Scientific-advice routes beyond the standard procedure
Besides the standard European procedure, a developer can obtain scientific advice by several other routes: orientation for an innovative or unclassified product, evidence aligned with health technology assessment bodies, parallel advice from the European agency and the FDA, support for a medicine meeting an unmet need, advice informed by a biosimilar's data, qualification of a novel methodology, national advice, accelerated advice in a public health emergency, and support for repurposing by developers who will not file themselves.
In 2020 the European Medicines Agency was constantly updating its existing processes and launching new pilot projects to expand the options available further.
Early orientation for an innovative or unclassified product
The European Medicines Agency's Innovation Task Force is a forum for dialogue between regulators and developers of innovative emerging therapies, methods and technologies in the early stages of research and development, and is usually reserved for innovative medicines. The developer of an innovative product who runs into scientific, regulatory or technical questions can request a meeting with the task force. If the agency judges the request a good fit, it asks for a briefing document of around 30 pages setting out the product's properties and the questions the developer wants to discuss. It then holds a briefing meeting, by 2024 a virtual one, to which it invites experts from outside the agency to look at the product, and afterwards checks the applicant's report of the meeting against what was discussed. Because the meeting is a dialogue, the applicant can expect questions from the agency about its product. The meeting is informal and free of charge. One developer who used it found the process quite easy.
One developer who met the task force reports that many of the developers who use its meetings work on stem cell therapies, and that one bottleneck that always comes up is where the cells go once they are injected into the body. Deciding whether a product is a medicinal product or a medical device is not the agency's responsibility, so the task force could not settle one developer's classification question, though discussing it there helped the developer think it through.
In May 2019 the agency opened early dialogue through the task force to all medicine developers working on the treatment or prevention of bacterial and fungal infections. It did so because of the growing threat to public health from antimicrobial resistance and the need for new treatments, to help strengthen the development pipeline for new antimicrobials. Any new medicinal product for the treatment of a life-threatening or debilitating fungal or bacterial infection would be considered for discussion. The early, broad-ranging discussion between innovators and regulators was to help developers orient themselves and then use formal regulatory tools such as the agency's scientific advice. Interested developers were encouraged to submit a briefing meeting request form to discuss their development plans. The agency expected this early dialogue ultimately to contribute to prioritising and speeding up the development of antimicrobial medicines, in line with the European Parliament's resolution of 13 September 2018 on a European One Health Action Plan against Antimicrobial Resistance.
Parallel advice with health technology assessment bodies
In 2010 the European agency established a pilot for parallel scientific advice with health technology assessment bodies, so that developers could receive simultaneous feedback on their development plans for new medicines at an early stage from regulators and assessment bodies alike. The early dialogue aimed to facilitate agreement on a development plan that generates data both can use: the agency to determine a medicine's benefit-risk balance, and the assessment bodies to determine its value. The agency regarded this interaction as critical for innovation to reach patients and, ultimately, for public health.
In May 2014 the agency published, for public consultation, best-practice guidance for the pilot procedures. The guidance was a key outcome of a workshop in November 2013 attended by over 280 representatives of, among others, the European Commission, European regulators, assessment bodies, the European network for health technology assessment, industry, payers, patients and healthcare professionals, and the workshop's report was published with it. The draft guidance set out the phases of the process and the ideal timelines and actions for all parties, including the assessment bodies, the agency and the applicant. It was drafted with the assessment bodies, on the basis of the pilot's experience and the input stakeholders gave at the workshop. The chair of the agency's human medicines committee believed the guidance could be a major tool for medicines development, helping new medicines with a positive benefit-risk balance and expected added value reach patients faster and more transparently.
Comments on the proposed process were invited until 14 July 2014. The pilot was then still running, and the agency was also associated with a Commission-financed consortium exploring scenarios for conducting early dialogues on health technologies. The pilot's outcome, the consultation and the consortium's results were all to be taken into account in the EU-level exercise on early dialogue for health technologies.
In 2020 the agency and the European Network for Health Technology Assessment had offered since July 2017 a parallel consultation to help generate the evidence for a new medicine's marketing authorisation and its reimbursement at once. It gave the agency and the assessment bodies opportunities for mutual discussion, understanding and problem-solving. The network recruited the assessment bodies centrally, so the applicant did not have to contact each one. The consultation required a letter of intent and a briefing package that followed a common agency–network briefing document template.
Parallel advice from the European agency and the FDA
Parallel scientific advice is a voluntary request with which a sponsor receives concurrent feedback from the European agency and the FDA, particularly when submitting for the global market. It is meant to harmonise the two agencies' expectations and streamline drug development.
The European agency and the FDA set up their parallel programme in 2004 to encourage dialogue between them, but by 2020 its adoption had been limited by the significant administrative and logistical resources it demands of applicants. It may be especially relevant for important medicines for which no development guidelines exist or the agencies' guidelines differ significantly, and for products with significant clinical safety, animal toxicology or unique manufacturing challenges. The agencies can discuss the applicant's questions with each other and try to give convergent answers. Each agency's advice nevertheless remains independent and may differ from the other's, and each agency keeps its own decision-making authority over development issues and marketing applications.
In 2020 parallel advice required a request to both agencies, a letter of intent and a briefing package for the European agency, as for its scientific advice and protocol assistance, and a meeting package for the FDA.
PRIME support for a medicine meeting an unmet need
On 7 March 2016 the European Medicines Agency launched PRIME, its scheme for priority medicines, to strengthen support for medicines targeting an unmet medical need. The scheme focuses on medicines that may offer a major therapeutic advantage over existing treatments or benefit patients with no treatment options, and these medicines are considered priority medicines within the EU. Through the scheme the agency offers developers early, proactive and enhanced scientific and regulatory support. It builds on the existing regulatory framework and on tools such as scientific advice and accelerated assessment. PRIME is specifically designed to promote accelerated assessment, but it will also help make best use of the other EU early access tools and initiatives, such as conditional marketing authorisation and compassionate use, which can be combined whenever a medicine fulfils their respective criteria. The scheme is similar to the FDA's Breakthrough Therapy Designation.
The scheme's goal is to support and optimise medicine development so that patients whose diseases cannot be treated, or who need better treatment options, have access to new medicines. Through early engagement it aims to strengthen clinical trial designs to facilitate the generation of high-quality data for evaluating a marketing authorisation application. Early dialogue and scientific advice also ensure that patients take part in trials likely to provide the data a marketing authorisation application needs, and help make best use of limited resources.
To be accepted, a medicine must show its potential to benefit patients with unmet needs on the basis of early clinical data. The scheme is open to all companies on the basis of preliminary clinical evidence, but micro, small and medium-sized enterprises and academic applicants can apply earlier, on the basis of compelling non-clinical data and tolerability data from initial clinical trials, and may request fee waivers for scientific advice. Because these applicants often lack experience with the regulatory framework, they can benefit in particular from earlier scientific and regulatory advice. Entry to PRIME falls in the exploratory clinical trial phase, and pre-submission support is available to assess eligibility.
Once a medicine has been selected for PRIME, the agency:
- appoints a rapporteur from the human medicines committee, or from the advanced therapies committee for an advanced therapy, to give continuous support and help build knowledge ahead of the marketing authorisation application
- organises a kick-off meeting with that rapporteur and a multidisciplinary group of experts from the relevant scientific committees and working parties, and gives guidance on the overall development plan and regulatory strategy
- assigns a dedicated contact point
- provides scientific advice at key development milestones, involving additional stakeholders such as health technology assessment bodies to speed patients' access to the new medicine
- confirms the potential for accelerated assessment at the time of application
A key feature of the scheme is the kick-off meeting, a type of meeting unique to medicines eligible for it. Its aim is to agree next steps for addressing identified issues, or to identify issues to be discussed in scientific advice, or both. The rapporteur and the chairs and experts of the relevant committees attend, to ensure that every aspect of the medicine's lifecycle, risk management included, is discussed early. The agency published guidance for applicants on interactions under the scheme, covering the preparation and conduct of kick-off meetings, questions and answers, and the template for applicants' requests.
The scheme was developed in consultation with the agency's scientific committees, the European Commission and its expert group on safe and timely access, and the European medicines regulatory network, and its main principles went to a two-month public consultation in 2015, whose comments were taken into account in the final version. The agency released guidance documents on PRIME.
In May 2018 the agency reported that in its first two years the scheme had driven innovation and improved the efficiency of development in the therapeutic areas with the most pressing unmet medical needs. By then it had received and assessed 177 requests for eligibility and accepted 36 of them, a rate of 21 per cent. Requests came from a wide range of therapeutic areas, with oncology and haematology the largest share and notable submissions in infectious diseases, neurology and psychiatric disorders. The accepted medicines showed the scheme's focus on therapeutic areas where new medicines could be particularly beneficial: 83 per cent concerned rare diseases, 44 per cent were intended for paediatric patients and 40 per cent were advanced therapy medicinal products. A large proportion were being developed by small and medium-sized enterprises, which often lack experience of the regulatory approval process. Of the 36, 22 (61 per cent) had received scientific advice from the agency. The first three marketing authorisation applications for medicines in the scheme had also been filed and were under evaluation, with the first opinion expected later in 2018.
On 4 April 2023 the agency announced new features for PRIME to strengthen its support for medicines in areas of unmet medical need, following a review of the scheme's first five years. The agency states that the scheme enables earlier availability of life-changing medicines for patients. By the end of 2022, 26 medicines that had benefited from its support had received a positive recommendation for approval in the EU. The agency's review, a report it published in March 2022, looked at how the scheme helped developers prepare for marketing authorisation assessments, and found a positive impact on the authorisation of medicines that benefit patients with no treatment options or offer a major therapeutic advantage over existing treatments. It also called for further enhancement, including more flexible provision of scientific advice and help for applicants preparing for the marketing authorisation assessment. The new features were these:
- To optimise early scientific and regulatory support, each PRIME development was to get a roadmap and a product development tracker, both meant to support continuous dialogue between regulators and developer as progress was monitored and critical points for discussion were identified.
- Expedited scientific advice became available, starting as a 12-month pilot until March 2024, specifically for PRIME developments where issues arose in a programme that had already received comprehensive initial advice, so that applicants' queries could be answered in a shorter timeframe.
- Submission readiness meetings were to be held with the developer about a year before the marketing authorisation application is submitted. They were to discuss the status of the development, including how earlier regulatory advice had been implemented, and the data package intended to support the application. Prospective applicants would be expected to present mature plans for post-marketing evidence generation, as applicable.
All these features aim to facilitate and accelerate the generation of robust and relevant evidence for evaluating a marketing authorisation application, to give patients earlier access to transformative treatments.
Medicines the agency recommended with PRIME's support include Ebvallo (tabelecleucel) in October 2022, Casgevy (exagamglogene autotemcel) in December 2023, Winrevair (sotatercept) in June 2024, Vimkunya in January 2025, Aucatzyl in May 2025, Zemcelpro in June 2025 and Teizeild (teplizumab) in November 2025.
Advice informed by a biosimilar's data
On 16 December 2016 the European Medicines Agency announced a pilot, launching in February 2017, to test the added value and feasibility of tailored scientific advice on the development path of biosimilar medicines. It aimed to advise developers on the studies and tests they should conduct on the basis of the quality, analytical and functional data they already had. The pilot was expected to better support the stepwise development that EU guidelines recommend for biosimilars, in which the extent and nature of the studies and tests required depend on the level and robustness of the data already accumulated.
The standard procedure can advise on a proposed biosimilar development strategy but does not allow a formal assessment of data. Under the pilot, the available quality, analytical and functional data were to be reviewed in depth, and advice given on the data submitted, allowing more tailored recommendations on the studies and tests for the next step of development. An applicant could then decide its strategy with more information once sufficient quality data had accumulated. The review was not to be a formal pre-assessment of the data later submitted with the marketing authorisation application.
The pilot was open to any company seeking advice on any type of biosimilar. A pre-submission meeting reviewed whether the data package was suitable, and the agency's scientific advice working party needed an extra month beyond the normal timelines for requests accepted into it. The pilot was to run until six requests had been completed, with at most one accepted per month, after which the agency would analyse the outcome.
Qualification of a novel methodology
A dedicated scientific advice procedure, the qualification process, supports the development of a novel methodology in medicine development, such as the use of a new biomarker or clinical endpoint. It results in either qualification advice or a qualification opinion from the agency's human medicines committee. In qualification advice, the committee evaluates the scientific rationale and preliminary data and advises on protocols and procedures for developing the method further towards qualification. In a qualification opinion, it evaluates the submitted data and decides whether the method is acceptable for use in medicine development. Because knowledge of a new method can evolve over time, the process may involve an ongoing interaction between applicant and agency. The information is also shared with the scientific community for scrutiny and discussion before a qualification opinion is adopted, and the agency may afterwards amend the relevant guidance to take in the newly qualified method.
In 2020 a request for qualification advice or a qualification opinion required a letter of intent and a briefing package. Qualification advice also required draft protocols and development plans for future studies with supportive data, and a qualification opinion required protocols and study reports with supportive data.
National scientific advice
Scientific advice can also be requested from the national competent authorities of EU member states. National advice has the same general purpose as the European procedure, though its document requirements and timelines may differ. In 2020 national advice was usually faster than the European procedure, and it might offer more opportunities for discussion meetings, including, because of COVID-19, virtual ones. In 2020 selected national procedures had the following submission timelines and document requirements:
- Denmark wanted initial documents (application form, list of questions and, where possible, background to the questions, capped at 30 pages) at least two to three months before the proposed meeting date, and the final presentation, the final briefing document or both at least two to three weeks before the meeting.
- France wanted a meeting request usually two months before the proposed meeting date, and the briefing document at least three weeks before the meeting; the documents were a cover letter and a briefing document including background information, the list of questions with the applicant's position, and the investigator's brochure.
- Germany's BfArM, in its standard procedure, took the full package at the initial application; in its procedure with supplemental submission, it took the list of questions without documentation at the initial application and the documentation at least four weeks before the meeting. The documents were a signed cover letter, the signed application form, the list of questions and the list of meeting participants on its own forms, and a briefing document of at most 50 pages.
- Germany's Paul-Ehrlich-Institut wanted a request form eight to twelve weeks before the proposed meeting date and a briefing document of at most 40 pages at least three weeks before the meeting.
- The Netherlands wanted a meeting request (the application form with a draft list of questions) usually one and a half to three months ahead, and documentation, presentation and list of attendees at least three weeks before the meeting; the documents comprised the application form, the briefing document and the list of participants.
- Spain wanted a meeting request (the application form) usually two to three months ahead and, once the request was validated, documents at least 30 days before the meeting: a letter of intent, the list of questions and the applicant's position, and other relevant documents such as previous advice or reports, guidelines and references.
- Sweden wanted an application form with well-specified questions usually two to three months ahead, and full documentation at least three weeks before the meeting: a briefing document of at most 100 pages, the list of questions, the list of meeting participants, and other relevant documents such as references and the investigator's brochure.
- The United Kingdom wanted a meeting request (the application form with a draft list of questions) usually two to three months ahead, and final briefing documents at least ten days before the meeting: the final list of questions and the applicant's position, the presentation to be given at the meeting if applicable, and relevant appendices such as background information, previous advice and guidelines.
A pilot for simultaneous national advice started on 1 February 2020 to optimise resources and improve regulatory support when an applicant seeks advice from different national authorities, allowing contact with two of them at once. An optimised best-practice approach covering more than two was to be developed after an evaluation at the end of that year of the authorities' and applicants' experience with the pilot.
Accelerated advice in a public health emergency
On 8 February 2016, a week after the World Health Organization declared the Zika virus outbreak a public health emergency of international concern, the European Medicines Agency set up a task force of European experts in vaccines, infectious diseases and other relevant fields to contribute to the global response to the threat of Zika virus infection. The task force was available to advise on any scientific and regulatory matter in the research and development of medicines or vaccines against the virus. The agency encouraged developers with promising projects to make contact and said it would proactively reach out to companies already planning investigational vaccines and offer them scientific and regulatory advice. For an emerging viral disease such as Zika, existing mechanisms and tools can already help speed up the research and development of medicines and vaccines, and companies may seek the agency's scientific advice on the tests and studies their products need.
As with past threats such as Ebola, the agency set up accelerated procedures to speed up the development and approval of medicines and vaccines for treating and preventing COVID-19. They included a rapid advice procedure, available for initial marketing authorisation applications for new active substances and for applications to extend the indication of authorised medicines repurposed to treat COVID-19. It was free of charge, had no specific submission deadlines, and took only 20 days instead of the original 40 to 70, with more flexibility on the type and extent of the briefing package, agreed case by case.
Advice for repurposing by developers who will not file themselves
In October 2021 the European Medicines Agency and the Heads of Medicines Agencies launched a pilot to support the repurposing of medicines, following discussions in the Commission's expert group on safe and timely access on a proposed repurposing framework. It aimed to help not-for-profit organisations and academia gather or generate sufficient evidence on an established medicine's use in a new indication for that use to be formally authorised, as a way of making new treatment options available to patients.
Marketing authorisation holders may develop medicines for other indications, but they sometimes lack the incentive or commercial interest to pursue the research, development and regulatory process needed to authorise a new indication for old medicines no longer protected by a patent or data exclusivity. That could be a wasted opportunity for public health. Academic institutions and patient organisations may be interested in that development for the benefit of public health, but they may lack the regulatory experience and have no intention of becoming authorisation holders.
Through the pilot, the agency and the national agencies offered not-for-profit organisations and academia regulatory support, primarily scientific advice, to build a data package for a new indication of an established medicine that is robust enough for a later application by a company. The pilot focused on conditions with few or no authorised medicines, or with high morbidity or mortality despite available medicines. A candidate medicine was to contain a well-established active substance, be authorised and out of data exclusivity, market protection and patent protection, and target an indication in a condition distinct from those already authorised, in an area where important public health benefits are likely. COVID-19 repurposing was excluded, because the development and authorisation of COVID-19 treatments is coordinated by the agency's COVID-19 pandemic task force.
The pilot was to run until scientific advice for the selected projects was complete, and optimally until a company filed for the new indication, and a report was to be published afterwards.