Euro Roundup: EMA finalizes reflection paper on biosimilar comparative efficacy studies

The European Medicines Agency (EMA) has finalized its reflection paper on a tailored clinical approach to biosimilar development, revising the wording on when it may waive the need for comparative efficacy studies (CES).

Last year, EMA released the draft biosimilar reflection paper for consultation and held a meeting focused on the topic. The agency received 400 comments. EMA said the feedback was broadly supportive, with many respondents recognizing the need to update the rules to reflect the agency’s biosimilar experience, advances in analytical technologies, and international convergence toward more efficient pathways.

Respondents told EMA that its proposed approach is scientifically well justified, noting that analytical technology is more sensitive than comparative clinical data at detecting differences during biosimilarity assessment. Reduced reliance on CES can shorten development timelines and improve patient access to biosimilars, respondents said.

EMA revised the paper's conclusion based on the feedback. The final text now concludes that EMA no longer expects CES to approve biosimilars that can be thoroughly characterized using state-of-the-art analytical methods and that have demonstrated similarity in physicochemical and functional properties. EMA added that it expects the tailored approach to apply to most biosimilars.

While the feedback supported the high-level changes, some respondents flagged the need for clarification or elaboration on several points. EMA identified expectations for robustness of the analytical similarity assessment when pharmacokinetic and immunogenicity studies are sufficient, and alignment with international efforts, as areas needing improvement.

The agency has clarified some details in response to the feedback. In the draft, EMA said, “a sufficient number of biosimilar batches needs to be tested.” The final version adds that, in most cases, six or more batches originating from independent drug substance batches are sufficient.

EMA also said in the final paper that, in general, at least 10 reference medicinal product (RMP) batches should be included in the similarity assessment, down from 15-30 batches in the draft. The agency retained the 15-30 range in the final text but said it is optimal in many cases, rather than generally appropriate.

Reflection Paper

UK MHRA posts batch of clinical trial guidelines

The UK Medicines and Healthcare products Regulatory Agency (MHRA) has published multiple clinical trial guidelines, including advice on how International Council for Harmonisation (ICH) documents will be affected by upcoming legislation. Amended UK clinical trial regulations take effect on 28 April.

One document addresses compliance with ICH E6 good clinical practice (GCP) guidelines, while another covers quality and risk proportionality and is intended to be read alongside ICH E8 (R1).

As part of the Brexit process, the UK is replacing an approach based on EU legislation with ICH E6 GCP principles. MHRA said compliance with the principles will be a legal requirement on 28 April. The agency expects sponsors of active trials to assess the impact of the GCP updates on their studies and justify any deviations from the new requirements.

The other MHRA guideline explains the need for study sponsors to apply ICH E8 (R1) and E6 (R3) when planning, conducting, and overseeing clinical trials. MHRA expects sponsors to define critical quality factors before or during protocol development and to communicate any risks they identify to investigators and service providers as appropriate. 

MHRA also published clinical trial guidance on statistical considerations, investigators' responsibilities, biological safety assessments, electrically powered devices, applying to run studies, approving clinical investigations, compiling submissions, and running studies in Great Britain and Northern Ireland. 

MHRA Guidance

EMA opens pharmaceutical quality system effectiveness pilot for applications

EMA has begun accepting applications from marketing authorization holders (MAHs) and manufacturers interested in participating in a pharmaceutical quality system (PQS) effectiveness pilot project.

An EMA working group is running the pilot to assess how the effectiveness of a site’s PQS for risk‑based change management can be demonstrated. The pilot will also evaluate whether the good manufacturing practice (GMP) certificate can serve as the primary evidence of PQS effectiveness, which, in January, became a requirement for using additional regulatory tools introduced under the revised variations framework.

Through the pilot, inspectors will assess site change control and change management processes against the EU Guide to GMP requirements. Assessments will take up to one day when no routine inspection is needed. Areas of focus will include the company’s overall approach to change management and how change management is documented within the site PQS.

Inspectors will use a Pharmaceutical Inspection Co-operation Scheme (PIC/S) PQS paper to support the facility's routine inspection. EMA wants companies to familiarize themselves with the paper before their inspections.

Manufacturers in the European Economic Area (EEA) can nominate themselves to participate in the pilot. MAHs can nominate EEA-based sites if a planned variation submission for a Product Lifecycle Management document relies on the manufacturer's PQS. Some sites, such as those that make cell and gene therapies, are ineligible for the pilot.

The nomination windows close in December, with inspections being performed through February 2027.

Pilot Page

EMA seeks feedback on plans to fix shortcomings of ALS clinical trial guideline

EMA has released a draft consultation paper setting out its intent to address issues with its guideline on amyotrophic lateral sclerosis (ALS) clinical trials.

The agency published the ALS guideline in 2015. Since then, researchers have developed new diagnostic criteria and tools for patient phenotyping. The standard of care has evolved, and divergence between drugs approved in the EU and other regions has raised questions about new trial design. Experience has also shown EMA that its advice on methodological aspects of trials needs updating.

EMA set out the issues in a draft concept paper. The agency proposed addressing the problems by updating the guideline, including adding recommendations on eligibility criteria and stratification factors, discussing the use of biomarkers, and detailing new diagnostic criteria. EMA foresees the ALS guideline achieving a high-level consensus on the evaluation and standardization of R&D plans.

The agency is accepting feedback until 30 September. Based on the responses, EMA plans to release a draft guideline for consultation by the first quarter of 2027.

Concept Paper

Other news

EMA is fully implementing an orphan device program after a successful pilot project. The program allows manufacturers and notified bodies to receive free support on orphan devices from expert panels. Expanding beyond the pilot, EMA will accept applications for all product classes covered in the 2024 guidance on the clinical evaluation of orphan devices. EMA Notice

The Swiss Agency for Therapeutic Products (Swissmedic) has published a set of questions and answers on the risk management of human medicinal products. The new document supplements existing guidance by answering frequently asked questions on topics including drug safety signals, periodic safety update reports, and risk management plans. Swissmedic Q&A

EMA has released a draft pediatric addendum to its pulmonary arterial hypertension (PAH) guideline. The draft highlights differences between adult and pediatric PAH and discusses their impact on clinical development programs, including when and how companies can extrapolate between the populations. EMA is accepting feedback on the draft until 30 September. Draft Addendum

MHRA has shared guidance on its alignment with the National Institute for Health and Care Excellence (NICE). The document explains how drug developers can use the MHRA-NICE-aligned pathway to get new medicines to patients three to six months sooner. MHRA Guidance