Wael HAYEK

A Risk Management Plan (RMP) is an essential element of pharmacovigilance activities. Its primary objective is to identify, characterize, and minimize the risks associated with a medicinal product, thereby ensuring continuous monitoring of the product’s benefit-risk balance. 

Responsibilities of the Marketing Authorization Holder (MAH) 

The MAH, together with the Exploitant in France, are responsible for: 

• Establishing a risk management system 

• Implementing, maintaining, and updating the RMP 

• Continuously monitoring the safety profile of the medicinal product by analyzing pharmacovigilance data  to detect new risks that may alter the product’s benefit-risk balance 

• Implementing risk minimization measures when necessary, and evaluating their effectiveness 

• Updating the risk management system and RMP accordingly when new safety information becomes available 

The RMP is a dynamic document that must be regularly updated throughout the product’s lifecycle — for example, in  case of a variation or extension of indication, upon request from competent authorities (EMA or ANSM), or when a new risk is identified or an existing one is reclassified. 

Submission of the RMP to the European Medicines Agency (EMA) 

An RMP must be submitted to the competent authority (EMA for centralized procedure) in the following cases: 

• As part of any initial Marketing Authorization Application (MAA) 

• When an updated RMP is required during the post-authorization phase, either at the request of regulatory authorities or due to a change to the MA (e.g., new indication, new dosage, new route of administration) that affects the risk profile of the medicinal product 

RMP Structure 

The structure and content of an RMP vary depending on the regulatory status of the product (e.g., generic, biosimilar, well-established medicinal use product, combination product, etc.). 

Key components include: 

• Summary of Safety Concerns : risks are categorized into three main types: 

• Important Identified Risk: a risk for which there is sufficient scientific evidence to establish a causal relationship with the medicinal product. It may require specific monitoring or risk minimization measures. 

• Important Potential Risk: a risk for which available data suggest a possible causal relationship, but the evidence is not conclusive. 

• Missing Information: gaps in knowledge regarding the safety profile, such as lack of data in specific populations (e.g., pregnant women, children) or long-term use. 

• Pharmacovigilance Plan : this section outlines how the MAH intends to monitor and manage the risks identified in the RMP. It includes: 

• Routine activities, which are mandatory for all medicinal products (e.g., adverse event reporting, periodic safety reports, signal detection) 

• Additional activities, conducted to further characterize or quantify known or potential risks (e.g., post-authorization safety studies) 

• Risk Minimization Measures : where applicable, measures are proposed to minimize identified risks. These may include: 

• Routine risk minimization measures, mandatory for all products (e.g., SmPC, patient leaflet, labeling) 

• Additional risk minimization measures, such as patient alert cards, educational materials, or healthcare professional training 

The effectiveness of these risk minimization activities must be evaluated. This is often done through specific studies, which are included in the pharmacovigilance plan. 

Relationship Between RMP and PSUR 

The RMP and the Periodic Safety Update Report (PSUR) are complementary documents and are both part of the core post-marketing pharmacovigilance strategy. 

The RMP should reflect the conclusions of the PSURs. If a new safety signal discussed in the PSUR is reclassified as an important identified or potential risk, it must be incorporated into the RMP. Consequently, updates to the pharmacovigilance and risk minimization plans should be made to outline the MAH’s proposed approach to managing this new risk. 

Confidentiality 

The EMA publishes RMPs for centrally authorized products, both at the time of initial authorization and for subsequent updates during the post-marketing phase. 

It is the MAH’s responsibility to anonymize any personal data and redact commercially confidential information before submitting the RMP to the EMA for assessment. 

Article written by Marion PETOT, Consultant in Pharmacovigilance 

To learn more about our pharmacovigilance services, visit Atessia Vigilance: our dedicated subsidiary specializing in risk management and drug safety.

Presentation of ICH (roles, history, missions, etc.) 

ICH (International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use) is an organisation that brings together regulatory authorities and the pharmaceutical industry to discuss scientific and technical aspects of drug registration. 

In particular, this instance develop harmonised guidelines for global pharmaceutical development: the “ICH guidelines“. 

Since its founding in 1990, the ICH’s mission is to promote and support harmonisation worldwide to ensure that safe, effective and high-quality medicines are developed and registered efficiently.  

Like other organisations, ICH has had to adapt to an increasingly globalised drug development industry. 

ICH was incepted in 1990 and was formerly named the International Conference on Harmonisation (ICH). At the first ICH Steering Committee meeting of ICH, it was decided that the topics selected for harmonisation would be divided into three distinct domains in order to reflect the criteria which are the basis for approving and authorising new medicinal products: Safety (S), Quality (Q) and Efficacy (E). 

Cross-cutting topics that do not fit uniquely into one of these three categories fall into the Multidisciplinary (M) domain. These include the “MedDRA” medical terminology, the “CTD” common technical format and the development of “ESTRI” electronic standards for the transfer of regulatory information. 

The ICH Assembly brings together all members and observers of the ICH Association as the overarching governing body of the organisation. 

Since October 2015, ICH has grown as an organisation and now includes 23 Members and 38 Observers. 

As an observer, the EDQM contributes to the development of ICH guidelines in a number of relevant areas (e.g.: control of impurities, development and validation of analytical procedures and continuous manufacturing). 

The evolutions of ICH 

Since its creation, the ICH has gradually evolved to meet the increasingly global challenges of the pharmaceutical industry. 

The key dates are listed below: 

>1980s: Lauch of harmonisation of regulatory requirements by the EC as Europe moved towards the development of a single market for pharmaceuticals. At the same time, discussions occur between Europe, Japan and the US on possibilities for harmonisation. 

>1989:  Specific plans for action for harmonisation begin to materialise at the WHO Conference of Drug Regulatory Authorities (ICDRA) in Paris. Soon afterwards, the authorities approached International Federation of Pharmaceutical Manufacturers and Associations (IFPMA) to discuss a joint regulatory-industry initiative on international harmonisation, and ICH was conceived. 

>April 1990: Birth of ICH  at a meeting hosted by EFPIA in Brussels. Representatives of the regulatory agencies and industry associations of Europe, Japan and the US met, primarily, to plan an International Conference but the meeting also discussed the wider implications and terms of reference of ICH. 

Now in its fourth decade of activity, ICH’s attention is directed towards extending the benefits of harmonisation beyond its founding regions (Europe, USA and Japan). In 2015, to facilitate this, a series of organisational changes took place. These changes constituted a number of reforms including: increasing international outreach; changing ICH’s governance structure; disseminating more information on ICH processes to a wider number of stakeholders; and establishing ICH as a legal entity to provide for a more stable operating structure. 

The resulting ICH association establishes an Assembly as the over-arching governing body with the aim of focusing global pharmaceutical regulatory harmonisation work in one venue that allows pharmaceutical regulatory authorities and notably concerned industry organisations to be more actively involved in ICH’s harmonisation work. 

The ICH’s work products 

The work carried out by the ICH falls into four areas: harmonisation activities, the development of guidelines, the development of standards (MedDRA dictionary, CTD format or ESTRI electronic standards) and other work (e.g.: the development of discussion papers). 

The ICH guidelines development process 

ICH harmonisation activities fall into 4 categories: Formal ICH Procedure, Q&A Procedure, Revision Procedure and Maintenance Procedure, depending on the activity to be undertaken. 

Each harmonisation activity is initiated by a Concept Paper which is a short summary of the proposal. Depending on the category of harmonisation activity a Business Plan may also be required. The Business Plan outlines the costs and benefits of harmonising the topic proposed by the Concept Paper. 

The Formal ICH Procedure (a step-wise procedure consisting of 5 steps) is followed for the harmonisation of all new ICH topics. 

The procedure is initiated with the endorsement by the ICH Assembly of a Concept Paper and Business Plan. An Expert Working Group (EWG) is subsequently established. 

The EWG works to develop a draft Guideline and bring it through the various steps of the procedure which culminate in Step 5 and the implementation in the ICH regions of a Harmonised Guideline. 

The five steps are as follows: 

• Step 1: Consensus building 

• Step 2a: Confirmation of consensus on the Technical Document 

• Step 2b: Adoption of draft Guideline by Regulatory Members 

• Step 3: Regulatory consultation and Discussion 

• Step 4: Adoption of an ICH Harmonised Guideline 

• Step 5: Implementation 

The ICH guidelines implementation process 

At Step 5 of the ICH process, harmonised ICH Guidelines are implemented by ICH Regulatory Members and Observers within their respective country/region. This is in line with the ICH Articles of Association and the aim and intention that all ICH Regulatory Members should implement all ICH Guidelines. 

For ICH Regulatory Observers, implementation of (certain) ICH Guidelines is a pre-requisite to become an ICH Regulatory Member. 

ICH Guidelines are implemented in accordance with the applicable national/local/regional rules, with the stage of implementation of all ICH Guidelines also being dependent on when a Member or Observer has joined ICH. 

In April 2025, a total of 163 guidelines (all domains combined) were published on the ICH website, broken down as shown in the graph below: 

Future ICH work impacting global regulation 

ICH continues to propose guidelines on pharmaceutical development topics requiring regulatory harmonization, or where a lack of recommendations has been identified. This is the case, for example, of the (long-awaited) draft ICH Q3E guideline on extractables and leachables. 

In addition, the updating of current guidelines is also supported, in order to take account of scientific progress. Examples include the recent update of the ICH Q2 guideline on analytical validation, and the forthcoming revision of the ICH Q1A-Q1F series of stability guidelines. 

Sources: 

EDQM – Pharmacopoeial Harmonisation 

ICH Official web site : ICH 

Article written by Isabelle MOUVAULT, Pharmaceutical Affairs Senior Consultant 

The need for a paediatric regulation for medicines

The need for a paediatric regulation in the EU is born almost 30 years ago with the report that:

• Medicines were used in children based on empirical knowledge and off-label, with not approved adaptations of doses,
• Pharmaceutical forms were not adapted to the paediatric population,
• Clinical trials were not conducted in children to preserve this population from exposure to medicines under development,
• Very few medicines were developed in this limited specific population partly.

In 2000, the International Conference on Harmonisation published a dedicated guideline (ICH E11 – « Clinical Investigation of Medicinal Products in the Pediatric Population ») with the objective to promote clinical research in the paediatric population.

In parallel, from 1997, the European Commission launched initiatives with different stakeholders that led to the publication of the so-called paediatric regulation (Regulation No. 1901/2006/EC) on 12 Dec 2006 that came into force in Jan 2007.

European Requirements for the paediatric development of medicines

That regulation, which has been amended twice, created the paediatric committee (PDCO) within EMA but also set up a comprehensive regulatory framework with obligations and incentives for Applicants and Marketing authorisation holders.

From 2007, any new Marketing authorisation application must be accompanied with the proof of compliance to an approved Paediatric Investigation Plan (PIP) that describes the studies that will be conducted in the paediatric population and associated timelines.

This requirement is also applicable to medicinal products with a valid patent or protection for which new indication (paediatric or not) new pharmaceutical form or new route of administration will be submitted.

This requirement is applicable whatever the chosen procedure (National, Decentralised, Mutual Recognition and Centralised).

The PIP details the following:

• A calendar and specific measures to assess quality, efficacy and safety of the medicines in all subsets* of the paediatric population;
• Any measure that will be put in place to adapt the formulation to the paediatric  population to enable a safer, more adapted easier use of the medicines in the paediatric population.

Template of the EU PIP is available on EMA Website and should be used by Applicant to support effective assessment of the PIP.

*ICHE11 defines the paediatric subsets as:

• preterm newborn infants
• term newborn infants (0 to 27 days)
• infants and toddlers (28 days to 23 months)
• children (2 to 11 years)
• adolescents (12 to 16-18 years (dependent on region))

In parallel, the paediatric regulation set up rewards and incentives for some situations to support the development of medicines in children :

• Scientific advice and protocol assistance linked to paediatric development are free of charge at EMA level;
• Extension* of the protection (Patent or Supplementary Protection Certificate) by 6 months for a product authorised across the EU and for which results of the paediatric studies planed in the PIP have been included in the MA dossier (and included in the product information).
• 2 additional years of market protection in case the results of the studies planed in the PIP are submitted in an application for an orphan medicinal products;
• Finally, it created the notion of PUMA: Paediatric Use Medicines Authorisation which has a 10-year market exclusivity period.

*in this case, the MAH must market the product in the paediatric indication within 2 years upon approval. These deadlines are made available with a list published on EMA Website.

This incentives and rewards can be completed by other national incentives that are not detailed here.

Finally, this regulation provides that Marketing-authorisation holders must submit the results of studies on authorised medicines conducted in children to the European Medicines Agency (EMA) or to national competent authorities in the European Union (EU) included or not in a PIP. From 2007, MAH are requested to submit clinical study results in the paediatric population within 6 month from the termination of the study. Modification of SmPC can be requested by the HAs based on those data.

Specific cases

There are cases where the inclusion of a PIP is not a prerequisite for the submission of a MA or above-mentioned post MA submissions or where some adaptations are possible.

Exemptions :

First of all, some MA are exempted from the requirement to perform a PIP. These legal basis are:

• Applications according to article 10*: Generic, Hybrid and Biosimilar
• Application according to Article 10a*: Well-Established Use
• Applications according to Articles 13 and 16*: Homeopathic and traditional herbal medicinal products

*of Directive 2001/83/EC

Waivers :

In addition, the regulators have considered cases where a PIP is not needed or requested:

• Medicines not expected to be efficient or safe in the paediatric population of subset of paediatric population,
• targeted disease does not exist in the paediatric population,
• no additional benefit expected in the paediatric population versus the already available treatment.

In those cases, class waivers or specific waivers are possible. For the first case, the PDCO publishes a list of class waivers that are applicable. For the second option, it is requested to submit a specific waiver request to the PDCO.

Deferrals :

Finally, the regulators also provided cases where the paediatric requirements is not requested to be performed before submission of the Marketing Authorisation Application: the PDCO may grant deferral.

Such situations are expected for scientific or technical reasons or on Public Health grounds or when clinical results in adults are necessary prior to administer the product to the paediatric population.

In the case of deferral, a detailed calendar agreed with the PDCO is approved and must be followed by the MAH. In addition annual reports on paediatric deferred measures must be submitted by the owner of the PIP.

These waivers and deferrals might concern the full paediatric population or only  some subsets of the paediatric population.

Regulatory activities

Pre-MA

It is expected that PIP (initial version), deferral, product specific waiver requests, confirmation of applicability of class waiver are submitted to the PDCO via the IRIS portal. Paediatric regulation requests that these requests must be submitted at the latest at the date by when Pharmacokinetics studies are achieved.

PDCO will appoint a Rapporteur that will be in charge of the PIP assessment, product specific waiver or deferrals assessment within 60 days form validation. This period can be extended by a further 60-day assessment period as necessary. There is no fixed timelines for responses.

When a PIP is approved, the PIP becomes binding for the applicant that must submit PIP modifications if relevant (e.g. delayed timelines).

MA and Post MA Regulatory activities

Before submission of a MA for which a PIP is mandatory or for which deferral has been approved, the applicant should submit a request for compliance check to the PDCO. The PDCO will assess this request within 60 days and provide the applicant with a statement to be included in the MA dossier. In not performed before, the PDCO can be included during the validation period of the MAA that could lead to delayed start of the procedure.

Results of paediatric studies, waivers and deferrals are included in the Product Information.

Regulatory perspectives

Some studies[i],[ii],[iii] (cf. references below) confirmed the positive impact of the paediatric Regulation on the availability of medicines for children. Nonetheless, needs to have medicines in children still exist.

It is also interesting to note that EMA developed an inventory of the needs for paediatric medicines that is available in their website to help developers to identify opportunities.

The revision of the pharmaceutical legislation in the EU includes a new regulation that will replace existing regulations including Regulation 1901/2006/EC. Among other changes, one of the intention from the Regulators is to bring a more strict framework of exemptions and thus increase the development of medicines in the paediatric population.

Atessia supports companies in defining paediatric strategy and writing PIPs.

This article was written by Agathe DAUBISSE, Senior Regulatory Affairs Advisor

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[i] Toma M, Felisi M, Bonifazi D, Bonifazi F, Giannuzzi V, Reggiardo G, de Wildt S, Ceci A and TEDDY European Network of Excellence for Paediatric Research (2021) Paediatric Medicines in Europe: The Paediatric Regulation—Is It Time for Reform? Front. Med. 8:593281. doi: 10.3389/fmed.2021.593281

[ii] Nordenmalm S, Tomasi P, Pallidis C More medicines for children: impact of the EU paediatric regulation Archives of Disease in Childhood 2018;103:557-564.

[iii] : Volodina A, Shah-Rohlfs R, Jahn A. Does EU and US paediatric legislation improve the authorization availability of medicines for children in other countries? Br J Clin Pharmacol. 2023;89(3):1056‐1066. doi:10. 1111/bcp.15553

The new regulation (EU) 2017/745 introduces new requirements to enhance the safety of patients and users. One of the novelties of this new regulation is the creation of a European database dedicated to information on medical devices called EUDAMED.

This database will allow:

– Increased transparency of information on medical devices with public access.

– Better coordination between Member States in the post-market surveillance of medical devices.

EUDAMED is a secure platform used to collect and share data related to medical devices placed on the European Union market, as well as those undergoing clinical investigation.

The regulation introduces new requirements for the various actors involved in EUDAMED.

This database will consist of six interconnected modules:

Module :		Who needs to record information?	Accessible to the public
1-Actors	Economic operators must register as actors in EUDAMED and provide the required information.	– EU and third-country manufacturers, – Authorized representatives, – System/procedure pack producers, – Importers.	Available on a voluntary basis since December 2020 and will be mandatory from Q1 2026.
2-Devices	Manufacturers must submit the basic-UDI and information of all devices they place on the EU market into EUDAMED.	– Only manufacturers. Registration of medical devices under MDR. No obligation for legacy devices (if registered in EUDAMED, a new registration will be required for products under MDR, considered as new products).	Available on a voluntary basis since October 2021 and will be mandatory from Q1 2026.
3- Notified Bodies (NB) and Certificates	. Notified bodies must register in EUDAMED all information regarding issued, suspended, reinstated, withdrawn, or refused certificates and other restrictions imposed on these certificates. This information is accessible to the public.	– Notified Bodies.	Available on a voluntary basis since October 2021 and will be mandatory from Q1 2026.
4-Vigilance	Module dedicated to all vigilance and post-market surveillance reports. – Safety information (Field Safety Notice, FSN), – Field Safety Corrective Action (FSCA), – Investigation report of incident causes and corrective measures (MIR), – Trend report, – Periodic Safety Update Report (PSUR).	– Manufacturer.	Will be mandatory from Q3 2026.
5- Market Surveillance	Coordination of market surveillance actions between the various competent authorities.	– Competent authority only.	Will be mandatory from Q1 2026.
6- Clinical Investigation/Performance Studies (CI/PS):	This module concerns the registration of clinical investigations (MD) and performance studies (IVD). – Clinical investigation report and summary, – Serious adverse event during clinical investigations.	– Sponsor.	Not yet available.

Source : European commission

And the Distributors?

The MDR imposes no requirements on distributors regarding EUDAMED. They have no secure access to EUDAMED and only have public access. However, some countries may set additional requirements, such as France, which requires distributors to register via the ANSM form.

EUDAMED Deployment Schedule

In October 2019, the European Commission announced a two-year postponement of EUDAMED’s launch to May 2022.

Some modules are already available and can be used voluntarily. A roadmap project was released on July 10, 2024, indicating a full deployment of EUDAMED scheduled for the second quarter of 2027. The dates present in the EUDAMED roadmap are provisional and in “Draft” mode. No dates are official at this stage.

Recently, on January 21, 2024, the European Commission published a proposal to amend regulation (EU) 2017/745 on medical devices (MDR) and regulation (EU) 2017/746 on in vitro diagnostic medical devices (IVDR) concerning the gradual deployment of EUDAMED. This proposal suggests a gradual implementation of EUDAMED modules once validated, potentially starting in Q4 2025. This proposal will need to be adopted and published in the Official Journal by May 2024.

Useful Documents and Guides:

– EUDAMED Release Note

– EUDAMED Roadmap

Since 1994, medical devices have had to comply with the requirements of European Directives 93/42/EEC and 90/385/EEC. Conformity with this regulation allows the affixing of the CE marking, enabling the free circulation of medical devices within the European Union (EU).

The European Union has recently revised this regulation through the European Regulation 2017/745/EU for medical devices (MDR), which finally came into effect on May 26, 2021. The adoption of a regulation instead of a directive ensures uniformity in the regulatory framework through its direct application.

This new regulation imposes new responsibilities on economic operators involved in the supply chain of medical devices: manufacturer, authorized representative, importer, distributor.

What are the main changes introduced by this new regulation (MDR)?

– Redesignation of Notified Bodies (NB) under MDR and EU control of Notified Bodies (NB)

– Improved traceability through the Unique Device Identification (UDI)

– Inclusion of certain aesthetic devices with the same characteristics and risk profile as medical devices covered by the regulation

– Enhanced transparency through EUDAMED, the medical device database

– Strengthened requirements for clinical data and post-market surveillance

What transition periods will apply?

Initially, the MDR was to come into effect on May 26, 2020. Due to the COVID-19 health crisis in 2020, the EU decided to postpone this date through Regulation (EU) 2020/561.

The implementation date was thus postponed to May 26, 2021, with a transition period for manufacturers with medical devices already on the European market (“LEGACY DEVICES”) until May 26, 2024 (end of the issuance of certificates under the directive) and the availability of these medical devices on the market until May 26, 2025. However, for class I medical devices and new medical devices entering the European market, they had to comply with the MDR since May 26, 2021.

On March 20, 2023, the EU assessed a potential shortage risk for many medical devices and adopted Regulation EU 2023/607, amending Regulation (EU) 2017/745 concerning transitional provisions (Article 120).

The extension dates of certificates under Directive 93/43/EEC are extended based on the class of the medical device:

However, manufacturers covered by this extension must meet the following conditions:

1/ The devices continue to comply with Directive 90/385/EEC or Directive 93/42/EEC, as applicable. ;

2/ There are no significant changes to the design and intended use.;

3/ The devices do not present an unacceptable risk to the health or safety of patients, users, or other persons, considering other aspects related to public health protection. ;

4/ no later than 26 May 2024, the manufacturer has put in place a quality management system in accordance with Article 10(9); ;

5/ The manufacturer or authorized representative has lodged a formal conformity assessment request under the MDR for a medical device or a replacement device to a Notified Body by September 26, 2024, and the Notified Body and the manufacturer have signed a written agreement.

Special case for custom-made class III implantable devices – transitional period introduced:

The conformity assessment of custom-made class III implantable devices requires an assessment by a Notified Body.

Custom-made class III implantable medical devices can be placed on the market without the corresponding certificate until May 26, 2026, provided that the manufacturer has submitted an application to a designated Notified Body under the MDR before May 26, 2024, and has signed a contract with that Notified Body before September 26, 2024.

MDR requirements applicable from May 26, 2021:

However, it is important to note that certain MDR requirements shall apply to devices  since May 26, 2021, such as requirements related to post-market surveillance, market surveillance, vigilance, and the registration of economic operators.

Removal of the availability date:

Additionally, Regulation EU 2023/607 completely removes the availability deadline, allowing “LEGACY DEVICES” to be available without a deadline (still respecting the device’s usage limit date). This removal also applies to in vitro diagnostic medical devices marketed before May 26, 2022, in Regulation (EU) 2017/746 (IVDR).

Are CE certificates under the directives still valid during this extension period?

Certificates that expired before the entry into force of Regulation 2023/607 (March 20, 2023) should only be considered valid if:

– Either before the certificate’s expiration date, the manufacturer and Notified Body signed a conformity assessment agreement before the certificate’s expiration date.

– Or if a competent authority has granted a derogation.

Notified Bodies can no longer issue or modify CE certificates under the directives since May 26, 2021. Therefore, they are considered extended unless they have been withdrawn.

Manufacturers can issue a self-declaration confirming that they comply with the extension conditions, indicating the end date of the transition period (the medical devices covered by the extension must be clearly specified). At the manufacturer’s request, the Notified Body can also issue a confirmation letter.

It is important to remember that despite these delays, manufacturers must now act toward this new regulation. The submission period to Notified Bodies can take from 6 to 18 months, depending on the Notified Body and the medical device.

Atessia supports its clients through all stages of MDR compliance.