Support for innovative medicines’ development at the EMA level
Introduction
At the European Union level, the European Medicines Agency is the regulator responsible for giving market access to medicines according to the centralised procedure, including Advanced Therapy Medicinal Products (please see entry 'Standard Marketing Authorisation Pathway: Centralised Procedure'), and regulating medicines that are manufactured at the industrial scale and intended to be placed on the European market in accordance with the European Union pharmaceutical legislation. Therefore, the services and regulatory procedures designed to establish an early contact between developers and the European Medicines Agency share the aim of clarifying what are the applicable regulatory requirements for medicinal products to obtain a centralised marketing authorisation. Early knowledge for regulatory compliance will support the development of new and innovative medicinal products through establishing as soon as possible the best strategies of development to obtain the required data (robust quality, pre-clinical, and clinical data) for their commercialisation in the European Union. Selecting as early as possible the studies to obtain the required regulatory data will allow to save time and resources, both being particularly challenging for innovative medicines.
The different mechanisms put into place by the EMA are of two kinds: services and procedures. First of all, the EMA innovation Task Force briefing meetings, the SME office and the quality innovation group are services provided by EMA to support medicines’ developers. Second of all, EMA supports the development of new and innovative medicines through regulatory procedures: scientific advice and protocol assistance, and the PRIority MEdicines scheme (so-called ‘PRIME’).
These services and procedures target the development of all innovative medicines. They are not specifically designed for ATMPs, even though ATMPs can also benefit from them.
Stakeholders
European Medicines Agency: The European Medicines Agency (EMA) is an agency of the European Union whose goal is to protect and promote human and animal health. The agency is responsible for the scientific assessment of Advanced Therapy Medicinal Products to be marketed within the European Union and the European Economic Area, including in the context of expediting marketing authorisations pathways. The Agency provides a number of incentives and procedures for medicines’ developers to support market access of quality medicines with a positive benefit/risk balance as regards as their safety and efficacy criteria for the final safety and health protection of patients.
Medicines’ developers: Actors of the health sector finding new treatment options and bringing new medicines to the market, after authorisation. Medicine developers are the target of early interaction with regulators such as the European Medicines Agency (EMA). Medicines’ developers can be academia industry, or non-profit organisations although they are generally from the industry sector (mainly big pharma but also SMEs) given the resources necessary for the commercialisation of medicines.
Seeker of interaction: A medicines’ developer interested in a specific procedure established within the European Medicines Agency to foster early interaction between regulators and stakeholders with the purpose to facilitate the development of marketable medicines.
Services to support medicines’ development through early interaction with EMA
Innovation Task Force: The innovation Task Force is a multidisciplinary group that is part of the European Medicines Agency. One of its purposes is to provide a discussion platform on scientific, regulatory, and legal issues of innovative medicines such as ATMPs, with medicines’ developers. More on the Innovation Task Force on the EMA website here.
SME office: The Small and Medium Enterprise office was set up by Article 11 of the Commission Regulation (EC) No 2049/2005. The office is dedicated to helping Small and Medium Enterprises (SMEs) to develop medicines and meet the European Union necessary administrative and legal requirements. The office provides support to companies registered as SMEs. Find more information on the SME Office on the EMA website here.
Quality innovation group: A group composed of experts in the field of quality assessment of chemicals, biological medicines (including Advanced Therapy Medicinal Products), and good manufacturing practice inspections. It was designed to help developers from an early stage of the product’s life cycle and unable discussions with various stakeholders (including ad hoc experts and academia, EU assessors and inspectors, international regulators, industry, and academic associations, working parties and groups such as the EU Innovation network) on innovation and innovative development. The group supports the use of innovative methodologies to develop medicines, such as innovative technologies, novel materials and devices, and digitalisation in manufacturing. Find more information on this group on the EMA website here.
Regulatory procedures to support medicine’s development through early interaction with EMA
Committee for Medicinal Products for Human Use: The Committee for medicinal products for human use (CHMP) is responsible for Human medicines at the European Medicines Agency, especially regarding the centralised marketing authorisation procedure. Furthermore, the committee also plays a key role in the development phase of medicines by advising developers through mechanisms of early interaction between EMA and stakeholders. It is charge of giving scientific advice for ATMP developers or Protocol assistance for the development of orphan medicines as well as on final decision on PRIME eligibility requests, on the basis of the recommendation of the Scientific Advice Working Party, and of the recommendation of the Committee for Advanced Therapies where ATMPs are concerned.
Scientific Advice Working Party (SAWP): The working group was set up by the CHMP. It is dedicated to providing scientific advice and protocol assistance to developers. It is involved in the choice of the PRIME requests. Therefore, the group is one of the major organs for early interaction between the EMA and stakeholders. More on SAWP on the EMA website here.
Committee for Advanced Therapies (CAT) at theEuropean Medicines Agency: The Committee for Advanced Therapies (CAT) notably contributes to scientific advice, in cooperation with the SAWP, where Advanced Therapy Medicinal Products are concerned. More on CAT on EMA website here.
Innovative medicine: A medicine that contains an active substance or combination of active substances that has not been authorised before. (Completed from EMA Glossary of Regulatory terms here.)
Early interaction: Possible contact with regulators early on in the development process of a medicinal product by a stakeholder, mostly at the research and development phase. For instance, different types of early interaction exist to establish contact with EMA. They vary depending on the type of product, the seeker of interaction and the need for interaction and the moment in the medicines’ development life cycle when the interaction is looked for.
Services to support medicines’ development through early interaction with EMA
ITF briefing meetings: The briefing meetings of the ITF are designed to facilitate informal dialogue, between regulators and stakeholders, on issues they encounter during the development of a medicine, including Gene and Cell therapy medicines. This type of early interaction completes other more formal procedures for early interaction such as ATMPs classification and certification, designation of Orphan medicines and scientific advice. The ITF meetings typically last 90 minutes. More on ITF briefing meetings on EMA website here.
Listen-and-learn focus group meetings of the Quality Innovation Group: Meetings holds by the QIP “with stakeholders from industry, academia and international regulators to hear about the regulatory challenges developers face in relation to innovative products, processes, control strategies and facilities, and to identify potential solutions together". More on the EMA website here.
Regulatory procedures to support medicines’ development through early interaction with EMA
Scientific advice and protocol assistance: Scientific advice is a form of early interaction provided by the EMA to answer specific questions at any stage of a medicine’s development. Different types of scientific advice exist; the choice of the applicable procedure depending on the type of medicine produced. Therefore, EMA offers scientific advice on medicine repurposing, for biosimilars, for medicines intended for a disease, causing public health emergency. The advice is set to give the developer recommendation on the appropriate studies and tests required in the development of a medicine. More on scientific advice and protocol assistance on EMA website here.
PRIME: PRIME is a regulatory scheme created to support the development of PRIority MEdicines. It was set up in March 2016. Prime targets all types of medicines that have a real benefit over existing ones, or ones that give a possibility for patient without treatment options and therefore fill in an unmet medical need. The goal of the scheme is to help the developers during the early stages of the product’s life cycle regarding scientific and regulatory issues; the final aim always being for patients to access the product promptly. The PRIME scheme is available for all medicines if they meet the criteria to be classified as priority medicines, even though one in two medicinal products using this scheme is an ATMP. The scheme helps developers to gather robust data on the medicines’ benefits and risks as well as optimise development plans, and to enable accelerated assessment of PRIority MEdicines. It uses the already existing regulatory framework for scientific advice and accelerated assessment. More on PRIME on EMA website here.
Challenges
The services and procedures put in place by EMA are designed to help developers to enter into early contact with the agency and overcome the challenges a developer may encounter when trying to bring an innovative medicine on the European Union market. Therefore, EMA is organising its support in accordance with the needs of the developers. The issues faced may vary with the types of medicines being developed or the methodology used, and this requires a case-by-case approach that is offered by the various schemes proposed for early interaction.
Another challenge to consider is the status of the medicines’ developer targeted as the various schemes are not always available for all types of stakeholders, given that they sometimes depend on different legislative requirements or incentives, and they are not necessarily involved in the same stage of the medicines’ development life cycle. EMA needs to adapt the support to the different actors involved all with the goal of fostering research and the development of new medicines to enable patient’s access to innovative medicines, in accordance with the applicable legislative provisions. In such context, SMEs have less resources to be dedicated to regulatory issues in particular, while academia has often considered to be far from the EMA given its main focus on proof of concept, pre-clinical and clinical studies in the early part of medicines’ life cycle.
Apart from finding new ways to allow dialogue between EMA and developers which is one of the main challenges faced by EMA taking into account its limited human resources, communicating on the existing procedures and services available to support the development of medicine is also fundamental. Despite the organisation of events by EMA, such as stakeholders’ meetings, its very complete website, and its participation in congresses, many stakeholders have no full knowledge of the available tools for early interactions with EMA. Moreover, the complexity of implementing legislative and regulatory requirements to innovative medicines as well as to develop appropriate guidance remain an inherent challenge to the development of these products.
Opportunities and incentives
EMA created several early interaction procedures to accompany medicine developers into navigating the legal requirements at any stage of a medicinal product life cycle, especially in order to obtain and maintain marketing authorisation. The available procedures for early interactions between stakeholders and regulators are meant to foster early patient’s access to medicines. For instance, medicines with granted marketing authorisation using the PRIME scheme are consistently experiencing a reduction of the clock-stop duration during the assessment of their applications for marketing authorisation.
They are mostly regulatory tools that help manufacturer to enter into contact with regulators. For example, EMA designed the procedures described to support the development of new medicines, or new indications, and research and development coming from smaller enterprises.
The European Medicines Agency tries to foster new ideas coming from SMEs and academia through these procedures for early interaction. The aim is to help developers navigate the complex regulatory landscape to enhance the product’s chances to be manufactured and to access the market later on, especially to have medicines available for unmet medical needs. Some procedures are available at waivered or lowered costs depending on the type of developer asking to enter into early contact with the EMA or the type of medicine developed.
Some incentives may be designed for a specific type of medicine developer facing more challenges in bringing medicines to the market such as SMEs and Academia. For instance, the services provided by EMA can be divided into two types, the ones providing informal discussion to maybe detect needs for a formal interaction on scientific or regulatory issues faced by the developers, with briefing meetings of the innovation office and the quality innovation group. The second type is a support given to SMEs.
Finally, it should be highlighted that early interaction with EMA do not only help to clarify questions regarding the regulatory pathway to market of innovative medicines, it also contributes to ensure EMA awareness and preparedness for the appropriate evaluation of medicines, including the most recent developments and state of scientific knowledge in innovative medicines.
Practical steps
Services for early interaction with EMA for innovative medicines’ developers
Innovation Task Force briefing meetings
ITF briefing meetings are free of charge. They can be requested at any time. Nevertheless, most of the meetings are organised during early stages (proof of concept) of medicines’ development.
How to apply
For general information on the briefing meetings visit the ITF page on EMA’s website
Applicant sends ITF briefing meeting request form (available on the ITF page on EMA’s website) , to ITF Secretariat via EudraLink (the EMA’s secure file transfer system) or email to ITF Secretariat:
Submit the following documents via IRIS once ITF briefing meeting is confirmed
Short presentation (3 slides in total) for presentation by the ITF Coordinator to the relevant EMA Scientific Committee containing:
Description of product (e.g., structure/technology/method);
Mechanism of action, use in drug development;
Key topics for discussion
Full presentation and list of participants (for the ITF BM)
ITF briefing meeting
After the ITF briefing meeting
The applicant provides a draft of the meeting report within 10 days of the meeting following the template sent by email with the topics discussed, a participants list and the outcome of the discussion.
Expert review
Final report shared by ITF on IRIS upload within 2 to 4 weeks
Specific procedures for early interaction for SMEs
SME support
SME office
The EMA has put in place an office with “dedicated administrative structures and specific procedures” for Small and Medium Enterprises (SMEs).
The SME Office has a number of designated tasks:
“to give advice to applicants on the administrative and procedural steps necessary to comply with the requirements laid down in Regulation (EC) No 726/2004”
“to ensure the appropriate monitoring of all requests and applications submitted by the same applicant and related to a particular medicinal product;”
“to organise workshops and training sessions for applicants on the administrative and procedural steps necessary to comply with the requirements laid down in Regulation (EC) No 726/2004.”
More information here on the SME Office on the EMA’s website.
SME Status
The SME status is required for a company to be able to benefit from the incentives of the SME office. The companies must apply for SME status with the SME office.
To acquire the SME status, conditions must be fulfilled:
The company must be a registered company in a Member State of the EU or the European Economic Area.
And the company must meet the definition of an SME:
Less than 250 employees AND annual turnover not more than 50 million euros
or Balance Sheet total not more than 43 M euros.
(Article 1 and Article 2 of the Commission Recommendation 2003/361/EC of 6 May 2003 concerning the definition of micro, small and medium-sized enterprises)
More information on how to apply for a SME status on the EMA’s website here.
Regulatory procedures for early interaction with EMA for innovative medicines’ developers
Scientific advice and Protocol assistance
Medicines’ developers may ask the EMA for scientific advice/ protocol assistance regarding the development of a specific medicine. One of the EMA’s roles is "advising undertakings on the conduct of the various tests and trials necessary to demonstrate the quality, safety and efficacy of medicinal products" (Article 57-1 (n) of Regulation (EC) No 726/2004 of the European Parliament and of the Council of 31 March 2004)
The advice/assistance is given by the CHMP following the recommendation of the scientific advice working party, and the CAT for ATMPs. Although scientific advice or protocol assistance is not legally binding, how it was followed by the developer is considered when assessing a marketing authorisation application. The developer will have to explain the reasons why they did not follow the advice given to them through the early interaction procedure.
EMA charges a fee for scientific advice/protocol assistance. Its amount varies according to the scope of the advice. Reductions or full waivers are possible for certain types of medicines (e.g., orphan medicines, PRIME products) and applicants (e.g., SMEs, academia). More information on fees payable to the EMA here.
All types of stakeholders can benefit from scientific advice for all the different types of medicines and methodologies listed above except for Medicine repurposing which is reserved for sponsors from Academia and non-profit organisations. Therefore, for medicine repurposing the eligibility for scientific advice depends not only on the type of medicine but also on the status of the developer asking to enter into contact with the EMA.
Registering on EMA’s secure online platform IRIS
Use EMA’s secure online platform IRIS to request scientific advice or protocol assistance. The process is common to all of the types of scientific advice and to protocol assistance.
Requesting “preparatory meetings”: Preparatory meetings from EMA for scientific advice
The aim: Formerly known as “Pre-submission meetings”, preparatory meetings may be used for different reasons, to get feedback on the development plan, feedback on the questions, identifying other issues, get detailed information on the scientific advice procedure, regulatory questions outside the scope of scientific advice, establish contact with Agency staff.
Target: First time users of the mechanism, SME’s, general advice on specific types of products such as complex medicines.
How: The meetings are held via teleconference since September 2018.
More information on scientific advice and protocol assistance are available here.
PRIME: PRIority Medicines scheme
Who
All types of seekers of interaction but special incentive for SMEs and Academia to support interaction demands from developers.
For SMEs, they should acquire the SME status through the dedicated office following criteria and steps listed above.
For Academia, they should meet the academia definition. To be considered as Academia the seeker of interaction wishing to have early interaction with EMA through the PRIME scheme needs to be:
A public or private higher education establishments awarding academic degrees
A public or private non-profit research organisations whose primary mission is to pursue research
Or an international European interest organisations as set out in Commission Regulation (EU) No 1290/2013 of 11 December 2013.
Applicants should not be financed or managed by private profit organisations in the pharmaceutical sector (“PPO”), nor should they have concluded any operating agreements with any PPO concerning their sponsorship or participation to the specific research project for which a fee exemption is sought for scientific advice under the PRIME scheme
PRIME is available to sponsors engaged in the exploratory clinical trial phase of development, as the applicants need to give preliminary clinical evidence.
Nevertheless, earlier support is provided for SMEs and Academia, who generally have less resource and experience on regulatory aspects. They can request an Early Entry PRIME Status “if:
compelling non-clinical data in a relevant model provide early evidence of promising activity, or proof of principle;
first-in-human studies indicate adequate exposure for the desired pharmacotherapeutic effects and tolerability”. (See the EMA’s website here)
Further data will be expected later on for granting full PRIME designation for SMEs and Academia.
Submit a request for eligibility to the PRIME scheme on the IRIS platform following the steps listed above, there is no fee applicable to submit a request
For PRIME eligibility request, send the following documents through the platform:
The Applicant’s justification based on the template (this should be submitted in MS Word format): Follow the template by giving a concise but comprehensive account of the research developed of not more than 30 pages. The document should explain why the medicine developed is a priority one by meeting an unmet need and therefore how the product is of Major Public Health interest.
Literature references cited in the justification (this should be appended in a zip file)
Review of the application to enter the PRIME scheme
The EMA has to confirm the request fits into the scope of the scheme.
A member of the SAWP and an EMA scientific officer (for ATMPs, CAT Rapporteur and CHMP co-ordinator) are appointed as reviewers of the request, and they will give reports on the request.
By day 30, the reports will be sent to the SAWP and the CHMP for comments. If the medicine developed falls into the category of an ATMP, the CAT will also review the request and give a recommendation to the CHMP.
The CHMP is the organ responsible for giving the outcome of the requests.
By day 40, The CHMP final recommendation will be adopted.
If an applicant receives a positive outcome, it means the product is eligible to benefit and enter the PRIME scheme.
All of the submission deadlines and timetables for the PRIME scheme are published on the EMA website here.
Commission Regulation (EC) No 2049/2005 of 15 December 2005 laying down, pursuant to Regulation (EC) No 726/2004 of the European Parliament and of the Council, rules regarding the payment of fees to, and the receipt of administrative assistance from, the European Medicines Agency by micro, small and medium-sized enterprises (Text with EEA relevance), OJ L 329, 16.12.2005, p. 4–7, CELEX number: 32005R2049
Commission Recommendation of 6 May 2003 concerning the definition of micro, small and medium-sized enterprises (Text with EEA relevance), OJ L 124, 20.5.2003, p.36-41, CELEX number: 32003H0361
It should be highlighted that the current proposal to reform the EU pharmaceutical legislation is planning to anchor the PRIME procedure at the legislative level for products that are likely to address an unmet medical need; are orphan medicinal products and are likely to address a high unmet medical need; are expected to be of major interest from the point of view of public health, in particular as regards therapeutic innovation, taking into account the early stage of development, or certain antimicrobials. (See in particular article 60 of the Proposal for a Regulation of the European Parliament and of the Council laying down Union procedures for the authorisation and supervision of medicinal products for human use and establishing rules governing the European Medicines Agency, amending Regulation (EC) No 1394/2007 and Regulation (EU) No 536/2014 and repealing Regulation (EC) No 726/2004, Regulation (EC) No 141/2000 and Regulation (EC) No 1901/2006, COM/2023/193 final.)
Toolbox guidance on scientific elements and regulatory tools to support quality data packages for PRIME and certain marketing authorisation applications targeting an unmet medical need, 22 April 2022 EMA/CHMP/BWP/QWP/IWG/694114/2019 Committee for Human Medicinal Products (CHMP)
