February 2021

Maurice Bancsi, PhD and Beatriz Criado, MSc The European Medicines Agency (EMA) facilitates a range of different submissions and application processes using several submission systems for electronic procedures, which have clear advantages over paper-based submissions. At present, first-time applicants cannot proceed with a regulatory submission unless they have set up several accounts and assigned roles and registered their companies and their assets. However, there is no “one-stop-shop” place on the EMA website for users to access guidance for setting up properly for each separate system. In the absence of such a central point of information, we provide here a step-by-step guidance for first-time applicants to set up appropriately for using electronic submissions at EMA. Introduction Until recently, submission of any kind of application to health authorities was a straightforward, but cumbersome, process. Originals were hand-typed on paper, copies were either carbon or photocopies, and applications, depending on the type and size, were sent by anything from regular mail to paper-filled truckloads. Submission processes started to change with the introduction of the

©2021 Regulatory Affairs Professionals Society

Navigating the maze of electronic submissions at EMA

February 2021

personal computer and advances in telecommunication, allowing limited-sized submissions to be sent by fax machine, which could be regarded as the first “electronic” submissions to health authorities. Documents could be drafted on personal computers with word-processors and copies were saved on floppy-discs and later, compact discs and digital video discs. These larger submissions were still sent by mail or courier services. The last 15 to 20 years have marked the rise of the internet and its huge potential as fax machines were replaced by email systems, and higher data transfer speeds facilitated the submission of large quantities of data using dedicated electronic portals. The EMA1 is the central European Union (EU) institute coordinating the evaluation of medicines for central approval in the EU. At the EMA, the Eudralink2 system – a secure email system for sending large documents – was introduced as one of the first electronic submission systems, combining the use of email and an electronic portal. Since Eudralink, the are continuous efforts to facilitate electronic submissions in a secure and reliable electronic environment. Several systems have been introduced in addition to Eudralink, email, and the EMA Service Desk:3

• The eSubmission Gateway and the eSubmission Gateway Web Client, which are secure electronic submission channels for electronic common technical document and some nonstructured submissions,4

• The IRIS portal,5 a secure online platform for handling product-related scientific and regulatory procedures with EMA,

• EudraCT,6 the EU database for all interventional clinical trials on medicines, and

• EudraVigilance,7 a secure system for managing information on suspected adverse reactions to medicines being studied in clinical trials or already authorized.

However, as it stands now, there is a multitude of different submissions and application processes and the existence of these apparently standalone submission systems, make it hard, and sometimes seemingly impossible, for first-time applicants to find their way in this maze of electronic submission systems, outlined in Figure 1 (see p. 3). In this paper, we will clarify the respective systems in use at EMA and propose a stepwise approach to help new applicants unravel the maze and facilitate proper use of the available EMA systems. Setting up to use EMA electronic systems When the development of a new project, whether it is a drug, device, or diagnostic, has progressed to a point where there is a need for interaction with EMA ‒ for example, for scientific advice or protocol assistance, an orphan

February 2021

FIGURE 1 The current maze of EMA e-submission systems

Source: EMA

medicinal product designation, or a pediatric investigation plan (PIP) ‒ or where it is advantageous to have that option available, an applicant needs to set up several accounts. Step 1 As a first step, three accounts need to be set up as shown in Figure 2:

• An EMA account on the EMA Account Management portal8 – This is required for access to multiple other systems, such as the EMA Service Desk, Eudralink, the SPOR (Substance, Product, Organization and

February 2021

FIGURE 2 Setting up accounts at the EMA

Source: EMA

Referentials)9 portal, the IRIS portal, and EudraCT. Sponsors of clinical trials and companies holding a marketing authorization in the European Economic Area (EEA) also need an active EMA account to register with EudraVigilance for the electronic reporting of suspected adverse drug reactions and the electronic submission of information on authorized medicinal products.

• An e-Sub account on the eSub registration webpage10 – This is required for submissions through the eSubmission Gateway, such as a PIP submission and a marketing authorization application (MAA).

• An EMA customer account number – This is set up through the EMA’s accounts receivable inbox.11 The account is needed for payment of invoices12 from EMA, but also for applications in the IRIS system, such as scientific advice and protocol assistance.

Step 2 The second step involves SPOR, IRIS, Eudralink, and EudraVigilance (Figure 3).

February 2021

FIGURE 3 Setting up systems at the EMA

Source: EMA

To have access to IRIS and to maintain Organizations Management Services (OMS)13 data in SPOR, appropriate user access roles for IRIS and SPOR are required. For both SPOR and IRIS, a first user admin role (SPOR industry superuser, IRIS industry user admin, or IRIS parallel distribution user admin), requested through the EMA Account Management portal, will need to be approved by EMA. The user admin roles will manage and approve all subsequent affiliations to the organization. These subsequent roles would include second superuser/user admin, user, manager, and contributor role, and would also be requested through the EMA Account Management portal. A Eudralink account can be requested through the EMA Service Desk. To have access to EudraVigilance, an EU qualified person for pharmacovigilance (QPPV) or responsible person (RP) role must be requested through the EMA Account Management portal. A service desk request needs to be raised with the required registration documents, including the Gateway (also called EV Post) connection details if this is the electronic transmission platform that will be used for reporting. An organization can alternatively use EVWEB14 (also known as Webtraders) as transmission platform.

February 2021

• SPOR provides users or will provide users with several data management services: o Substance management services (not currently activated) o Product management services (not currently activated) o Organizations Management Services – OMS is a central repository

of organization data. If the organization on whose behalf an applicant will be acting is not listed in OMS, a change request needs to be raised to have the organization registered. When the organization has been successfully registered, the applicant will receive an organization identification code. OMS support the continuous exchange of data between information systems across the European medicines regulatory network and across the pharmaceutical industry.

o Referentials management services – RMS provides referentials lists and terms, such as routes of administration and dosage forms, in multiple languages. RMS supports the continuous exchange of data between information systems across the European medicines regulatory network and the pharmaceutical industry.

• IRIS provides a platform for the following procedures to be accessed: o Orphan designation o Scientific advice (human and veterinarian) o Protocol assistance (scientific advice for orphan designated

medicines) o Parallel distribution o Innovation task force (ITF) consultation and general procedures

(e.g., requests for a research product identifier [RPI]) o Change of name and address of an applicant on regulatory

entitlements. o Several quick links are accessible in the IRIS portal for guidance

through the IRIS registration process, information on parallel distribution notices, organizations and substances, guidance and support documents and latest news.

• EudraVigilance is the system for managing and analyzing information on suspected adverse reactions to medicines that have been authorized or are being studied in clinical trials in the EEA. The EMA operates the system on behalf of the EU medicines regulatory network.

• Eudralink can be used for secure transfer of large documents. Step 3 In step three, the user admins assign further roles in the individual systems (Figure 4):

• The first SPOR industry superuser can approve a second SPOR industry superuser (recommended by EMA) and the SPOR industry user role.

• The IRIS industry user admin can approve a second IRIS industry user admin (recommended by EMA) and the IRIS industry manager, contributor, and user roles.

February 2021

FIGURE 4 Assigning roles in systems at the EMA

Source: EMA

• The IRIS parallel distribution user admin can approve a second IRIS parallel distribution user admin (recommended by EMA), and the IRIS parallel distribution manager, contributor, and user roles.

• The user admins are responsible for these approvals, and the EMA is not involved.

• The QPPV/RP can approve new EudraVigilance user role requests. Once SPOR and IRIS roles have been assigned, the applicant will need to verify whether their active substances are registered and appear as “authorized” and “current” on the official EMA list of all substances, the European Union Telematics Controlled Terms.15 If an active substance is not listed, then a request must be raised at the EMA Service Desk to have it registered. Once the substance is registered, the applicant can proceed to create a request for an RPI through IRIS, necessary to proceed with certain types of scientific procedures (Figure 5).

February 2021

FIGURE 5 Active substance registration at the EMA

Source: EMA Sponsorship/authorization to act on behalf of a sponsor Once accounts have been created, roles have been assigned and companies and products have been registered, the final consideration concerns the accessibility of procedures. When a company is not established within the EEA (or has no affiliate), some procedures are not immediately accessible, such as the orphan medicinal product designation or classification as small- or medium-sized enterprise or MAA. In those instances, that company will need to establish a presence (e.g., an affiliate) within the EEA or designate a third party (established within the EU) as sponsor for their procedures. For other procedures, such as PIP, scientific advice or protocol assistance, a company may appoint a third party to act on their behalf, while retaining sponsorship. Use of EMA eSubmission platforms After the accounts have been created, roles assigned, and companies and products registered, all eSubmission platforms should be accessible, as outlined in Figure 6.

February 2021

FIGURE 6 eSubmission platforms at the EMA

Source: EMA There are two major submission platforms:

• The eSubmission Gateway/Web Client is the mandatory system for submissions related to the authorization and maintenance of medicinal products, such as the initial MAA, a postapproval safety study, a postapproval efficacy study, a periodic safety update report, a risk management plan, a postapproval measure, a plasma master file, a variation and a renewal.

• IRIS is used mostly during product development, for orphan applications, for ITF meeting documents, parallel distribution

February 2021

applications, scientific advice/protocol assistance requests and general request, such as related to RPIs. The exception is the PIP submission (initiated early in clinical development and maintained throughout development), which is also done through the eSubmission Gateway/Webclient.

The remaining submissions still reside under legacy platforms/systems, such as:

• Eudralink (priority medicines, or PRIME, applications),

• Email (name recognition group submissions, advanced therapy medicinal product classification requests,

• ITF briefing meeting requests, and reporting shortages of medicines,

• The EMA Service Desk (requests for accelerated assessment of an MAA, eligibility for the centralized procedure requests and notification of quality defects), and

• The EMA account for access to clinical data. Given that the scientific advice and protocol assistance procedures have recently moved under the IRIS umbrella, it may be a matter of time before the other processes linked to email, the EMA Service Desk and Eudralink will also be transferred. Summary The EMA facilitates a range of different submissions and application processes, using several submission systems for electronic procedures, which have clear advantages over paper-based submissions. However, with the multitude of different submissions and application processes and the existence of several apparently stand-alone submission systems, it is hard for applicants to find their way in this maze of electronic submission systems. Here we have described a stepwise approach for new applicants to facilitate the use of the available systems at EMA. These steps included setting up accounts (EMA account, eSub account, EMA Account Number) and systems/platforms (SPOR, IRIS) and registration of organization and active substances. Abbreviations EEA, European Economic Area; EMA, European Medicines Agency; EU, European Union; ITF, innovation task force; MAA, marketing authorization application; OMS, Organizations Management Services; PIP, pediatric investigation plan; QPPV, qualified person for pharmacovigilance; RMS, referentials management services; RP, responsible person; RPI, research product identifier; SPOR, substance, product, organization, and referentials. References

1. European Medicines Agency website. https://www.ema.europa.eu/en. Accessed 12 February 2021.

2. European Medicines Agency. Eudralink homepage. https://eudralink.ema.europa.eu/. Accessed 12 February 2021.

3. European Medicines Agency. Login page for service desk. https://servicedesk.ema.europa.eu/jira/servicedesk/customer/user/login?destination=portals. Accessed 12 February 2021.

4. eSubmission website. eSubmission gateway and eSubmission web client. http://esubmission.ema.europa.eu/esubmission.html. Last updated 19 November 2020. Accessed 12 February 2021.

February 2021

5. IRIS, a secure online platform for handling product-related scientific and regulatory procedures with EMA. https://iris.ema.europa.eu/~/. Accessed 12 February 2021.

6. EudraCT, the EU database for all interventional clinical trials on medicines. https://eudract.ema.europa.eu/index.html. Accessed 12 February 2021.

7. EudraVigilance system overview. https://www.ema.europa.eu/en/human-regulatory/research-development/pharmacovigilance/eudravigilance/eudravigilance-system-overview. Accessed 12 February 2021.

8. European Medicines Agency. EMA account management. https://register.ema.europa.eu/identityiq/login.jsf?prompt=true#/accessRequestSelf/add. Accessed 12 February 2021.

9. European Medicines Agency. SPOR https://spor.ema.europa.eu/sporwi/. Accessed 12 February 2021.

10. European Medicines Agency. eSubmission Registration – Step 1. https://esubregistration.ema.europa.eu/registration/. Accessed 12 February 2021.

11. European Medicines Agency. Email address for accounts receivable inbox. AccountsReceivable@ema.europa.eu. Accessed 12 February 2021.

12. European Medicines Agency. EMA invoicing portal. https://fees.ema.europa.eu/bd/public/zindex.jsp. Accessed 12 February 2021.

13. European Medicines Agency. Organisations Management Service (OMS). https://spor.ema.europa.eu/omswi/#/. Accessed 12 February 2021.

14. EudraVigilance website. EVWEB. https://eudravigilance.ema.europa.eu/human/evweb01.asp. Last updated 26 October 2012. Accessed 12 February 2021.

15. European Union. European Union Telematics Controlled Terms (EUTCT) System. https://data.europa.eu/euodp/en/data/dataset/the-european-union-telematics-controlled-terms-eutct-system. Modified 14 December 2018. Accessed 12 February 2021.

About the authors Maurice Bancsi, PhD, is a director of regulatory affairs at Regulatory Professionals, a division of Premier Research. He has more than 24 years of experience with biologicals, as well as small molecules developing EU regulatory strategies, leading cross-functional teams in health authority interactions (both on national and EU level) and submission of regulatory applications. Bancsi has a doctorate in medicines from the University of Leiden, Netherlands. He can be contacted at Maurice.bancsi@regprofessional.com. Beatriz Criado, MSc, is an associate director of regulatory affairs at Regulatory Professionals, a division of Premier Research. She has more than 23 years of experience in regulatory affairs in the pharmaceutical and biotech industry and has held a range of leadership positions in regulatory affairs. Criado has broad experience in a variety of therapeutic areas, including immunology, neuroscience, women’s health, rare diseases, and pediatric indications. She has a master of science degree in pharmaceutical and parapharmaceutical industry from the CESIF [Centre of High Studies of the Pharmaceutical Industry], Madrid, Spain. She can be contacted at Beatriz.criado@premier-research.com. Citation Bancsi M, Criado B. Navigating the maze of electronic submissions at EMA. February 2021. REGULATORY FOCUS. Regulatory Affairs Professionals Society.