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A new member within EIPG


The European Industrial Pharmacists Group (EIPG) is pleased to announce the Romanian Association (AFFI) as its newest member following the annual General Assembly of EIPG in Rome (20th-21st April 2024). Commenting on the continued growth of EIPG’s membership, EIPG President Read more

The EU Parliament voted its position on the Unitary SPC


by Giuliana Miglierini The intersecting pathways of revision of the pharmaceutical and intellectual property legislations recently marked the adoption of the EU Parliament’s position on the new unitary Supplementary Protection Certificate (SPC) system, parallel to the recast of the current Read more

Reform of pharma legislation: the debate on regulatory data protection


by Giuliana Miglierini As the definition of the final contents of many new pieces of the overall revision of the pharmaceutical legislation is approaching, many voices commented the possible impact the new scheme for regulatory data protection (RDP) may have Read more

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EMA’s reflection paper on AI in the pharmaceutical lifecycle

September 22, 2023 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,

by Giuliana Miglierini

The rapidly evolving role of artificial intelligence (AI) and its possible application in the pharmaceutical field led the European Medicines Agency (EMA) to publish a draft Reflection paper on the use of AI along the entire lifecycle of both human and veterinary medicines.

The Reflection paper summarises the current view on the possible use of AI and machine leaning (ML) technologies and is open to public consultation until 31 December 2023. Comments, together with the outcomes of the joint HMA/EMA workshop to be held on 20-21 November 2023, will support its finalisation, as well as the possible development of new guidance. The initiative aims to identify the aspects of AI/ML use that would fall within the remit of EMA or of the single National Competent Authorities (NCAs) in charge of the dossiers’ assessment.

The document is part of the effort to improve the European Medicines Regulatory Network’s capability in data-driven regulation set forth by the joint HMA-EMA Big Data Steering Group (BDSG), and it has been developed in coordination with EMA’s CHMP and CVMP committees.

“The use of artificial intelligence is rapidly developing in society and as regulators we see more and more applications in the field of medicines. AI brings exciting opportunities to generate new insights and improve processes. To embrace them fully, we will need to be prepared for the regulatory challenges presented by this quickly evolving ecosystem” said Jesper Kjær, Director of the Data Analytics Centre at the Danish Medicines Agency and co-chair of the BDSG.

“With this paper, we are opening a dialogue with developers, academics, and other regulators, to discuss ways forward, ensuring that the full potential of these innovations can be realised for the benefit of patients’ and animal health” added Peter Arlett, EMA’s Head of Data Analytics and Methods, co-chair of the BDSG.

The main contents of the Reflection paper

The Reflection paper addresses the use of AI/ML with a dedicated chapter for each one of the steps, part of the overall lifecycle of a medicinal product. The interactions with regulators are then explored, as well as the different technical aspects to be taken into consideration. The final chapters discuss the governance of AI/ML applications, the integrity, and ethical aspects to be considered and how to address data protection.

The increasing use of AI technologies is based on the wide availability of big amounts of data produced and captured in electronic format on a routine basis. This data can be analysed by machine learning algorithms to inform the training of other systems able to analyse data and take actions with some degree of autonomy in order to achieve specific goals. These latter systems are the truly intended AI algorithms, those use is under discussion also in the field of regulatory decision making.

The Reflection paper recalls how the diffusion of these new technologies carries with it also some new risks, due to the “exceptionally great numbers of trainable parameters arranged in non-transparent model architectures”. Measures should thus be taken to ensure the safety of patients and the integrity of data, as well as to avoid the integration of bias into AI/ML applications.

The contents of the Reflection paper may also refer to combinations between a medicinal pro-duct and AI/ML-including medical device, as in such occurrence EMA is involved in the assessment of the characteristics of the device.

In general terms, existing guidelines, best practices, and recommendations relative to model in-formed drug development and biostatistics also apply to AI/ML; the adjacent methodology guidelines which may be relevant to this instance are listed in the document. The Reflection paper warns readers about the differences between the human and veterinary regulatory domains, suggesting that another reflection document specific for veterinary may be developed in future.

A risk-based approach

The usual risk-based approach typical of pharmaceutical development should be used to identify risks throughout the entire AI/ML tool lifecycle, including regulatory impact. According to the Reflection paper, the level of risk may depend also on the context of use and the degree of influence the AI technology exerts.

Developers should always seek early regulatory interaction and scientific advice, especially in cases where the AI/ML system may impact on the benefit-risk ratio of the medicinal product un-der development. To this instance, the EMA Innovation Task Force (ITF) is responsible for pro-viding early interaction on experimental technology, while scientific advice and qualification of novel methodologies in medicines development is provided by the Scientific Advice Working Parties (SAWP) of the CHMP for human medicines and of the CVMP for the veterinary ones.

As for all other steps of pharmaceutical lifecycle, the final responsibility for the suitability and use made of AI/ML algorithms, as well as their compliance to ethical, technical, scientific, and regulatory standards (GxP standards) and to current EMA scientific guidelines falls under the Marketing Authorisation Holders (MAHs) or applicants.

According to the Reflection paper, risks referred to in the discovery step may be limited, but they may impact the final evidence presented for regulatory review, thus principles for non-clinical development should be followed. This second step may include, for example, AI/ML modelling approaches according to the 3R principles. Regulators would expect to receive Standard Operating Procedures (SOPs) for AI/ML applications in preclinical studies; advisory documents on Application of GLP Principles to Computerised Systems and GLP Data Integrity should be also considered where appropriate. A pre-specified analysis plan would be needed for preclinical data potentially relevant for the assessment of the benefit-risk balance.

In the field of clinical trials, ICH E6 and VICH GL9 on human and veterinary GCPs should also be applied to the use of AI/ML. In particular, regulators expect the full model architecture and description of the data processing pipeline would be made fully available for comprehensive assessment should a model be generated for clinical trial purposes, as they would be considered parts of the clinical trial data or trial protocol dossier.

From precision medicine to pharmacovigilance

Particular considerations may be needed for applications of AI/ML in precision medicine, to individualise treatment according to the patient’s characteristics. AI/ML application supporting indication or posology decisions should be referenced in the Summary of product characteristics and their assessment falls under medicines regulation, representing a high-risk use both from the patient and regulatory perspectives. Close human supervision is also expected for AI applications used to draft or translate product information documents.

Many are the possible applications of AI/ML in the manufacturing of medicinal products, where they should follow the usual quality risk management principles (ICH Q8, Q9 and Q10) to guarantee safety, quality, and data integrity. New recommendations are also expected from EMA.

In the post-authorisation phase, AI/ML tools can effectively support efficacy and safety studies and post-marketing surveillance studies for veterinary medicines, as well as pharmacovigilance activities. Good pharmacovigilance practices should always be respected, and the used model should be validated, monitored and documented under the responsibility of the MAH. For conditional marketing authorisations, AI/ML applications should be discussed within a regulatory procedure unless details are agreed already at time of authorisation.


EMA, new features for the PRIority Medicines (PRIME) scheme

May 19, 2023 , , , , , , , , , , , , , , , , , , , , , , , , , , ,

By Giuliana Miglierini

Based on the review of results obtained in the first five years of implementation of the PRIority Medicines (PRIME) scheme, the European Medicines Agency has launched a set of new features to further enhance the support to developers of new medicinal products in areas of unmet medical needs (see the revised guidance for applicants seeking access to PRIME scheme).

The guideline complements contents of other documents, i.e. EMA’s Guidance on accelerated assessment, the guidance on the preparation of the PRIME kick-off meeting and submission readiness meeting, the one specific for applicants seeking scientific advice and protocol assistance, and the toolbox guidance for robust CMC data packages.

The new set of measures to speed up approval

The major goal of the PRIME scheme, introduced by EMA in 2016, is to accelerate the regulatory pathway for new medicines seeking approval and that may have a high impact on severe conditions currently lacking treatment options. The scheme aims to facilitate the generation of robust data packages supporting the compliance to regulatory requirements for all aspects of development and production of a new medicine.

A critical aspect to ensure efficiency of this process is the ability to build a constructive and continuous dialogue between regulators and sponsors, fundamental for the continuous monitoring of development activities. To this regard, EMA will establish a new roadmap for each PRI-ME development, that will parallel and complement the already existing product development tracker. The combination of the two should allow the optimisation of early scientific advice and regulatory support provided by EMA committees. It should also facilitate the prompt identification of critical aspects and emerging issues in the development, requiring further discussion between regulators and sponsors to positively solve them.

Should issues occur with a specific programme that has already received comprehensive initial advice, EMA is now entitled to provide expedited scientific advice specifically for PRIME developments. The new approach will be tested in a one-year pilot project started in March 2023. Requests of expedited scientific advice have to meet some criteria: the request is a follow-up advice, subsequent to the initial scientific advice procedure; it refers to issues with a specific, well-defined scope; and its urgency has to be justified, in comparison to standard scientific ad-vice timelines. The PRIME Scientific Coordinator is the first point of contact for sponsors to discuss these requests, which have to be submitted via IRIS, as well as all other issues referred to the PRIME scheme.

The pilot phase also includes the new roadmap and tracker to replace the previous PRIME annual update for any products that have not yet been discussed in a Kick-off meeting. Contents of both the roadmap and development tracker are detailed in the updated guidance.

Submission readiness meetings are the third new measure introduced by EMA. The meetings will serve as the final checking point to assess the status of development, with respect to the implementation of the regulatory advice previously provided by the Agency, and the resulting data package intended to support the MA application. Mature plans for post-marketing evidence generation should also be presented, as needed. Applicants are expected to start organise the submission readiness meeting approx. 15 months prior to the intended MAA submission date; the meetings should occur approx. 9-12 months prior the same date. Confirmation of eligibility to accelerated assessment should be checked 2-3 months before submission of the MA application.

Key features of PRIME scheme

At the end of 2022, the PRIME scheme supported the development and final recommendation for approval for 26 medicines. Sponsor can voluntarily file an application to access the scheme, providing evidence the eligibility criteria are met, in particular with reference to a potential major public health interest. These include conditions for which there is an unmet medical need in prevention, diagnosis or treatment, a new therapeutic method is introduced providing significant benefit over the existing ones or bringing a major therapeutic advantage to patients in a given indication.

The PRIME scheme articulates its support through different actions along the planned pathway. Depending on the type of medicinal product under development, the early appointment of a Rapporteur from the Committee for Medicinal Products for Human Use (CHMP) or the Committee for Advanced Therapies (CAT) allows for the discussion of all preparatory aspects of the ap-plication from both a technical and scientific perspective. Opinions may be also provided by other relevant EMA’s Committees and Working Parties, as needed.

Sponsors can also benefit from an initial Kick-off meeting with all the above-mentioned regulators and experts, to obtain preliminary guidance on the overall development plan. Key development steps subject to future scientific advice and the recommended regulatory strategy should be addressed during this meeting.

Special provisions are set forth to facilitate access to the PRIME scheme for SMEs and academic applicants. Upon demonstration of proof of principle, these may be granted Early Entry PRIME status, allowing for introductory meetings to raise awareness on regulatory requirements, and provide early advice on the overall development plan and relevant milestones. The requested proof of principle should be based on compelling non-clinical data in a relevant model providing early evidence of promising activity, and first-in-human studies indicating adequate exposure for the desired pharmacotherapeutic effects and tolerability.

Advice on the generation of proof of concept data is also provided at this stage by the EMA pro-duct team, and it must be fulfilled in order to confirm transition to full PRIME eligibility. In this instance, appointment of the CHMP/CAT Rapporteur is also activated.

The main steps of the procedure

Upon a first checking of acceptability of the application and related documentation, a Scientific Advice Working Party (SAWP) reviewer and a EMA scientific officer are appointed (plus a CAT reviewer in case of advanced-therapy products), and sponsors are informed of the start of the procedure and expected timelines. The SAWP committee should provide its comments to the reports by day 30, followed by final adoption by CHMP by day 40. A flowchart describing the criteria to determine eligibility is reported in Annex 1 of the guideline. The opinion of the CHMP is followed by the issuing of a letter detailing the reasons for the positive/negative decision. The outcomes of the CHMP meetings including discussions of PRIME developments are published as part of the highlights on the monthly adopted recommendations.

The confirmation of eligibility to the centralised procedure triggers the appointment of the CHMP Rapporteur, according to the specific procedure. A letter of intent to submit an MAA (approximately 6-7 months prior to submission of the MAA) is also requested.

In the case of SMEs accessing Early Entry PRIME, the appointment of the Rapporteur follows the generation of data confirming eligibility at proof of concept stage. SMEs or academic applicants also benefit from a full fee waiver for scientific advice or follow-up requests.

The Kick-off meeting is usually scheduled around 3-4 months after granting of the PRIME eligibility; submission of relevant background information and a detailed regulatory roadmap is requested to applicants in order to prepare the meeting.


A new joint work plan to 2023 for EMA and EUnetHTA 21

April 29, 2022 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,

by Giuliana Miglierini

The new Regulation (EU) 2021/228 on Health Technology Assessment (HTA) will assume full validity in January 2025, at the end of the 3-year transition period. To this instance, it is time to define the actions needed to establish the new framework for HTA in the field of medicinal products.

A central point of the new approach is represented by joint scientific consultations (JSCs) to be carried out in coordination between the European Medicines Agency (EMA) and the bodies entitled of HTA at the level of single member states.

After the termination of the European Network for Health Technology Assessment (EUnetHTA) initiative, in 2021, the new consortium EUnetHTA 21 has been created grouping thirteen HTA agencies from The Netherlands, Spain, Italy, Austria, Germany, France, Portugal, Belgium, Ireland, Hungary and Norway. EUnetHTA 21 signed a contract service in 2021 with the Health and Digital Executive Agency (HaDEA) for the provision of joint health technology assessment up to September 2023.

On this basis, EMA and EUnetHTA 21 have now published a joint work plan of the activities to be put in place until 2023; the initiative represents the continuation of the EUnetHTA Joint Actions, started in 2010 and concluded in May 2021.

The document identifies the priority areas of future collaboration between regulators and HTA bodies at European level, with the final goal to “improve efficiency and quality of processes, whilst respecting the respective remits of different decision makers, and ensure mutual understanding and dialogue on evidence needs”.

The transition to the new legislative framework shall be based on a flexible approach to the different tasks; the work plan includes both methodological and operative actions, and it will be monitored in close cooperation with the EU Commission. Progresses will be discussed during the four bilateral meetings planned until September 2023.

Under the new framework, high priority HTA activities related to the service contract will be delivered by EUnetHTA 21. Other voluntary activities can be actioned through individual HTA bodies from a European (EU/EEA) member state that expressed their interest to participate. Should this be the case, the work plan clarifies that the position is that of the individual HTA body, not of EUnetHTA 21. A public consultation on deliverables part of the EUnetHTA’s mandate is also planned.

Actions in support of JSCs

Joint scientific consultations are the core of the new approach to HTA, aimed to generate a robust evidence relative to the entire life cycle of medicinal products, including the post-licensing and launch.

The work plan establishes a new European process of “parallel joint scientific consultation” involving both HTA bodies and EMA, that will take the place of the current procedures of parallel scientific advice, parallel consultation and early dialogue. This action shall make available a single assessment process, reflecting both regulatory and HTA’s needs.

Interested parties can apply to access the EMA/EUnetHTA parallel JSC procedure; a joint guidance on how to apply and the dates of EMA’s Scientific Advice Working Party (SAWP) meetings are available at the dedicated page of the Agency’s website, together with the template of the parallel consultation briefing document and submission deadlines. The joint guideline also provides details for applicants on how to respond to a EUnetHTA 21 open call for joint scientific consultation.

Exchange of information

The setting up of the JSC procedure includes the optimisation of the use of registries to facilitate post-licensing evidence generation (PLEG) and/or launch evidence to support decision making. To this instance, and depending on the specific products selected during the JSC, advice may be provided on requirements for data collection and analysis of disease registries in the context of development plans, or for qualification of registries in disease areas of particular mutual interest (including advanced therapies, ATMPs).

This exchange of information between EMA and EUnetHTA 21 may lead to discussions in order to monitor progress in the identification of PLEG. Under this action, a voluntary pilot might be activated to explore the feasibility of earlier engagement with an HTA agency during regulatory assessment, including evidence sharing and managing of uncertainties. A main outcome of this area of cooperation shall see the initial drafting of the rules for the exchange of information on the preparation and update of joint clinical assessment of medicinal products.

Capturing patient relevant data and information

The ability to generate patient relevant data and information is key to support the process of decision making. The joint work plan aims to develop new methodologies to improve reliance of patient relevant data. To this instance, the cooperation with EUnetHTA is expected to contribute to EMA’s initiative to establish an EU network of experts on Patient Reported Outcomes (PROs). The work plan also includes voluntary actions focused on the discussion and exchange of relevant data in bilateral meetings, in parallel with the development of the respective guidelines, and a workshop on patient experience data planned in June 2022.

The work plan shall also favour a better engagement of patients and healthcare professionals in areas of mutual interest. To this regard, EMA and EUnetHTA 21 will share their best practices as for compensation for expert participation and how to incorporate the input received in regulatory and HTA deliverables.

Preparedness for future challenges

The need to better understand challenges arising from the development of innovative treatments will benefit the sharing of horizon scanning activities between EMA and EUnetHTA 21. This may include, on a voluntary basis, joint discussions on data requirements and preparative measures relative to high-impact innovative medicines for patients with high unmet needs. Other voluntary activities by individual HTA bodies may focus on the optimisation of regulatory assessment reports in order to facilitate the uptake of their outcomes as part of the HTA process. Sharing of experience and guidance on the optimisation of information on subpopulations (e.g. labelling and EPARs) may also be considered, as well as the improvement of Orphan Medicines Assessment Reports (OMARs). Under the methodological perspective needed to make real-world evidence more available, a main goal of the plan shall achieve HTA representation in the advisory board of Darwin EU, the Data Analysis and Real World Interrogation Network established and coordinated by EMA to provide timely and reliable evidence on the use, safety and effectiveness of medicines for human use from real-world healthcare databases across the EU.

Other voluntary activities in this area may include multi-stakeholder discussions aimed to optimise the design, quality and utilisation of disease registries and the training on new guidance on registry-based studies. Joint methodological work may be also carried out to identify key concepts supporting the acceptance of extrapolation and/or evidence transfer, and to share best practices and experiences in the field of the integrated assessment of companion diagnostics, or other diagnostics for targeting therapeutics not directly related to the use of specific medicines.