GLOBAL REGULATORY INFORMATION DOCUMENT MANAGEMENT SUBMISSIONS REGISTRATION PLANNING

GLOBAL REGULATORY INFORMATION : DOCUMENT MANAGEMENT , SUBMISSIONS, REGISTRATION PLANNING & TRACKING Best Practices – Do’s and Don’ts for Areas of Deficiency or Insufficient Information in e. CTD Format Helen Teichman April 29, 2014 www. chestnutsolutions. com

GLOBAL REGULATORY INFORMATION : DOCUMENT MANAGEMENT , SUBMISSIONS, REGISTRATION PLANNING & TRACKING § The submission to Health Canada § How to get to a successful NDS filing in e. CTD format § A “word” about post approval sequences www. chestnutsolutions. com

GLOBAL REGULATORY INFORMATION : DOCUMENT MANAGEMENT , SUBMISSIONS, REGISTRATION PLANNING & TRACKING A bit of history § Interested in e. CTD since 2000 § § Partnership with Submission Consulting Group since 2010 § § Submission readiness, templates, process Submitted 100’s of sequences in e. CTD § NDS, IND, other regions § Conversion to Nee. S and Print Ready PDF Client management and submission management § § Keep cost down and quality up through standards and process Push the process – submit as close to the receipt of last document as possible www. chestnutsolutions. com

GLOBAL REGULATORY INFORMATION : DOCUMENT MANAGEMENT , SUBMISSIONS, REGISTRATION PLANNING & TRACKING Validation at HC § § Generally not much goes wrong…. One time: large files (2) identified by publisher were flagged at validation § § Publisher had heard at industry meeting that HC would accept the “odd” large file Pointed out in cover letter A couple of telephone calls and resolved without further issue Meta data inherited from NDA did not apply to NDS § Agreed to change it in next sequence www. chestnutsolutions. com

GLOBAL REGULATORY INFORMATION : DOCUMENT MANAGEMENT , SUBMISSIONS, REGISTRATION PLANNING & TRACKING …. . two more for the same reason § § Sequence rejected because documents included with response document Do not assume that new documents can be included as a separate document along with the Response § § Additional documents should be in the pertinent Module and Section and hyperlinked to the response document That’s it! www. chestnutsolutions. com

GLOBAL REGULATORY INFORMATION : DOCUMENT MANAGEMENT , SUBMISSIONS, REGISTRATION PLANNING & TRACKING A successful NDS filing in e. CTD format § Develop the NDS from an NDA or MAA in e. CTD format whenever possible § § Complexity of the submission is proportional to the level of effort § § § Relatively easy from technical standpoint to import the NDA or MAA, swap out the new documents and add HC Module 1 Number of volumes is no longer the measure Bookmarks, hyperlinks, size of the submission (mb), numbers of studies, references, CRFs etc. Ability to submit close to the MAA or NDA facilitates the publishing of the first application www. chestnutsolutions. com

GLOBAL REGULATORY INFORMATION : DOCUMENT MANAGEMENT , SUBMISSIONS, REGISTRATION PLANNING & TRACKING You need to have a plan! § § Use a “Document Inventory” to provide guidance to publisher on specific contents of NDS (documents that will be submitted, new documents to be added, order, leaf titles) Incorporating post NDA/MAA changes into the NDS must be planned carefully to avoid rework CTD Section CTD Sub. Section MODULE 2 - CTD SUMMARIES 2. 2 Introduction N/A 2. 3 Quality Overall Summary N/A 2. 4 Nonclinical Overview N/A Title Document Notes Introduction To be based on a hybrid of NDA/MAA Quality Overall Summary one document vs. more granular Nonclinical Overview NDA version to be updated 2. 5 Clinical Overview N/A Clinical Overview 2. 6 Non clinical and Written Tabulated Summaries 2. 6. 1 Introduction 2. 6. 2 Pharmacology Written Summary NDA version to be modified for CA NDA version to have administrative edit to reflect proposed indication www. chestnutsolutions. com

GLOBAL REGULATORY INFORMATION : DOCUMENT MANAGEMENT , SUBMISSIONS, REGISTRATION PLANNING & TRACKING Assign clear roles § § § Regulatory lead: content related issues Submission manager: liaise with the publisher, ensure submission readiness, manage the inventory Publisher: triage documents, publish, first level QC QC’er: verify that hyperlinks go to the correct document, check leaf titles, order of documents, meta data Regulatory leads: learn your way around the submission § Use a viewer, if you have one or browse via Index. xml § Don’t be afraid to click around § Learn the language: sequence, leaf titles, meta data www. chestnutsolutions. com

GLOBAL REGULATORY INFORMATION : DOCUMENT MANAGEMENT , SUBMISSIONS, REGISTRATION PLANNING & TRACKING Pay attention to Submission Readiness § All documents need to be submission ready: bookmarks, internal hyperlinks, correct table and page orientation etc. § § Documents that are part of initial MAA or NDA are usually submission ready Establish clear responsibility for submission readiness for Canadian specific documents § § Format of WORD documents Generating PDF Correct hyperlinks Associated references www. chestnutsolutions. com

GLOBAL REGULATORY INFORMATION : DOCUMENT MANAGEMENT , SUBMISSIONS, REGISTRATION PLANNING & TRACKING Pay attention to your Canadian documents § QOS, CPID, Canadian specific M 3 narratives and other regional documents (batch records) § § Product Monograph § § Use templates! Start PM as early as possible! Check the references to support the PM You may need to add some beyond the NDA references Module 3 and Regional § § If using NDA documents, check for references to U. S. DMF, IND Plan…. . time to make additional technical documents are submission ready www. chestnutsolutions. com

GLOBAL REGULATORY INFORMATION : DOCUMENT MANAGEMENT , SUBMISSIONS, REGISTRATION PLANNING & TRACKING Plan the QC process § Establish QC approach § § § Diagnostics from publisher identify early issues § § § Original NDA/MAA documents: how much 100% QC of all new documents and related links QC of Index. xml (for leaf titles) and meta data Where will you QC? Hyperlinks and/or bookmarks that go to documents (or data sets) not in the NDS Incorrect or broken links from the original submission (don’t panic!) Most rework due to submission readiness issues § § Format (e. g. table splitting), bookmarks Cross references www. chestnutsolutions. com

Ex am rec ple en fro t. M m 3 GLOBAL REGULATORY INFORMATION : DOCUMENT MANAGEMENT , SUBMISSIONS, REGISTRATION PLANNING & TRACKING 3. 2. S. 2. 1, page 4, section 3. 2. S. 2. 2 is invalid 3. 2. S. 2. 3 page 2, add "List of" page 5/6 and page 9/10 table splits across cell page 10 Table 3. 2. S. 2. 3. 2 -4 no table with this number pages 15 -17, header and footer alignment 3. 2. S. 2. 6 pages 1 -12 footer is incorrect First bookmark 3. 2. P. 2 is incorrect 3. 2. S. 3. 2, page 3, heading 3. 2. S. 3. 3 is invalid 3. 2. S. 4. 2, pages 1 -2 footer is incorrect 3. 2. S. 7. 1 is missing 3. 2. S. 7. 3, page 1, To. C needs formatting, page 3, Table 3. 2. S. 7. 3 -1 should not be blue/bold 3. 2. P. 2, page 1, "Table" should be "List of Tables" page 3 Table 3. 2. p. 1 -1 is linked to Table 3. 2. p. 2 -1 www. chestnutsolutions. com

GLOBAL REGULATORY INFORMATION : DOCUMENT MANAGEMENT , SUBMISSIONS, REGISTRATION PLANNING & TRACKING Understand the Meta Data § § Use the guidance document: Creation of the Canadian Module 1 Backbone Meta data tables are important www. chestnutsolutions. com

GLOBAL REGULATORY INFORMATION : DOCUMENT MANAGEMENT , SUBMISSIONS, REGISTRATION PLANNING & TRACKING Last checks before submission § Compliance: sequences pass validation as per their publishing systems and at least one other validator § § § Lorenz used by HC is available at no charge Different validators flag different things for same document FDA validator flags non-embedded fonts, HC will not. Check the media…. . www. chestnutsolutions. com

GLOBAL REGULATORY INFORMATION : DOCUMENT MANAGEMENT , SUBMISSIONS, REGISTRATION PLANNING & TRACKING …. . and then come the Clarifaxes § § § No one wants to allocate days for preparation of the sequences…. so plan and set up the sequence Pay attention! Module 1 is only for Module 1 documents Do not include new documents as part of the Response document § § Sequence will be rejected Additional documents should be in the pertinent Module and Section and hyperlinked to the response document . www. chestnutsolutions. com

GLOBAL REGULATORY INFORMATION : DOCUMENT MANAGEMENT , SUBMISSIONS, REGISTRATION PLANNING & TRACKING Product Monograph changes § § § Product Monograph versions are in 1. 3. 1 Track changes and annotated (with citations and hyperlinks to summary sections) are treated as 'annotated' Once the Pristine PM is provided all supporting 'annotated' PMs should be DELETED www. chestnutsolutions. com

GLOBAL REGULATORY INFORMATION : DOCUMENT MANAGEMENT , SUBMISSIONS, REGISTRATION PLANNING & TRACKING Product Monograph…the reality of life § § § 20 -25 changes, several on the same day Changes e mailed to the reviewer - e. CTD is out of synch Tried to replicate the order § § § Difficult to figure out what the dates should be for each sequence How to build the sequences when versions had already been superseded Lesson Learned: e mail copies to the submission manager and build the sequences with the dates submitted to the reviewer § Submit them at the end, if necessary www. chestnutsolutions. com

GLOBAL REGULATORY INFORMATION : DOCUMENT MANAGEMENT , SUBMISSIONS, REGISTRATION PLANNING & TRACKING Post marketing sequences § § Maintain the LCM Go through all the steps Use a document inventory Consistency: between sequences § Leaf titles, PDF names, folder titles, study titles www. chestnutsolutions. com

GLOBAL REGULATORY INFORMATION : DOCUMENT MANAGEMENT , SUBMISSIONS, REGISTRATION PLANNING & TRACKING What is success? ü ü ü Submit on time (be aggressive) Minimize rework (and stress) through standards and process Ensure submission is navigable for reviewer (bookmarks, hyperlinks) Every time validation at Health Canada Refine the process with each sequence www. chestnutsolutions. com

GLOBAL REGULATORY INFORMATION : DOCUMENT MANAGEMENT , SUBMISSIONS, REGISTRATION PLANNING & TRACKING Helen Teichman hteichman@chestnutsolutions 416 -525 -4903 www. chestnutsolutions. com