The latest from the FDA Preparing for the New Module 1 and Validation Criteria Recording 05122011

This video provides an in-depth exploration of the FDA's proposed changes to eCTD Module 1 and updated validation criteria, as presented in 2011. Harve Martin of expedo, a seasoned expert in life sciences information systems and a key figure in ICH M2 and IRISS, offers a unique perspective as a software designer tasked with implementing these complex regulatory requirements. The presentation aims to clarify the reasons behind varying eCTD validator outcomes and highlight critical areas for pharmaceutical companies to focus on as the FDA moved towards implementation of these new standards.

The discussion begins by detailing the FDA's draft validation criteria version 2.0, released in December 2010, which introduced 58 new rules, removed 14, and significantly revised many existing ones. Martin explains the technical underpinnings of eCTD, emphasizing its XML basis and the role of DTDs (currently version 3.2) in defining rules. He highlights the challenges faced by software developers in interpreting and implementing ambiguous or technically impossible rules, citing specific examples of problematic criteria that could lead to submission rejections. A significant shift noted was the FDA's intention to become tougher on enforcement, with a heavy emphasis on document quality, the content validation of fillable forms, and robust PDF validation, including checks for broken or corrupt hyperlinks and bookmarks.

Following the validation criteria, the presentation shifts to the anticipated changes in eCTD Module 1, which was not yet published but expected in draft form by July 2011. These changes aimed to address inconsistencies and improve granularity, particularly for CBER/CDER (DD Mac and CBER APLB) submissions. Key updates included reorganizing administrative information, allowing multiple applications per submission instance, and introducing more detailed headings and attributes for promotional materials to distinguish between professional and consumer audiences. Martin also outlines the FDA's internal "to-do list" for updating related guidance documents and specifications. He concludes with practical recommendations for companies, focusing on transition planning, impact on document lifecycle, reviewing SOPs, ensuring PDF compliance, and engaging with vendors and industry groups like IRISS to navigate these evolving regulatory landscapes.

Key Takeaways:

• Evolving FDA Validation Criteria: The FDA's draft validation criteria version 2.0 (circa 2010) introduced a substantial number of new rules (58 total, including 4 high-severity), removed problematic ones, and aimed for stricter, more uniform enforcement, particularly for high-severity issues that could lead to submission rejection.
• Technical Challenges in Implementation: Software designers faced significant challenges in implementing validation rules due to ambiguities, technical impossibilities (e.g., "more than one version of the US Regional XML file exists"), or lack of clear definitions, leading to inconsistencies across different eCTD validators.
• Emphasis on Document and PDF Quality: The new criteria placed a heavy emphasis on the quality of submitted documents, including the content validation of fillable forms downloaded from the FDA website and comprehensive PDF validation, checking for issues like broken hyperlinks, corrupt bookmarks, and proper embedded fonts.
• Module 1 Granularity and Multiple Applications: The anticipated Module 1 changes aimed for greater granularity, especially in administrative information and promotional materials, and a significant departure from previous standards by allowing submissions to target multiple applications within a single submission instance.
• Impact on Lifecycle Management: The increased granularity and structural changes in Module 1 were expected to have a significant impact on the lifecycle management of regulatory documents, requiring companies to re-evaluate their document authoring SOPs and potentially their content management systems.
• Importance of Industry Standards and Interoperability: The presentation underscored the role of ICH M2 and the newly formed IRISS (Implementation of Regulatory Information Submission Standards) in fostering interoperability and addressing implementation challenges for electronic regulatory submissions across the industry.
• Strategic Planning for Transition: Companies were advised to plan carefully for the transition to the new Module 1, considering its impact on existing processes, engaging with software vendors, conducting pilot submissions, and ensuring robust internal validation processes.
• PDF Compliance Beyond Basic Generation: Beyond simply generating PDFs, companies needed to focus on the quality of hyperlinking, bookmarking, and embedded fonts, as these elements would be subject to more rigorous validation checks by the FDA.
• The Role of XML in eCTD: The eCTD structure is fundamentally based on XML, with rules defined by DTDs (e.g., version 3.2). Understanding the XML backbone and its validation against DTDs is crucial for ensuring submission compliance.
• Collaboration and Continuous Feedback: The iterative nature of regulatory updates (e.g., draft criteria, comment periods) highlighted the importance of industry feedback to the FDA and collaboration with vendors and peer organizations (like IRISS) to refine and improve submission standards.

Key Concepts:

• eCTD (electronic Common Technical Document): A standard format for submitting applications, amendments, supplements, and reports to regulatory authorities.
• Module 1: The region-specific administrative information and prescribing information within an eCTD submission.
• Validation Criteria: A set of rules and checks applied by regulatory authorities (like the FDA) to ensure the technical and structural compliance of eCTD submissions.
• XML (Extensible Markup Language): The foundational language used for structuring eCTD submissions.
• DTD (Document Type Definition): A set of markup declarations that define the legal building blocks of an XML document, used to validate the structure of eCTD files.
• ICH M2: An expert working group within the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use, focused on electronic standards.
• IRISS (Implementation of Regulatory Information Submission Standards): A multi-industry, multinational, non-profit organization established to advance technical and electronic regulatory submission standards, with a focus on implementation and interoperability.
• RPS (Regulatory Product Submission): A standard for electronic submissions that aims to provide a harmonized approach across different regulatory agencies and product types.
• DD Mac (Document Data Management Center) / CBER APLB (Center for Biologics Evaluation and Research, Advertising and Promotional Labeling Branch): FDA centers/branches that accept eCTD submissions, specifically mentioned in the context of Module 1 changes.