Health authorities are turning to digitalization to streamline their processes in response to global crises (such as the COVID-19 pandemic) that have affected the supply chain. The growing complexity of information and data in regulatory submissions has encouraged health authorities to implement structured data submissions and centralized e-submission processes through shared workspaces (1, 2). Some ongoing initiatives seek to simplify review and assessment processes through increased global cooperation and harmonization.
As of 2024, the European Medicines Agency (EMA) is exploring revised transparency rules in its Clinical Trials Information System (CTIS) to simplify and expedite clinical trial application (CTA) approval processes (3). Meanwhile, the US Food and Drug Administration (FDA) is moving toward structured-data systems with its pharmaceutical quality/chemistry, manufacturing, and controls (PQ/CMC) initiative and Knowledge-Aided Assessment and Structured Application (KASA) computer-assisted review tool (4).
Such developments will cause significant process changes for the industry. Companies that submit documentation to the EMA will need to input data directly into the agency’s information technology (IT) systems. Although that change will streamline product approval, it affects how companies must document and manage the data required for health-authority submissions.
Similarly, health authorities will need to overcome challenges with digital readiness in some markets. Although the EMA has a digital mandate, digitalization strategies are diverse across Europe. In its strategy report, the European Medicines Regulatory Network (EMRN) expressed the need to consider diverse forms of digitalization across all EU member states and establish a more comprehensive digital interface to optimize interaction with stakeholders (2).
Changes on the Horizon
Several key initiatives are on the horizon. The electronic Common Technical Document 4.0 (eCTD 4.0) is expected to take effect in both the United States and the European Union in the coming years. The FDA’s Center for Drug Evaluation and Research (CDER) and Center for Biologics Evaluation and Research (CBER) are both testing eCTD 4.0 software and plan to accept new applications using that format in 2024 (5).
The EMA’s timeline for implementation begins in 2024 with initial pilots of centrally authorized products (CAPs). Optional use of the eCTD 4.0 for CAPs is scheduled for 2025, expanding in 2026 to include products authorized through mutually recognized procedure (MRP), decentralized procedure (DCP), and national procedure (NP). Mandatory use of eCTD 4.0 software in centralized procedures is scheduled to begin in 2027 (6).
That draft timeline may change, however, depending upon the accuracy of the EMA’s complexity estimation and on whether national competent authorities (NCAs) can prepare fully for the shift to the eCTD 4.0 platform. Agencies will require updated IT infrastructure and software to implement eCTD 4.0 software, which also will need additional infrastructural investment for its most beneficial features. National agencies are not yet budgeted for such an investment. That presents a risk that eCTD 4.0 will be implemented by the EMA but not by NCAs.
Structured Data Formats
Some data standards that are under development complement the content of submission documents with structured information. These include the ISO Identification of Medicinal Products (IDMP) FDA’s PQ/CMC standards (7). In the long run, structured data formats are meant to replace traditional documents in the submission process.
PQ/CMC data models provide quality information in a structured way without requiring reviewers to search documents for key quality information that must be reentered into databases. The FDA has said that PQ/CMC will “significantly enhance the KASA system, by removing manual (semi-automated) data transposition” (5). KASA was created to assess and process CMC information based on structured data records rather than submission documents.
The EMA’s IDMP-based substance, product, organization, and referential (SPOR) database seeks to capture all the relevant properties and characteristics of a pharmaceutical product using structured information (8). The SPOR database consists of four subsystems: Substance Management Services (SMS), Product Management Services (PMS), Organisation Management Services (OMS), and Referentials Management Services (RMS). Each of those provides master data to other connected systems at the EMA and across the European regulatory network. SMS, OMS, and RMS are operational. In most cases, companies submitting applications must use terms from picklists to describe application details. The picklists are fed with values from different SPOR services. Examples of such agency systems are the EMA eSubmission Gateway and the IRIS and Product Lifecycle Management (PLM) platforms.
The industry prioritizes the accuracy and currency of master data in the SPOR database. However, SPOR remains incomplete because the agency is struggling to implement the PMS system, which is the largest part of the overarching database.
The EMA is collecting an initial subset of information, using data on pharmaceutical products already stored in the older Extended EudraVigilance Medicinal Product Dictionary (XEVMPD) database. Currently, the EMA claims that all product entries from XEVMPD will become available through PMS in 2024. But underlying data models for IDMP and XEVMPD do not match, and XEVMPD data can contribute only about a third of the information needed for a PMS product data record. Therefore, the industry must clean up and correct all data imported from XEVMPD to provide a complete PMS record.
Although the EMA is furthest ahead with IDMP initiatives, other health authorities are following suit. Swissmedic has communicated privately to industry organizations that it is building an IDMP-compliant database that is highly aligned with the EMA’s SPOR database, including the controlled vocabularies. The United Kingdom’s Medicines and Healthcare products Regulatory Agency (MHRA) also has initiated an overhaul of the UK regulatory management system based on IDMP-structured master data for drug substances and medicinal products. To ensure readiness for IDMP and other structured data initiatives in 2024, biopharmaceutical companies must prioritize improving their end-to-end business processes, harmonizing data, and eliminating blocked data flows.
IRIS, PLM, and CTIS
The EMA has established a series of shared workspaces, called portals, through which sponsors are required to enter information as part of their application processes. These portals include:
• a PLM for managing application forms, electronic product information (ePI), and authorized product data (PMS) (9)
• an IRIS portal used for a number of different procedures, including orphan-drug designation, marketing status, scientific advice, and priority medicines (PRIME) (10)
• a CTIS portal to support applications under clinical-trial regulation (11).
Companies must include a number of considerations when using the CTIS portal. The process requires employees with specific knowledge to log into the portal and type information manually in addition to inputting data into the document narrative (12). Sponsors cannot prepare information offline and then upload it later. Employees also need access credentials and assigned roles to retrieve specific applications within the EMA portal. Furthermore, when control terms are missing from the portal, employees must log onto the SPOR database and add them to the platform before continuing with their submission.
Some companies have called upon the EMA to implement application programming interfaces (APIs) that enable sponsors to prepare applications in their own IT systems and upload them as needed. However, integrating such a feature is not among the EMA’s top priorities for the CTIS. Some companies turn to process-automation tools to help. Management should consider adding such capabilities in the year ahead as more submission processes move to shared portals.
Harmonization Through the Access Consortium
Although process and technology changes create additional burdens for the industry, there is a growing movement among regulators to streamline submissions through harmonization. A prime example is the Access Consortium, comprising Australia’s Therapeutic Goods Administration (TGA), Health Canada, Swissmedic, the Health Sciences Authority (HAS) in Singapore, and the UK MHRA (13). Pharmaceutical companies prioritize markets with large populations during the first wave of applications. The consortium benefits its member countries by combining their collective markets to represent more than 146 million people.
The Access Consortium became particularly relevant during the COVID-19 pandemic, which compounded the need for efficient review processes. Because all five member countries use the eCTD standard, the scientific part of the application is structured in the same way for each jurisdiction, although some aspects such as product information for healthcare professionals and patients differ.
Preparing for Change in 2024
Many companies have experienced fatigue from complying with changing regulatory standards that don’t always align with one another while being required to pay fees to multiple industry groups. Indeed, some intended efficiency gains envisaged by regulatory agencies bring additional burdens and costs to industry. Biopharmaceutical companies should investigate the options provided when they adapt their work to better align with agency trends.
Such organizations should focus their data strategies on data governance and master data management (MDM) to streamline company processes and fulfill regulator demands. It is important that drug sponsors identify information that is missing from their master data so that they can maintain and update such information. Companies also must ensure that master data have the required quality and coverage without any missing components. Data should not be limited to specific tasks, departments, and IT systems. Companies must identify original source data and ensure that all systems across every department use them because such information must be transferred to regulatory agencies during submission.
Achieving a single, accurate, company-wide source of data requires different systems and databases to communicate with one another. That will increase efficiency by preventing employees from needing to collect and reenter information into multiple systems. Agencies have adopted such a single-source approach in an effort to streamline their own processes.
Furthermore, improving data management enables companies to leverage artificial intelligence (AI) and automation tools, which can help to further streamline and speed up laborious and error-prone manual processes. Through proper data governance, MDM, and well-defined performance metrics, companies can use analytics to support process improvement. That will not only help streamline their systems for business improvement, but also allow them to align their systems with requirements from health authorities. And that should help the industry proactively meet the growing movement toward digitalization, structured data, and shared workspaces.
References
1 Never the Same Again: How COVID-19 Created Seismic Change in Life Sciences Regulations. Deloitte: London, UK, 2021: https://www.deloitte.com/content/dam/assets-shared/legacy/docs/perspectives/2022/gx-rfa-grit-life-sciences-never-the-same-again.pdf.
2 European Medicines Agencies Network Strategy to 2025. European Medicines Agency: Amsterdam, Netherlands, 2020; https://www.ema.europa.eu/en/documents/report/european-union-medicines-agencies-network-strategy-2025-protecting-public-health-time-rapid-change_en.pdf.
3 Revised CTIS Transparency Rules. European Medicines Agency: Amsterdam, Netherlands, 2023; https://www.ema.europa.eu/en/documents/other/revised-ctis-transparency-rules_en.pdf.
4 Schmuff NR. Standardizing Quality Submissions and Assessments: PQ/CMC and KASA. US Food and Drug Administration: Rockville, MD, 2022; https://www.fda.gov/media/161618/download.
5 Electronic Common Technical Document (eCTD) Version 4.0. US Food and Drug Administration: Rockville, MD, 2023; https://www.fda.gov/drugs/electronic-regulatory-submission-and-review/electronic-common-technical-document-ectd-v40.
6 eSubmission, eCTD Version 4.0. European Medicines Agency: Amsterdam, Netherlands, 2023; https://esubmission.ema.europa.eu/eCTD%20NMV/eCTD.html.
7 Pharmaceutical Quality: Chemistry, Manufacturing & Controls: PQ/CMC. US Food and Drug Administration: Rockville, MD, 2024; https://www.fda.gov/industry/fda-data-standards-advisory-board/pharmaceutical-quality-chemistry-manufacturing-controls-pqcmc.
8 Substance, Product, Organisation and Referential (SPOR) Master Data. European Medicines Agency: Amsterdam, Netherlands, 2024; https://www.ema.europa.eu/en/human-regulatory/research-development/data-medicines-iso-idmp-standards/substance-product-organisation-referential-spor-master-data.
9 Welcome to PLM Portal. European Medicines Agency: Amsterdam, Netherlands, 2024; https://plm-portal.ema.europa.eu.
10 Welcome to IRIS. European Medicines Agency: Amsterdam, Netherlands, 2024; https://iris.ema.europa.eu.
11 CTIS for Sponsors. European Medicines Agency: Amsterdam, Netherlands, 2023; https://euclinicaltrials.eu/ctis-for-sponsors.
12 IRIS Guide to Registration and RPIs. European Medicines Agency: Amsterdam, Netherlands, 2024; https://www.ema.europa.eu/en/documents/regulatory-procedural-guideline/iris-guide-registration-and-rpis_en.pdf.
13 Access Consortium Work-Sharing Initiative: An Industry Perspective. DIA Global Forum: Washington, DC, 2022; https://globalforum.diaglobal.org/issue/january-2022/access-consortium-work-sharing-initiative-an-industry-perspective.
Karl-Heinz Loebel is director and principal consultant of regulatory operations and Cary Smithson is senior director and international service lead for the business transformation and systems management service line, both at PharmaLex. Please address inquiries to Elizabeth Hunt at [email protected].
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