Introduction to the NDA to MAA Transition
Between 2013 and 2023, 347 of the 583 novel drugs approved by the FDA were also approved by the EMA, nearly 60% (Springer, Naunyn-Schmiedeberg’s Archives of Pharmacology, 2025). Sponsors often file their NDA/BLA in the US first, targeting the world largest medicines market. The next step for many Sponsors is Europe, where the NDA to MAA transition involves regulatory requirements that are similar in terms of dossier content. While this may be the case, there are however areas of the dossier that are different in the EU, and Sponsors can underestimate the resources required for EU Marketing Authorisation Applications or fail to put in place adequate forward planning resulting in costly delays. In this blog we cover trends in EU approval, the European Medicines Agency (EMA) Policy 0070 on Publication of Clinical Data for Medicinal Products for Human Use that can impact the NDA to MAA process, as well as some of the nuanced areas of EU dossiers.
Trends in EU Marketing Authorisation Applications (MAAs)
Over the past two decades, the European pharmaceutical market has demonstrated a remarkable level of innovation, evidenced by the steady growth in EU marketing authorisations (MAs) of new active substances (NAS), including orphan medicinal products, conditional marketing authorisations and other expedited development and approval programs. These trends highlight European authorities’ commitment to advancing medical science, in a concerted effort with regulatory agencies that balance rigorous safety and efficacy standards, aiming to provide patients with cutting-edge therapies. Understanding these trends is essential context for Sponsors planning the NDA to MAA submission pathway.
In 2024, the European Medicines Agency recommended 114 drugs for EU marketing authorisation including 46 drugs classed as NAS, 28 biosimilars, and 15 orphan medicines (EMA Human Medicines 2024 report). This was up significantly from the 2023 figures where 77 positive opinions were issued including 39 for new active substances, with 17 orphans and 8 biosimilars (EMA Human Medicines Highlights 2023). Indeed the 2024 figure is amongst the highest number in the 30 years of the agency’s existence. The percentage of conditional marketing authorisations (CMA) have held relatively steady over the 2021 to 2024 period (approximately 10% of approved medicines), as well as the overall proportion of orphan medicines (13 to 24%).
These recent numbers are backed by a long track record showing a thriving European pharmaceutical market.
New Active Substances
During the last decade, the authorization of NAS by the European Medicines Agency has shown a steady increase between 2015 (with 39 NAS) and 2024 (with 46 NAS), totaling 392 MAs of NAS (EMA Medicine Evaluation Figures).
Orphan Drugs in EU Marketing Authorisations
The approval of orphan drugs through the EU Marketing Authorisation Application process has seen substantial growth. From 2010 to 2022, the EMA authorized 192 orphan medicinal products (OMPs). This increase is driven by the growing focus on rare diseases and the incentives provided by the orphan drug legislation. Notably, 40% of these OMPs have oncological therapeutic indications, and 56% are intended to treat adults. The use of accelerated assessment for orphan drugs has also become more common, with 64% of MAAs benefiting from this expedited process, according to a 2024 analysis published in Orphanet Journal of Rare Diseases.
EMA Policy 0070 and Clinical Data Transparency
One key area of difference in European MAAs relative to NDAs/BLAs is the need to adhere to EMA’s Policy 0070 on Publication of Clinical Data for Medicinal Products for Human Use. This requirement is a major consideration in the NDA to MAA transition, since US submissions don’t require comparable transparency. The European Medicines Agency originally introduced this policy in 2016 in an effort to enhance transparency, foster innovation, and build public trust in the scientific and decision-making processes of the EMA. Policy 0070 mandates the publication of clinical data submitted by pharmaceutical companies to support marketing authorization applications for human medicines. While the policy has been temporarily paused a number of times due to EMA relocation out of the UK, and because of COVID-19, the policy is now a requirement for all new active substances that receive a Committee for Medicinal Products for Human Use (CHMP) opinion after September 2023 or for applications that were withdrawn before the opinion stage.
Looking ahead, the EMA plans to expand activities related to Policy 0070 from April 2025 (‘Step 2’ of the policy roll out). This expansion will include all new MAAs, line extensions, and major clinical Type II variations (such as the extension of indications). Biosimilars, generics, and hybrid applications, which typically include minimal clinical data, will remain excluded from the scope of the policy. In addition, Step 2 will include the publication of clinical data from legacy marketing authorisations granted during the suspension of Policy 0070 (December 2018 to September 2023). This will be triggered on a case-by-case basis when an access-to-documents request is submitted by the public or by an organization.
Marketing authorisation holders (MAHs) are required to prepare and submit clinical data for publication in accordance with the EMA’s guidelines. This involves anonymising clinical reports to protect personal data (PPD) and justifying any redactions of commercially confidential information (CCI). The documents in scope at present include the clinical overview and clinical summaries, CSRs, study protocols, sample case reports forms and documentation of the statistical methods. The EMA reviews the MAH’s redaction proposals and provides comments and requests for changes and/or additional justifications, with the final versions published on the EMA’s clinical data website. For initial MAs, Sponsors must submit the redaction package between Day 181 of the procedure to 30 days after the CHMP opinion. Sponsors should be aware of the significant resource and specialist expertise requirements to satisfy the requirements for Policy 0070 and prepare well in advance the Redaction Proposal Document Package for submission. To comply with Policy 0070, Sponsors must employ sophisticated data-anonymization methods, such as data transformation, to protect patient privacy while maintaining data utility. The anonymization strategy is based on quantitative risk assessment to determine the level of anonymization required based on the sensitivity of the data and the risk of re-identification. It is noted that Health Canada (HC) have an essentially identical policy in place, the Public Release of Clinical Information (PRCI), and sponsor’s anonymized clinical data packages compliant with Policy 0070 are also currently accepted by Health Canada. Moreover, both agencies have implemented a joint procedure allowing for a single review procedure lead by one agency, for MAs granted in both regions less than 6 months apart and where the content of the anonymized/redacted packages overlaps by more than 70%.
What are Key Differences between EU MAA and US NDA/BLA Submissions?
Beyond the more straightforward Module 1 differences, several EU-specific requirements can pose significant challenges compared to US submissions. These can become bottlenecks in the NDA to MAA process if not anticipated early, making expert regulatory publishing and submissions support especially valuable. Addressing these effectively is critical to avoiding delays and ensuring regulatory acceptance. Key areas include:
1. Risk Management Plan (RMP) in the EU vs REMS in the US
Module 1.8.2 of the EU dossier consists of the EU risk management system presented in the form of the EU Risk Management Plan (RMP). The objective of the RMP is to document the risk management system considered necessary to identify, characterise and minimise a medicinal product’s important risks. To this end, the RMP contains sections related to the following:
- Safety specification – the identification or characterisation of the safety profile of the medicinal product, with emphasis on important identified and potential risks and missing information, and on which safety concerns need to be managed proactively or further studied
- Pharmacovigilance Plan – the planning of pharmacovigilance activities to characterise and quantify clinically relevant risks, and to identify new adverse reactions
- Risk Minimisation Plan – the planning and implementation of risk minimisation measures, including the evaluation of the effectiveness of these activities.
While some FDA approved drugs are subject to a Risk evaluation and mitigation strategy (REMS) programs, these are different to an RMP in that may constitute actions, materials, safeguards, trainings etc. to mitigate specific risks associated with a medication. In our experience, RMPs require multidisciplinary input including from the qualified person for pharmacovigilance (QPPV), regulatory, medical, epidemiology, medical writers and the broader pharmacovigilance team. Smaller companies often do not have this breadth of experience in-house, leading to deficiencies in the RMP, which can lead to the need for significant rework during dossier review.
2. Paediatric Investigation Plan (PIP):
Section 1.10 of EU dossiers require information relating to paediatrics. This includes a mandatory PIP compliance check that is at the time of validation of the Marketing Authorisation Application (in case PIP compliance verification by the Paediatric Committee (PDCO) has not already taken place). Here the agency will assess if all the measures, which are not deferred or due to be completed at the time of a regulatory submission, including the conduct of the studies or collection of the data, have been completed exactly as described by the key elements specified in the PIP decision. We strongly recommend that the PIP compliance check is requested to the PDCO at least 2 months ahead of MAA submission to avoid unnecessary delays in validation of the application. The MAA pre-submission meeting with the EMA represents an opportunity to discuss and clarify all potential questions regarding the PIP compliance check. More serious and lengthy delays can be encountered by Sponsors who have completed fillings in non-EU territories and have not considered the need to have an agreed PIP in place before filing in the EU. For companies that file in the US first, this is often overlooked during the NDA to MAA strategy.
3. Environmental Risk Assessment
Module 1.6 of the EU dossier requires an Environmental Risk Assessment (ERA) detailing the assessment of the potential environmental risks and hazards of the medicinal product. In addition to being required for centralised filings, ERAs are also a requirement for mutual recognition, decentralised and national procedures.
- Note that EMA issued an updated guidance on environmental risk assessments
- effective from September 2024, and Sponsors should familiarise themselves with it ahead of filing. While reforms to the EU Pharma Legislation have yet to be finalised, the European Parliament amends to the reforms from April 2024 suggest that applicants that fail to submit a complete or sufficiently substantiated ERA or do not propose risk mitigation measures to sufficiently address the risks identified in the environmental risk assessment, could in some circumstances have their Marketing Authorisation Application refused. In our experience, and as echoed by sentiment across the industry, ERAs are an area not taken seriously by the MAHs. Yet ERAs are increasingly critical in the NDA to MAA process and could become a cause of refusals under future legislation. If this were to change and tighten up in forthcoming legislation, it may become a resource-intensive exercise.
4. New Active Substance (NAS) Justification
If a MAA is submitted claiming a New Active Substance, a justification must be provided as Annex 5.23 to the electronic Application Form (eAF). This justification will need to demonstrate that the active substance’s therapeutic moiety is not the same, from a chemical structure point of view, as any other previously authorised in a medicinal product for human use in the EU.
5. Labelling and User Testing Requirements
While product labelling may seem like a simple task to put together, it is often one of the most heavily scrutinized areas of EU MAA dossiers. The EU Product Information documents include the Summary of Product Characteristics (SmPC), the Labelling, and Package Leaflet. Applicants and marketing authorisation holders for human medicines must use the Quality Review of Documents (QRD) templates to develop the proposed product information to be included in the MAA dossier.
6. Orphan Similarity
In advance of a MAA, regardless of its orphan designation status, the applicant needs to demonstrate that the proposed product will not infringe the market exclusivity protection period of an already authorized orphan medicinal product for the same therapeutic indication. For that purpose, the applicant prepares a report assessing the similarity between its product and the authorized orphan medicinal products, which is based on three criteria: 1) principal molecular structural features; 2) mechanism of action; and 3) therapeutic indication. If significant differences can be demonstrated for at least one of these criteria, the products will not be considered as similar and the MAA can be accepted for review.
7. Application for Maintenance of Orphan Designation
For products with Orphan drug designation, in order for the EMA to determine if the product can maintain its orphan status for the proposed indication and benefit from the 10-year market exclusivity, the applicant must submit a report for maintenance of orphan designation, which will be reviewed by the COMP in parallel with the MAA review, around Day 121 of the MAA (or after validation for accelerated assessments, or indications extensions within the same orphan condition). This report must demonstrate that the criteria for orphan designation (prevalence and nature of the condition, the existence of alternative options, and, if so, justification of significant benefit).
What Are the Key Strategic Planning Considerations for EU Marketing Authorisation Application Submissions?
We recommend that Sponsors plan ahead and build sufficient time into their submission strategy to avoid delays during marketing authorisation application validation. Especially when mapping an NDA to MAA submission, early planning is the best safeguard against costly delays. Key actions include:
- Request a pre-submission meeting with the EMA 6-7 months before the planned MAA submission through the centralized procedure. These interactions represent an invaluable opportunity to get procedural and regulatory advice directly from the Agency, ensuring the application dossier is compliant with all legal and regulatory requirements to avoid delays during MAA validation.
- Submit a centralised eligibility request as early as 18 months, and no later than 7 months, in advance of submission.
- Provide a notification of intent to submit approximately 7 months in advance of the planned submission date.
Proactively scheduling these steps will help ensure a smoother review process and reduce the risk of administrative delays.
Conclusion
Converting an NDA to MAA is far from a straightforward exercise, it demands substantial forward planning and dedicated resources. In the EU, most Marketing Authorisation Applications follow the centralized procedure, where a single application is reviewed by the European Medicines Agency for authorization across all EU member states. One indicator of the growing complexity is the sharp rise in EMA “clock stops”, periods when the formal review is paused while the applicant responds to the Agency’s questions. For centralised procedures, the average clock stop length increased from 168 days in 2019 to 198 days in 2021, with small and medium-sized enterprises (SMEs) experiencing even longer pauses, averaging 245 days in 2023 (EMA Annual Report 2023), likely reflecting the greater resource and staffing constraints these companies face when preparing submissions.
Navigating the EU Marketing Authorisation Application process demands early, strategic planning and a detailed understanding of the region’s unique regulatory expectations. Requirements such as Risk Management Plans, Paediatric Investigation Plans, and Environmental Risk Assessments, combined with proactive eligibility requests and timely notifications, can negatively impact timelines if not addressed well in advance.
With the right regulatory expertise guiding each stage, even complex EU-specific demands become manageable, ultimately accelerating the journey from submission to market authorization. Discover how Allucent’s team of regulatory consulting experts can support you in successfully navigating the complexities of Market Authorisation Application submissions. Regulatory Submissions | Allucent
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