Guidance updates Archives | European Regulatory Affairs Specialists

ERA at TOPRA 2025: Tailored development of biosimilars without efficacy and safety studies – is this the future?

3rd October 2025

With growing experience and coverage of the biosimilar market, regulatory strategies must evolve to balance scientific rigor with the need for efficient development.

One of the currently most debated topics in the biosimilar arena is the potential waiver for traditional efficacy and safety studies, a move that could significantly reduce development timelines and costs.

This session focused on the increasing interest in shifting the emphasis to establish similarity mainly based on CMC comparability data, as opposed to relying on results from comparative clinical efficacy trials (CES).

The session explored the scientific rationale behind using robust CMC evidence as the cornerstone of biosimilar approval, while addressing concerns regarding the adequacy of clinical data.

Experts in CMC presented their views on how advanced manufacturing technologies, analytical techniques, and product characterization can generate the necessary evidence to support a waiver for extensive efficacy and safety studies. These experts shared insights on how consistent manufacturing and comparability of biosimilars can be sufficiently demonstrated through state-of-the-art analytical methods, highlighting the potential for regulatory flexibility in this area.

On the other hand, clinical specialists provided arguments from a clinical point of view, discussing the feasibility and concerns about the lack of efficacy and safety data in these developments. They examined the implications of waiving clinical trials, particularly in terms of patient safety, real world outcomes, and public confidence in biosimilars.

By bringing together experts from both the CMC and clinical fields, this session provided a comprehensive, balanced view of the challenges and opportunities in biosimilar development.

Points to note:

There is 20 years of experience now in EU (both Industry and Regulators)

Are Clinical efficacy studies (CES) still needed?

Analytical tools are more sensitive to detect differences than CES.
CES can not always contribute relevantly to decision making and could not solve PK issues
Trials can cost $100-$300 million dollars
Biosimilar void is coming (many products off patent soon with no generics in development)
Regulators are getting ready for less clinical data to make decisions (when appropriate)
You do need a comparative PK study, supportive safety/immunogenicity data, CES may only be needed to answer outstanding scientific questions
Quality and Non-clinical evidence grounded in comparability (ICH Q5E) – better knowledge of mode of action today than before

EMA/CHMP/BMWP/60916/2025 (Reflection paper – https://www.ema.europa.eu/en/reflection-paper-tailored-clinical-approach-biosimilar-development)

EMA/CHMP/138502/2017 (Reflection paper – https://www.ema.europa.eu/en/documents/scientific-guideline/reflection-paper-statistical-methodology-comparative-assessment-quality-attributes-drug-development_en.pdf – use it for discussion and clarification with Regulators. It won’t always be applicable to your product)

Impacts on potency (discussion in dossier required), Critical Quality Attributes (CQA) risk ranking approach (examples given on how to justify)
Quality of Reference Product can differ over time and so needs to be monitored by R&D, PK/PD study data becomes essential when CES is excluded.
Protein quantity similarity assessment is necessary
PK/PD could be used to supplement immunogenicity data requirements (via better assays)
Ask Regulators not to get bogged down in differences that don’t matter (convince them in your submission)

EMA perspective:

Quality data has evolved
Reflection paper on statistics is a tool box of options (not a requirement).
Industry should use Quality data as appropriate.
Immunogenicity topic is still under discussion at EMA.
Structural analysis needs to be robust, guideline for biosimilars is being developed.

Q&A:

Discuss CES requirement with EMA in scientific advice – Application must be mature enough to allow for Regulator advice, see reflection paper – Approach them after batch manufacture once you can see how things are aligning
Prescribers may need help to accept Biosimilars approved without CES.
IPRP workshop was valuable (https://admin.iprp.global/sites/default/files/2024-07/IPRP_BWG_Final%20IPRP%20Scientific%20Workshop%20Summary%20Report_2024_0506.pdf)
Wider community is pretty open to waivers, follow-up with NCA initiated (Reflection paper).
WHO guidance is already followed by many countries and also mentions CES waiver.

Written by

Alice D’Alton

Alice Dalton 1

ERA at TOPRA 2025: Session 8 – Human – ePI is on Fire! (I mean FHIR !!)

1st October 2025

This session focused on the regulatory implications and readiness strategies for the implementation of electronic Product Information (ePI) based on the HL7 FHIR® standard.

As outlined in the EU pharmaceutical strategy and reinforced by EMA’s digital initiatives, the structured, interoperable ePI format will play a critical role in improving the accessibility, reliability, and lifecycle management of product information.

Regulatory authorities and marketing authorisation holders must prepare for changes in submission formats, review procedures, and data governance models.

The session provided an overview of current status of the EU ePI project including linking to ePI from EU medicine packages, regulatory frameworks, and anticipated timelines.

Practical insights were shared on how regulatory professionals can adapt internal processes and evaluate IT infrastructure needs to ensure compliance and facilitate the seamless integration of FHIR-based ePI into existing regulatory operations.

Points to note:

Guidance on PLM portal (incl style guide). ePI pilot report available. Reflection paper published Q2-2025. You Tube videos. Quarterly system demos ongoing
Free software from regulators via PLM portal. Pilot showed it took just 4 hours for a company to create ePI from scratch using these tools
Technology used is the FHIR common standard for healthcare data exchange. Harmonised EU approach. PLM portal storage and access (FHIR repository)
User testing would still be required in some form in future
Better supply chain management for industry
73% of delegates at this session said their company have not implemented any ePI process yet
ePI will be submitted as additional material alongside word and pdf version for assessment (for a while)
Once ePI is approved it is put into the central repository and then is available to the patient for download
Go live for CAPs and early adoption NCA is planned soon (ePI type 1) – likely with New legislation implementation (~2028) – implementing act may have more specific information to clarify ePI requirements
What does the future look like?: ePI type 4 is under development (ePI 2 & ePI 3 exist but not implemented). ePI type 5 is in the idea stage
ePI is already implemented in other jurisdictions so EU needs to catch up

Written by

Alice D’Alton

Alice Dalton 1

ERA at TOPRA 2025: Session 6 – Human – How AI is Transforming Regulatory Approaches towards CMC

30th September 2025

This session explored the transformative role of Digital tools including Artificial Intelligence (AI) in enhancing Chemistry, Manufacturing, and Controls (CMC) processes within the pharmaceutical industry.

As AI technologies continue to advance, their integration into CMC activities offers exciting opportunities to streamline development, optimize manufacturing, and improve regulatory decision-making.

Points to note:

The Quality Innovation Group (QIG) supports the development of new technologies throughout the product lifecycle. They want to collaborate with as many groups (regulators) as possible to avoid silos (contact qig@ema.europa.eu)
Revision of EU GMP guide Annex 11, 22 and Chapter 4 ongoing (all under stakeholder consultation – comments by 7th October)
New Annex 22 does not cover Generative AI or Large Language Model (LLM). Detailed overview of the requirements and expectation were presented
UK: Centres of Excellence for Regulatory Science and Innovation (CERSIs) & MHRA – Regulatory science and innovation network. They are looking at the regulatory challenges that are slowing the adoption, and realising of the full potential of, digital tools so they can be used in lieu of generating new data. Using VERA (virtual assistant) to find and review content of documents they already have

https://www.gov.uk/government/news/mhra-showcases-next-phase-of-regulatory-science-to-bring-innovative-treatments-to-patients-sooner

Digital CMC sandbox for testing digital tools in a safe place
Industry perspective: using models whenever possible and LLM, GenAI, Deep Learning (DL), Neural Network (NN) for e.g. visual inspection on production floor, Machine Learning (ML).
EMA/90634/2024 guidance – decision tree under consultation
Risk management approach to AI (EU AI act)
ISPE guideline 2025 – use in parallel with GAMP 5 (2022)
Panel discussion: Models already used in manufacturing for years, AI is an evolution of digital tools already being used (not a revolution)
AI being used to generate annual product reviews, analysis of trends.
Regulators are exploring possibilities of using AI for CMC review (there is potential)
Industry needs Regulators around the world to accept the data generated or it will not be cost effective to implement process modelling technology
Training will be critical

Written by

Alice D’Alton

Alice Dalton 1

ERA at TOPRA 2025: Session 5 – Human – Programme COMBINE – Clinical Trials with Medicine + Medical Device

30th September 2025

This session looked into opportunities and challenges with application procedures when performing a combined clinical trial in Europe, that involves a medicinal product and an in vitro diagnostic (IVD), or companion diagnostic (CDx) and/or a medical device (MD) component.

The clinical trial application for the medicinal product is submitted under the Clinical Trial Regulation (CTR) via CTIS, while the device/diagnostic follows different national procedures.

An update on the COMBINE project was provided.

The device regulation (MDR and IVDR) has introduced major changes and has been suggested as a contributing factor to the decrease in the number of clinical trials in Europe.

The European Commission and EU Member States have launched the COMBINE initiative to propose solutions for combined trials (drug using a device in a clinical trial), specifically looking at the interplay of IVDR, MDR and CTR, also identified as one of “most important issues” by stakeholders ACT-EU workplan ‘25-’26.

The panel discussion explored whether the proposed solutions stemming from this highly welcomed initiative are already demonstrating benefits. It also offered concrete strategies to ensure the European clinical trial ecosystem is well-suited to promote the conduct of clinical trials in Europe.

Points to note:

Guidance will be published but in the meantime please seek scientific advice
The COMBINE project team would like to see devices included in the Regulatory sandbox concept
There are 8 applications in the pilot phase of COMBINE already
UK involvement in the project could be beneficial in order to manage the complex requirements currently in place for Northern Ireland and to encourage clinical trials to be located there.

Written by

Alice D’Alton

Alice Dalton 1

ERA at TOPRA 2025: Session 4 – Human – Revision of the EU variation Regulation

30th September 2025

The EU variation Regulation was updated in March 2024 and the new Detailed guideline for classification of variations [last dated from 2008, last update 2013] was published this month.

Nevertheless, this is the first step, limited by the current legislation, and a second step is awaited after the new EU general pharmaceutical regulation is in force (expected 2028).

The current European Commission updates simplify the requirements and procedures, modernise the framework, adapt the rules for grouping and work-sharing, adapt the classification for some products, reduce administrative burden, and implement a risk-based approach.

This session presented an overview of the original goals of the revision, the new changes in the management of post-approval changes; including a comparison of the previous and proposed classifications with statistics and impact for both regulators and industries in term of volume of variations being generated.

The session discussed opportunities to continue re-inventing both submission policies and processes for post-approval changes in the EU for centrally and nationally registered products.

Points to note:

Second revision will come with implementation of new Directive ~ 2028 and will aim to reduce the number of Type IA variations
Reinforcement of Annual Reporting and now mandatory worksharing (e.g. Update RMP, ASMFs, CEPs, etc.) discussed
Supergrouping can now include NAPs and Type IA variations
Worksharing (WS) now includes CAP, MR/DC and NAPs. New Declaration in eAF. Letter of Intent required.
MEB have seen significantly increased in WS applications. MEB is seeing a decline in IB variations already. Supergrouping applications have also increased in NL.
EMA Q&As are being compiled and will be published in Q4 2025 (e.g. Stability testing, classification of changes, skip/periodic testing, PLCM, etc.). More Q&As planned for Q1 2026
SPOR (referential lists) and eAF/PLM updates to follow
EMA encourages the use of the Change Management Protocol and hope to see it used more in future
Mandatory worksharing should be useful for both industry and Regulators, to increase efficiency and get faster approvals for multiple MAs
EMA allows the grouping of related IA and IAin despite the fact that variation regulation does not technically allow this (and it is not allowed for MR/DC), new guidance should help to clarify
Article 5 recommendations will remain as an option for variations that are not included in the new regulation
ICH Q12 should be reviewed in conjunction with new regulation and guidance

Written by

Alice D’Alton

Alice Dalton 1

ERA at TOPRA 2025: Session 3 – Human – Applying Artificial Intelligence in Real-Life

30th September 2025

Artificial Intelligence has already been a hot topic in numerous workshops, conferences, symposia and more in the past years. This session focused on questions such as:

How is it actually being applied in pharmaceutical development and regulation?

Where has it made the most impact in the field?

The session put aside the high-level discussions on what is possible with AI and discussed the real-life examples of where AI is already making a difference.

Points to note:

Auto dossier was presented and Demo shown of how it can automate CTD building
Collaborare: Unleashing the power of
patient voices using AI. This was presented and showed how patient voices can be added to decision making with AI tools
The Paul-Ehrlich Institut presented their ICSR processing tool and its benefits
The EMA presented its Signal detection tool and it benefits
Large Language models are routinely used today by industry and regulators to aid decision making and streamline their processes leaving more time for analysis and less time spent on admin, data collection and sorting
The AI workplan to 2028 is published – ‘Data and AI in medicines regulation
Fears of error introduced by AI was tempered by asking why we expect 100% accuracy from AI when humans do not output 100% accuracy all the time either
AI guidance from EMA will be principles based to future proof it as much as possible. Reflection papers will be followed by guidance in time

Written by

Alice D’Alton

Alice Dalton 1

ERA at TOPRA 2025: Session 1 – Human – General Pharmaceutical Legislation – Sandbox

29th September 2025

This session explored key elements of the EU General Pharmaceutical Legislation (GPL) that aim to foster innovation and accelerate patient access to new treatments. Key focus included Platform Technology approaches and Regulatory Sandboxes.

By bringing together perspectives from patients, regulators, legislators, academia and industry, the discussion highlighted how these regulatory tools can support cutting-edge pharmaceutical development and manufacturing while keeping the EU region competitive and attractive for innovation.

This session provided a comprehensive regulatory and scientific perspective on how these approaches can drive the future of pharmaceutical development in Europe, ensuring faster access to innovation while maintaining regulatory scientific robustness.

A regulatory sandbox is a controlled framework that allows the testing of an innovative development in a controlled environment for a limited period of time.

The creation of a regulatory sandbox might be necessary when it is not possible to develop a medicinal product unless targeted adaptations or derogations to certain requirements are applied, under direct supervision of the relevant competent authorities.

The EC legal proposal is still under discussion with the Parliament and Council, and a final decision on inclusion of the Regulatory Sandbox in the EU pharmaceutical framework has not yet been reached.

However, as part of the Agency’s monitoring horizon scanning on future innovative products, informal ITF meetings with medicine developers may help to identify, at an early stage during development, potential case studies that could inform a regulatory sandbox approach in the future (if endorsed by the co-legislators). These meetings are:

Early informal dialogue between medicine developers and regulators to gather information
Not a pre-assessment of product eligibility for a future regulatory sandbox approach or any other procedure.

https://www.ema.europa.eu/en/human-regulatory-overview/research-development/innovation-task-force-briefing-meetings#how-to-apply-76207

Points to note:

Foreseen for MAA only at present
R&D with Industry, Regulators, Patients and Academia involved
Masterfile concept
Patent protections to be considered in advance

Written by

Alice D’Alton

Alice Dalton 1

Type IA Annual Reporting in the UK

13th May 2025

Following on from our News Article: “You need to apply Type IA Annual Reporting in the EU in 2025” we can further advise that the MHRA has also adopted the EU changes in relation to Type IA variations for UK products.

This means that the MHRA do also require the submission of Annual Updates for Type IA variations, and these should be submitted nationally, unless the Type IA variations are submitted as part of a group with other variations applied for via the International Recognition Procedure (IRP).

IRP Variations:

You can use IRP during the lifecycle of UK products that have been initially authorised or subsequently varied via standalone;

National route
Decentralised and mutual recognition reliance procedure (MRDCRP) route
European Commission (EC) Decision Reliance Procedure (ECDRP) route

Conversely, where a product has been authorised via IRP, it is acceptable to submit standalone national post-authorisation procedures, including variations.

Variations submitted via IRP should be classified according to MHRA guidance on variations to MAs. To facilitate lifecycle management of the MA, variations should be submitted as soon as possible after approval by the Reference Regulator (RR).

The MHRA will be publishing updated guidance on Annual Updates very shorty. So, watch this space for a more detailed overview when it becomes available.

Written by

Fiona Downey

Fiona Downey 1

You need to apply Type IA Annual Reporting in the EU in 2025

15th April 2025

The Type IA Annual Update, also known as the “Annual report”, is a single submission of all the Type IA variations (not requiring immediate notification) which have been implemented during the previous twelve months.

The Annual report should be submitted as close to 12-month deadline as possible, but ultimately no earlier than 9 months and no later than 12 months after the first implementation date of the Type IAs included in the report.

Meaning of implementation for type-IA variations:

For quality changes, ‘implementation’ is when the company makes the change in its own quality system.

This implementation date must be carefully planned and recorded to facilitate submission of your Annual Reports.

How to plan the submission of your Annual Report:

As submission of the Annual report is dependent on the implementation of the first type IA variation, its submission date can change every year.

It is very important to note that the Type IA Annual report must fulfil the variation conditions for grouping (or super-grouping if it concerns more than one marketing authorisation).

It is expected that Type IA variations included in an Annual report will not be rejected. However, if rejected, Type IA variations from the annual report can be resubmitted as individual Type IAs immediately (outside of an annual report).

CMDh confirmed that although not specified in their guidance, Type IA variations implemented before 1 January 2025 can still be submitted as single type IA variations according to the current rules. The EMA confirmed that Type IA variations implemented in 2024 and not submitted to the Agency by 31 December may also be submitted by MAH no later than 12 months after implementation.

Therefore, Type IA variations implemented from 1 January 2025 should be submitted as part of the Annual report.

Type IAs can still be submitted outside the Annual report in the following cases:

If they are part of a grouped Type IB or Type II variation
If they are part of a super-grouping variation
If it involves the resubmission of a Type IA variation previously refused in the Annual report (12-month reporting period is criteria in this situation)
In exceptionally cases which should discussed and agreed with the EMA/NCAs.

eAF:

There are no current plans to amend the eAF to reflect Annual Reporting, instead, Applicants are advised to include a note in the cover letter and an additional note in the eAF scope to clarify that the application relates to the Annual Update of Type IA variations e.g. as foreseen in the updated Cover letter template:

<Annual update of type IA variation(s)

[X] We confirm that the annual update is submitted within 12 months following the implementation of the first type IA variation applied for in this notification. Implementation date of the first type IA variation: >

If you need any assistance with planning and submission of your Annual Reports, contact us and we will be happy to help.

Written by

Fiona Downey

Fiona Downey 1

Back to Basics – The Decentralised Procedure (DCP)

17th June 2024

We continue our back to basics series for those who may be new to Regulatory Affairs (If you need help with the jargon visit our A-Z Glossary of Regulatory abbreviations).

In the EU, there are two different procedures available to apply for a marketing authorisation application (MAA) for the same medicinal product in more than one Member State at a time:

the Decentralised Procedure (DCP)
the Mutual Recognition Procedure (MRP).

This Article focuses the Decentralised Procedure (DCP).

The DCP is only applicable if no marketing authorisation has previously existed in the EU/EEA, as per Directive 2004/27/EC and if an identical dossier is submitted simultaneously in all selected Member States.

To prepare for a DCP submission:

Establish a Reference Member State (RMS).
- One Member State called the RMS will be selected by the Applicant to lead the assessment of the MAA.
- To do this, complete a “Request for RMS in a Decentralised Procedure” Form and send it to your preferred RMS at least 2 months before the planned date of submission of the marketing authorisation application.
- Only one RMS request can be submitted at a time. It is advisable to establish an RMS as soon as possible as DCP slots get booked up very quickly.
- The guidance, Decentralised Procedure – Requests to act as RMS, provides an overview of the booking system & links to the various National Competent Authorities who act as RMS
Prepare a dossier in accordance with the current legislation and EU guidelines.
Check that the requirements for submissions for new Marketing Authorisations are met for the various Member States to avoid validation comments (at Day -14) and also for any additional requirements to determine if any wet/original/notarised signatures are required
Ensure the correct fee amount has been paid.
Check the dossier for common validation issues raised by the RMS and the CMSs in DCP procedures to prevent them being requested during the validation of your application.
The applicant then simultaneously submits an identical dossier to the RMS and all CMS by the agreed submission date booked with RMS.
The application will be submitted via CESP portal, according to eCTD Guidelines, & then applicant will send any hard copies/original documents required by various Member States as per national requirements.

Assessment Reports (Day 70, D120, Day160, D210):
- The RMS is responsible for preparing an Assessment Report (AR) which summarises the dossier presented by the applicant. The AR characterises and critically evaluates the medicinal product concerned with regard to its quality, safety and efficacy.
- This AR will be made available to all Concerned Member States (CMS) together with SmPC, PL and labelling by the RMS and forms the basis for the evaluation by CMS.
- In the case a Member State concerned by the procedure is unable to accept the AR or draft AR on the basis of a “potential serious risk to public health”, the application will be sent to the CHMP for arbitration.
End of Procedure can be in 90-210 days after validation phase is closed.
It is advisable to plan the national translations in time. It is critical that the translation service used is reliable and technically competent to translate medical text.
Seven calendar days after end of procedure the Applicant should send high quality national translations of SmPC, PL and labelling and mock-ups to individual CMSs.
There is usually a 30-day National assessment before of the granting of the MA, however the timelines differ in each MS.
If consensus is not reached at the end of the procedure, a pre-arbitration (CMDH) and arbitration (CHMP) phase may take place.

We can help you to do all of the above or even better we can do it for you – to save you time and money let our experienced team take the pain out of it for you.

Written by

Marian Winder

ERA at TOPRA 2025: Tailored development of biosimilars without efficacy and safety studies – is this the future?

ERA at TOPRA 2025: Session 8 – Human – ePI is on Fire! (I mean FHIR !!)

ERA at TOPRA 2025: Session 6 – Human – How AI is Transforming Regulatory Approaches towards CMC

ERA at TOPRA 2025: Session 5 – Human – Programme COMBINE – Clinical Trials with Medicine + Medical Device

ERA at TOPRA 2025: Session 4 – Human – Revision of the EU variation Regulation

ERA at TOPRA 2025: Session 3 – Human – Applying Artificial Intelligence in Real-Life

ERA at TOPRA 2025: Session 1 – Human – General Pharmaceutical Legislation – Sandbox

Type IA Annual Reporting in the UK

You need to apply Type IA Annual Reporting in the EU in 2025

Back to Basics – The Decentralised Procedure (DCP)

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