Variations and post-approval procedures
A marketing authorisation keeps changing after it is granted. The holder submits each change to its terms as a variation, in a category set by the change's risk, and a review of an authorised medicine can narrow its indication, add a use or make a new study a condition of keeping the authorisation.
Why an authorisation is varied
Medicine developers are required to take account of technical and scientific progress and to keep updating the terms of their marketing authorisation, so that it reflects the current understanding of the quality, safety and efficacy of the medicine. To modify any aspect of its marketing authorisation, a company must submit a variation application to the European Medicines Agency (EMA) for that change and, where applicable, wait for its approval. The EU medicines regulatory system ensures that every post-approval change maintains the positive benefit-risk balance of the approved medicine, while enabling the updates a product needs throughout its lifecycle.
Variation categories
Variations are classified on a risk-based approach into three types:
- Type IA, minor changes with minimal impact, such as a change of the company's address or of the product name
- Type IB, minor changes requiring notification, such as agreed safety updates
- Type II, major changes, such as a new indication
The European Commission's new Variations Regulation came into force in January 2025, and the Commission's new Variations Guidelines, published in September 2025 and developed with support from the EMA and the European medicines regulatory network, support its implementation. They apply to variation applications that marketing authorisation holders submit to the EMA from 15 January 2026, and holders should consult them and ensure they are prepared for the changes. To assist holders, the EMA undertook to publish updated and new procedural guidance by the end of December 2025, covering regulatory and procedural information on managing variations under the new classification system and how to make appropriate use of additional regulatory tools, such as the post-approval change management protocol (PACMP) and the product lifecycle management document (PLCM).
The new framework is part of the overall effort to improve the efficiency of the EU regulatory framework for human medicines, including medicines used in combination with medical devices, with the goal of delivering medicines to patients in the EU optimally and faster throughout their lifecycle. It also responds to the increasing number of variation submissions driven by scientific and technological advances in medicine development. The changes are part of the EU's broader pharmaceutical strategy and an intermediate step towards a more comprehensive reform of the pharmaceutical legislation.
Notification of type I variations
As the EMA described them in October 2014, type I variations were minor changes to the marketing authorisation, and type IAIN and IA variations had no impact on the quality, safety or efficacy of the medicine. A type IAIN variation had to be notified to the national competent authority or the EMA immediately following implementation, to ensure the continuous supervision of the medicine. A type IA variation did not require immediate notification, and should be notified to the national competent authority or the EMA within 12 months of implementation, or earlier in certain cases. A type IB variation had to be notified before implementation but did not require a formal approval, and once receipt of a valid notification was acknowledged, the holder had to wait 30 days, to ensure the notification was deemed acceptable, before implementing the change.
For 2014, the EMA advised holders to submit any type IAIN and IA variations by Friday 28 November wherever possible, so that it could acknowledge their validity within the 30-day timeframe set out in Article 14 of Commission Regulation (EC) No 1234/2008 before its closure from 24 December 2014 to 2 January 2015. Holders intending to submit type IB variations, or groupings of type IB and type IA variations, in December 2014 should contact the EMA by email before submitting, giving the name of the product, the intended submission date and the scope to be applied according to the Classification guideline.
Assessment timetable for type II variations
From March 2015 the EMA introduced weekly start dates for the assessment of most type II variations, including grouped and worksharing variations. The change was one outcome of the agency's structural reorganisation, begun in September 2013 to improve the efficiency and effectiveness of its operations, and it was expected to give applicants more flexibility and to streamline assessment by allowing certain variations to conclude outside the plenary meeting of the Committee for Medicinal Products for Human Use (CHMP).
Under this process, companies sent their applications according to weekly submission slots, assessment started weekly, and the CHMP adopted its opinion either outside or at its meeting, depending on the start date of the review. The assessment of responses to requests for supplementary information followed the weekly-start timetables too. The validation period between submission and procedure start, and the assessment timelines provided for in the legislation, remained unchanged. Linguistic review of product information changes for these variations continued to follow the monthly cycle starting five days after the CHMP's monthly plenary meeting.
Weekly starts did not apply to variations for which the European Commission had to amend the marketing authorisation within two months of the CHMP opinion, nor to variations involving the Pharmacovigilance Risk Assessment Committee (PRAC) or the Committee for Advanced Therapies (CAT), and these variations continued on the existing monthly-start timetables. The post-authorisation guidance on type II variations was revised to reflect the changes, and the weekly-start timetables were published on the agency's website.
Who at the agency handles a procedure
From 1 April 2014 the EMA began revised operations for type IA and IB variations, type II variations, periodic safety update reports (PSURs), and administrative procedures such as transfers, 61(3) notifications and corrigenda. The changes applied to new applications for these procedures submitted from that date, and for ongoing applications a controlled transition plan foresaw proactive and direct communication with applicants if and when changes occurred. The main change for applicants was a change of their EMA contact persons. Applicants were informed directly, by product and by procedure, if and when their contact person would change, and nothing changed before an applicant had been notified. The handling of all other evaluation procedures, including initial evaluation applications, remained unchanged for the time being, with their rollout planned for later in 2014.
The changes followed the agency's structural reorganisation from September 2013 and introduced a new operating model for managing medicines through their entire lifecycle, focused on scientific and procedure management. The model was designed to strengthen the regulatory science and procedural support that EMA staff give the scientific committees throughout a medicine's lifecycle, so that the committees can focus on their core expertise, the scientific assessment of medicines and the delivery of high-quality opinions, while the handling of applications is consistent and streamlined. It was also part of the agency's effort to streamline its internal processes so that increases in workload can be absorbed by existing resources.
Under the model, the product team lead concept was replaced by two roles:
- A Procedure Manager oversees all aspects of the management of specific procedures, ensures regulatory consistency at the EMA, is responsible for managing the regulatory process surrounding each application, provides guidance on regulatory procedural matters, and is the primary contact for applicants and for experts from the national competent authorities on that procedure.
- An EMA Product Lead (EPL) maintains oversight of a medicine as it moves through the stages of its lifecycle, is responsible for the overall knowledge about the medicine and the wider context of its therapeutic area, provides regulatory science input, and facilitates discussions within and between the EMA's scientific committees when needed.
A Procedure Manager is appointed at the start of a new application procedure and is the primary contact for applicants during the evaluation. For queries arising before an application is submitted, the EMA set up a dedicated service that applicants contact by email, operational from 1 April 2014 for all pre-submission queries on these post-authorisation procedures and to be expanded in scope over time. All the procedural changes were to be incorporated in the EMA's post-authorisation procedural advice for users of the centralised procedure, which would give applicants more detailed information, including how to use the pre-submission queries service for each evaluation procedure.
Reviews that narrow an indication
In June 2017 a review by the EMA concluded that the probiotic Symbioflor 2 and associated names could continue to be used to treat irritable bowel syndrome (IBS) in adults, but should no longer be used more widely to treat functional gastrointestinal disorders, a group of disorders with a variety of causes that may require different treatment approaches. Symbioflor 2 contains Escherichia coli bacteria and was first made available in Germany in the 1950s and subsequently in Austria and Hungary. The CHMP reviewed all available evidence on its effectiveness and safety, including clinical studies, scientific publications, post-marketing experience, information provided by the company and the views of an expert group formed to evaluate it. The review found no new evidence on its effectiveness since the product was last approved, the available evidence suggested that its risk of harm is low, and benefit had not yet been established in children with IBS.
Because the available data were not robust enough for the CHMP to conclude how well Symbioflor 2 works and whether it is effective for any particular type of IBS, the committee asked the company to carry out a well-designed study of effectiveness and safety among patients with different features of IBS, such as diarrhoea or constipation as an important feature. Submission of the study report to national authorities would be a condition for maintaining the marketing authorisation. The CHMP's recommendation was then sent to the European Commission for a legally binding decision valid throughout the EU.
Omega-3 fatty acid medicines containing a combination of an ethyl ester of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), taken by mouth at 1 g a day, had been authorised in several EU countries since 2000 for use after a heart attack in combination with other medicines, when the available data showed some benefits in reducing serious problems with the heart and blood vessels. The CHMP reassessed the evidence accumulated over the years on these medicines for this use and consulted additional experts, and concluded that, although there were no new safety concerns, the medicines' effectiveness in preventing recurrent problems with the heart and blood vessels had not been confirmed, and that their marketing authorisations should be updated to remove this use. In March 2019, after a re-examination requested by some of the companies that market the medicines, the EMA confirmed its recommendation of December 2018: the medicines should no longer be used after a heart attack, but can still be used to reduce levels of certain blood fats called triglycerides.
Extensions of an indication
In September 2020 the EMA recommended extending the indication of Velphoro (sucroferric oxyhydroxide), a phosphate binder, to the control of serum phosphorus levels in children aged 2 years or older with chronic kidney disease (CKD) stages 4–5 or with CKD on dialysis. Velphoro had been authorised throughout the EU since 26 August 2014, as 500 mg chewable tablets for use in adults only. The CHMP based its recommendation on an open-label, randomised phase 3 study in 85 children from 2 years of age with CKD and hyperphosphataemia, in which a large proportion of patients reached the normal phosphorus range after treatment, comparable to what was observed in adults, and the adverse reactions most frequently reported were gastrointestinal disorders, including diarrhoea, vomiting, gastritis and discoloured faeces. In the new indication Velphoro brings a significant clinical benefit compared with existing treatments. No phosphate binder was indicated to control serum phosphorus levels in children aged 2 to 6 years with CKD stages 4–5 who are not on dialysis. The medicine was also reformulated as a 125 mg powder for oral suspension, which is easier to give to small children. Following the recommendation, the summary of product characteristics, the package leaflet and the labelling were to be updated.
Also in September 2020, after reviewing results from the arm of the RECOVERY study that used dexamethasone to treat patients admitted to hospital with COVID-19, the CHMP concluded that dexamethasone can be considered a treatment option for patients who require oxygen therapy, from supplemental oxygen to mechanical ventilation. The EMA endorsed its use in adults and adolescents from 12 years of age and weighing at least 40 kg who require supplemental oxygen therapy, at 6 mg once a day for up to 10 days, taken by mouth or given as an injection or infusion into a vein. Dexamethasone is a corticosteroid that has been authorised in the EU by national medicines authorities and has been available for several decades. Companies that market dexamethasone medicines can request that this new use be added to their product's licence by submitting an application to national medicines agencies or to the EMA.
A holder's particulars after a change of jurisdiction
According to EU law, the marketing authorisation holder, the qualified person for pharmacovigilance (QPPV), the pharmacovigilance system master file (PSMF) and certain manufacturing sites need to be based in the European Economic Area (EEA) for a company to be able to market a medicine in the EU. For holders of centrally authorised products, the United Kingdom's withdrawal from the EU may imply changes to the marketing authorisation itself, such as a transfer of the marketing authorisation to a legal entity established in the EEA or a change of the QPPV or PSMF to a location in the EEA, as well as adaptations to their logistics, manufacturing sites, supply chains and contracts. Regulatory authorities and marketing authorisation holders both play an important part in preparing for the consequences of the withdrawal, to safeguard the continuous supply of human and veterinary medicines. Since May 2017 the European Commission and the EMA had informed companies of the need to put the necessary measures in motion, and had published and regularly updated information notices on legal issues and guidance on practical and simplified requirements for companies. Companies were reminded to plan for the withdrawal on 29 March 2019.
An EMA survey launched in January 2018 went to the holders of 694 centrally authorised products, 661 human and 33 veterinary, who were located in the United Kingdom or had quality control, batch release, import or manufacturing sites, or a QPPV or PSMF, there. It aimed to identify products potentially at risk of supply shortages and to obtain information on the timelines for submitting the necessary regulatory changes. By July 2018, the holders of more than half of the products, 58%, were on track with their regulatory planning to ensure that their marketing authorisation remains valid once the United Kingdom leaves the EU. For 108 of the products, or 16% (88 human and 20 veterinary), with manufacturing sites in the United Kingdom only, there were serious concerns that the necessary actions would not be carried out in time, and for 10% the EMA had received no feedback from the companies. The EMA was liaising directly with the holders that had not replied, or that did not plan to submit the required changes by 30 March 2019 and had manufacturing sites in the United Kingdom only, as this could potentially lead to supply disruptions. It also undertook to regularly monitor the submission of changes to the marketing authorisations of all 694 products, to check whether the relevant variations and notifications were being submitted, noting that the figures were likely to change as regulatory changes were submitted.