which fulfils the requirements of article 59 of the Directive as amended – all leaflets should be combined into one file even if a number of different product names are to be used)

m1-3-1-leaflet

Suppliers (lists of suppliers) m1-2-suppliers

Company Function List (including assemblers, importers, storage and batch release).

m1-2-company-function-list

2. Responses to requests for information (RFIs) sent by the MHRA (PLPI Unit)

Covering letter (dated appropriately with date of submission).

m1-0-cover-dd-mm-yyyy

Application form (supply the complete form, and not just amended pages, highlighting clearly where the changes have been made).

m1-2-form-dd-mm-yyyy

Labels (full colour image of all components e.g. Carton label, bottle label, blister label, carton mock-ups & Braille labels – all components should be combined into one file even if a number of different product names and pack sizes are to be used with changes clearly highlighted).

m1-3-1-label-dd-mm-yyyy

Leaflet (A leaflet is a full colour image of a document which fulfils the requirements of article 59 of the Directive as amended – all leaflets should be combined into one file even if a number of different product names are to be used with changes clearly highlighted).

m1-3-1-leaflet-dd-mm-yyyy

Suppliers (indicate clearly how the list has been amended i.e. deletions or additions).

m1-2-suppliers-dd-mm-yyyy

Company Function List (including assemblers, importers, storage and batch release - indicate clearly how the list has been amended).

m1-2-company-function-list-dd-mm-yyyy

Special Mail 5 FAQs – Annex E

45

Information to be Provided* Document Naming Convention for Parallel Import Applications to the MHRA

3. PLPI Variation applications Covering letter (appropriately dated with date of submission)

m1-0-cover-dd-mm-yyyy

Application form (the sections ‘from’ & ‘to’ should be completed fully and correctly – do not use terms like ‘as before’ or ‘as previously on licence’)

m1-2-form

Labels (full colour image of all components e.g. Carton label, bottle label, blister label, carton mock-ups & Braille labels – all components should be combined into one file even if a number of different product names and pack sizes are to be used with changes clearly highlighted)

m1-3-1-label

Leaflet (A leaflet is a full colour image of a document which fulfils the requirements of article 59 of the Directive as amended – all leaflets should be combined into one file even if a number of different product names are to be used with changes clearly highlighted).

m1-3-1-leaflet

Suppliers (indicate clearly how the list has been amended i.e. deletions or additions).

m1-2-suppliers

Company Function List (including assemblers, importers, storage and batch release).

m1-2-company-function-list

Special Mail 5 FAQs – Annex F

46

Annex F – List of documents required for different PLPI variations – NEW v2.0 Fee Type Variation Type Variation reason Var.

code Documents required

m1-2-form NO FEE LIABILITY

Imported MA number change.

To update / add *Greek* MA number to ‘xxxxxx’.

48 m1-3-1-label m1-2-form m1-3-1-label

or

Urgent amendments to label or PIL for safety reasons at MHRA request.

As appropriate 49

m1-3-1-leaflet

m1-2-form m1-3-1-label

VAR PLPI ADMIN NATIONAL

Change in name and / or address of the Holder of the Product Licence (Parallel Import).

To update the name and / or address of the PL Holder from ‘yyyyyy’ to ‘xxxxxx’.

1

m1-3-1-leaflet

Change in imported MA holder name and / or address.

To update the name and address of the *Greek* MA Holder from ‘yyyyyy’ to ‘xxxxxx’.

51 m1-2-form

m1-2-form m1-3-1-label

Change in name of manufacturer but not site or address.

To update the name of the manufacturer from ‘yyyyyy’ to ‘xxxxxx’ with consequential changes to the labels and leaflet.

52

m1-3-1-leaflet

m1-2-form Change in suppliers details. To change the list of suppliers of the Belgian product (to the three page list dated 01 Nov 2007.

53 (Suppliers List dated appropriately)

m1-2-form Addition of importers/storage sites.

To change the list of importers/storage sites of the Belgian product adding Medichem SA (to give the undated list of eight addresses).

54 (Amended importers / storage sites dated appropriately)

m1-2-form Deletion of sites of importation, supply, manufacture, assembly, batch release, storage, distribution.

To change the list of importers/storage sites of the Belgian product deleting Medichem SA (to give the undated list of seven addresses).

55 (Amended lists [storage, assembly, batch release, supply, manufacture, distribution] indicating clearly sites for deletion dated appropriately)

m1-2-form m1-3-1-label

Removal of product details (e.g. pack size, product name).

To delete the product name ‘yyyyy’ with consequential changes to the labels and leaflet.

56

m1-3-1-leaflet Change in PL number and /

or name and address of the cross referenced UK product.

To change the cross-referenced UK MA from PL 00001/0001 to PL 00002/0002 held by AstraZeneca UK Ltd., Capability Green, Luton Bedfordshire LU1 3LU.

57 m1-2-form

m1-2-form m1-3-1-label

Nomenclature Change from BAN to rINN

To change the name of the active from ‘BAN’ to ‘rINN’ with consequential changes to the labels and leaflet.

61

m1-3-1-leaflet

Special Mail 5 FAQs – Annex F

47

Fee Type Variation Type Variation reason Var. code

Documents required

m1-2-form m1-3-1-label m1-3-1-leaflet

VAR PLPI STAND NATIONAL

Site of manufacture of imported product

To change the address of the manufacturer of the Belgian product to ‘AstraZeneca, Madrid, Spain’ with consequential changes to the labelling and leaflet (to the version dated 20 August 2007).

58

m1-2-form Change in assemblers /

batch release sites/ storage sites.

To change the list of importers/storage sites of the Belgian product (to give the undated list of seven addresses).

8 Amended lists

(storage, assembly, batch release, supply, manufacture, distribution) indicating clearly the changes and dated appropriately.

m1-2-form m1-3-1-label and

Change in product name To change/add the product name to ‘yyyyyyy’ with consequential changes to the labels and leaflet.

2

m1-3-1-leaflet m1-2-form Change in description/or

appearance of dosage form To change the description of imported product to ‘yellow, round, film coated tablet with a score line on one face and plain on the other’ with consequential changes to the leaflet.

40 m1-3-1-leaflet

m1-2-form m1-3-1-label and

Change in packaging To change the packaging from a product packed in a bottle of 100 tablets to a blister packed product of 28 (2x14) tablets with consequential changes to the labels and leaflet.

59

m1-3-1-leaflet

m1-2-form m1-3-1-label and

Change in pack size To change the pack size to 28 (2x14) with consequential changes to the labels and leaflet.

41

m1-3-1-leaflet m1-2-form m1-3-1-label (if

excipients of known effect) and

Change to Excipients To update the list of excipients to include ‘’ with consequential changes to the leaflet.

60

m1-3-1-leaflet m1-2-form m1-3-1-label and

Change in shelf life or storage conditions

To change the storage precautions to ‘Do not store above 25oC’ with consequential changes to the labels and leaflet.

42

m1-3-1-leaflet

PLPI LAB/LEA m1-2-form STnD NATIONAL

Change in labels with no other change.

To add Braille to over labels and cartons.

62 m1-3-1-label m1-2-form Change in information

leaflet. To amend ‘XXXX’ and ‘YYYY’ sections in line with the current UK PIL dated ‘dd/mm/yyyy’. PLPI revision date ‘dd/mm/yyyy’

64 m1-3-1-leaflet

Special Mail 5 FAQs – Annex G

Annex G – Updated submission route summary - UPDATED v2.1

Abbreviations Submission Types IPU Area number*

Paper*2 - please do not send email boxes*3

Cancellations 4 4 Withdraw.Cancel@MHRA.gsi.gov.uk

COAs Change of Ownership Applications 1 1 n/a *2

CTAs Clinical Trial Applications*4 6 n/a n/a

AS(D)MFs Active Substance (Drug) Master Files 7 7 Letter.Access@MHRA.gsi.gov.uk

HRs, NRsHomeopathic Registrations, New Homeopathic Registration Scheme

5 5 n/a *2

Information Updates (Add/Amends) - error in initial Application

10 10 n/a

Information Updates (Add/Amends) - error in Post-Approval Applications (variations, renewals)

10 10 n/a

MAAs National Marketing Authorisation Applications 1 1 n/a *2

MRPs, DCPsMutual Recognition Procedures (Incoming and Outgoing), DeCentralised Procedures

2 2 n/a *2

NBs Notified Bodies 5 5 n/a *2

PIU Patient Information Updates (Label & Leaflets) 9 9 n/a *2

PLPIs Product Licence Parallel Import applications 5 5 n/a *2

PL Variations (National & MR) 3 3 n/a *2

PL Renewals (National & MR) 4 4 n/a *2

PSURs Periodic Safety Update Reports 4 4 n/a *2

THRs Traditional Herbal Registration applications 1 1 n/a *2

*Information Processing Unit, Area X, MHRA, Market Towers, 1 Nine Elms Lane, London SW8 5NQ*2 For courier deliveries, and other deliveries by van, or hand deliveries, use:information Processing Unit, Area X, MHRA, Market Towers, 1 Nine Elms Lane, London SW8 5NQ

*3 For Responses to RFIs, the RFI.Responses@MHRA.gsi.gov.uk emailbox may be usedNOTE: all responses on CD should be sent to the same Area as the original submission

PLEASE DO NOT INCLUDE INDIVIDUAL’S NAMES AS WELL AS AREA NUMBERS – THIS WILL ONLY CAUSE A DILEMMA FOR OUR POST ROOM IN DECIDING WHERE TO SEND THE PACKAGE

You will be contacted on receipt to request an e-copy, and, if processing of paper is required, it may be delayed by scanning, OCR, document splitting and re-naming