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In December 1999, the European Parliament and Council adopted Regulation (EC) No. 141/2000 on so-called “orphan” medicinal products. These are drugs developed to treat rare diseases. They are called “orphan” because the pharmaceutical industry has little interest in developing and marketing products that are only intended for a small number of patients.  

This Regulation established a Community procedure for designating certain medicinal products as orphan medicinal products and introduced incentives to promote the research, development and marketing of such designated medicinal products. A large proportion of advanced therapy medicinal products claim orphan drug status. This “orphan drug” designation can be granted at any stage of the drug’s development, prior to obtaining marketing authorization. 

However, certain conditions must be met. According to the regulations, in order to obtain orphan designation, the sponsor must demonstrate: 

> that the medicinal product is intended for the diagnosis, prevention or treatment of a life-threatening condition or chronic disability affecting no more than 5 in 10,000 people in the European Union;  

> or that, in the absence of incentives, the sale of this medicine in the EU is unlikely to generate sufficient profits to justify the necessary investment; 

> and that there is no satisfactory alternative method or, if available, that the treatment in question will provide a significant benefit. 

Once the “application” file is ready, the sponsor submits their application for orphan designation via the Regulatory & Scientific Information Management Platform (IRIS*).  

Applications for orphan designation are evaluated by a specific committee set up within the EMA, the COMP*. This committee is responsible for examining the applications for designation submitted, in order to issue an opinion to the European Commission within 80 days of receipt of the application. Subsequently, the Commission adopts its final opinion on an application for designation of a medicinal product as an orphan medicinal product within 30 days of receipt of the Committee’s opinion, in the light of the eligibility criteria set out in Regulation (EC) No 847/2000 laying down the provisions for implementation of the criteria for designation of a medicinal product as an orphan medicinal product and definitions of the concepts ‘similar medicinal product’ and ‘clinical superiority’. 

Orphan drug legislation offers sponsors an attractive opportunity to benefit from reductions in regulatory fees payable to the EMA. This incentive leads to reduced fees for protocol assistance, MA applications, pre-authorisation inspections and post-approval MA variation applications.  

Obtaining orphan drug status also brings many other significant advantages that manufacturers can benefit from, such as protocol assistance. This is scientific advice specific to orphan drugs that guides sponsors on the types of clinical studies needed to demonstrate the quality, significant benefits and risks of the drug.  

Another factor encouraging sponsors to apply for orphan designation is the 10-year market exclusivity of their drug after MA is granted. Authorized orphan drugs benefit from ten years of protection from competition on the market from drugs with similar indications. That is, each indication with an orphan designation confers ten years of market exclusivity for that particular indication.  

All of these incentives have proven successful since the implementation of orphan drug legislation in the EU in 2000. The ongoing revision of European drug legislation would retain most of the incentives, according to current discussions. 

Atessia supports its clients in their efforts to obtain orphan designation for their drugs.  

*IRIS: Integrated Regulatory Information System 

*COMP: Committee for Orphan Medicinal Products 

Article written by Blandine LATROBE, Regulatory & Pharmaceutical Affairs Consultant 

In France, certain drugs are covered by the National Health Insurance system. They are referred to as reimbursable drugs. Obtaining reimbursement is not based solely on a product’s therapeutic value. It involves a specific regulatory process, involving several authorities and affecting the price, prescription conditions, and patient access to the drug. 

The reimbursement request must be submitted by the pharmaceutical company that markets the drug. 

Assessment by the Transparency Committee 

The French National Authority for Health (HAS), through its Transparency Committee, assesses each specialty based on: 

• Actual benefit (Service Médical Rendu – SMR), which determines the applicable reimbursement rate (15%, 30%, 65%, or 100%). 

• Drugs whose SMR is considered insufficient are not reimbursable. 

The price of a reimbursable drug is then set by the Economic Committee for Health Products (CEPS), following negotiations with the pharmaceutical company, based on: 

• The Improvement in Medical Service Rendered (Amélioration du Service Médical Rendu – ASMR), which ranks the product in relation to comparators already available, with 5 ASMR levels : from I (major therapeutic progress) to V (no improvement). 

This price, combined with the reimbursement rate, subsequently determines the registration of the drug on the regulatory lists that allow it to be covered by Health Insurance : 

• List of specialties reimbursable to Social Security Insured (City list): drugs available in community pharmacies, covered by Social Security based on a price negotiated with the CEPS and a reimbursement rate determined according to the SMR. 

• List of pharmaceutical specialties approved for use by communities (Hospital list): drugs used in hospitals, covered through the standard hospital budget (GHS), without price negotiation with CEPS, as hospitals manage their own budgets and tenders. 

• Supplementary List (“Liste en sus”): expensive and innovative drugs administered in hospitals, excluded from the GHS budget, reimbursed on an invoice basis, with prices negotiated directly with CEPS, taking into account their therapeutic value and impact on hospital costs. 

A drug only becomes eligible for standard reimbursement after publication in the Official Journal. Note that some medicines are tacitly included on the hospital list. This is the case for medicines under compassionate use or early access programs. According to these prescription and dispensing conditions, the medication must be prescribed by a healthcare professional (doctor, midwife, dental surgeon, chiropodist, nurse) on a prescription in accordance with the regulations and within the limits of prescription rights. It is then dispensed to the patient either in community pharmacies or hospitals. 

Obtaining reimbursement is not just an administrative formality: it is a key step that determines access to the French market. The pharmaceutical company must prepare a solid dossier and anticipate the authorities’ expectations, while ensuring that the product is correctly positioned in relation to existing alternatives. An unfavorable reimbursement or reimbursement obtained within a restrictive framework can limit the drug’s adoption by prescribers and hinder its access to patients. 

Article written by Lamya SAOUSSEN, Junior Regulatory Affairs and External Communication Advisor  

From a legislative point of view, the mutual recognition procedure is defined by the Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the Community code relating to medicinal products for human use.

Directive 2004/27/EC subsequently laid the foundations for the decentralised procedure.

These two procedures are available for all marketing authorisation applications that do not fall within the mandatory scope of the centralised procedure. They are applicable whenever an applicant wishes to register its medicinal product in more than one Member State.

1/ The Mutual Recognition Procedure (MRP)

Article 28.2 of Directive 2001/83/EC, as amended, specifies the scope of this procedure: the principle is to extend a national MA already obtained in one of the EU Member States, to one or more other Concerned Member State(s) (or “CMS”) in which the laboratory wishes to market its product. The Reference Member State (or “RMS”), which granted the existing MA, manages the procedure.

Once the evaluation procedure has been completed, the MAs are issued by each of the competent authorities of the member states concerned.

Source EMA

After a possible upgrade of the MA dossier, the RMS sends the MA dossier and its assessment report, including the Summary of Product Characteristics (SPC), package leaflet and labeling, to the CMS 14 days before the start of the procedure.

The concerned Member States must then recognize the authorization already issued by the RMS within 90 days (without clock-stop).

The procedure may, however, end on Day 60 if the CMS has no further comments.

Once the MA (including the SPC, package leaflet and labeling) is recognized by the CMS, this recognition is followed by a 30-day national closing phase to issue the national MA. Procedures successfully closed are published on the CMDh website.

If a Member State has objections to recognizing the dossier’s assessment report, summary of product characteristics (SPC), package leaflet and labeling, on the grounds of a potentially serious risk to public health (as defined by Article 29(1) of Directive 2001/83/EC), the dossier is referred back to the CMDh for further discussion. This procedure lasts 60 days. If the CMDh is unable to reach a decision within 60 days, the application is sent to the CHMP for arbitration (art. 29(4) of Directive 2001/83/EC). This procedure also lasts 60 days.

2/ The decentralized procedure (DCP)

This procedure differs from the MRP in two main points :

• No marketing must first have been granted in the EU,
• The dossier is submitted simultaneously in all Member States.

In this case, the laboratory requests a member state to act as reference state (“RMS”) in order to carry out the evaluation, among the states where it wishes to obtain authorization for its medicinal product.

Source EMA

* EEA = European Economic Area

MA = Marketing authorization

The RMS draws up a preliminary assessment report on the dossier submitted and the draft SPC, package leaflet and labeling.

This report is submitted to the CMS and the applicant for comments on Day 70 of the procedure.

On Day 105 of the procedure, the clock stops to allow the applicant to submit answers to the questions raised by the Member States at the end of phase 1.

When the answers have been submitted, the clock starts again on Day 106, and on Day 120 of the procedure, the RMS circulates at the same time an update of all documents (assessment report, SPC, package leaflet and labeling) to the applicant and the CMS.

A second phase of Questions and Answers begins, and the procedure may be closed on Day 150 if all comments have been resolved.

Otherwise, a new 60-day phase begins to finalize outstanding issues.

The DCP therefore lasts a maximum of 210 days. This period is followed by a 30-day national closing phase to issue the national MA. Procedures successfully closed are published on the CMDh website.

As with the MRP, if there is no consensus between member states, the dossier is referred back to the CMDh for further discussion. This procedure lasts 60 days. If the CMDh is unable to reach a decision within 60 days, the application is sent to the CHMP for arbitration (art. 29(4) of Directive 2001/83/EC). This procedure also lasts 60 days.

3/ To sum up:

MRP	DCP
Existing initial national MA	No MA granted in the EU
No choice of the RMS (national MA already existing th the EU)	The choice of the RMS is up to the applicant
Request a recognition by the other Member States	Simultaneous application to all member states: the RMS evaluates the dossier for the first time (as for the CMS)
Only one evaluation phase	Two evaluation phases
Decision within 90 days, or up to 150 days in the event of arbitration by the CMDh if no consensus can be reached between Member States.	Decision in 210 days (excluding clock-stop period), or up to 270 days in the event of arbitration by the CMDh if no consensus can be reached between Member States.
MA Dossiers identical in all member states
Principle of recognition of the evaluation of the Reference Member State (RMS) by the other Member States concerned (CMS)
The choice of the States involved in these procedures is up to the applicant
National closing phase of 30 days planned to issue the national MA
A European Public Assessment Report (“PAR”) for each medicinal product approved via the MRP/DCP is published in the directory « Mutual Recognition Index » by the RMS on the HMA website.

ATESSIA supports laboratories throughout the registration process: from the registration strategy to the draft and submission of the marketing authorization applications.

Article written by Mathilde ISRAEL, Regulatory Affairs and External Communication Advisor.

French always do it different In many domains, French people like to stand out, either in a positive or negative way. In the Healthcare field, France has set a system that is highly effective, and very protective for the patient, but at the price of a heavy state involvement and of one of the most complex regulations. As a result, understanding the regulatory specificities of France is key for entering the French market. ATESSIA can help you in this process and provide you assistance and expertise. Here are a few areas where France follows its own, often complicated and restrictive, rules.

Prior control of advertising

The control exercised by the French Health Authorities over advertising for medicinal products is probably one of the most demanding. Any advertising for a medicine is therefore subject to control and authorization by the ANSM*. Since 2012, this authorization system has been entirely based on an a priori process, i.e. the distribution of an advertisement can only start once the precious visa has been granted. In the absence of a visa, the distribution of an advertisement may lead to criminal and financial penalties.

Regarding the content of promotional documents, in application of the French Public Health Code and taking into account the state of scientific and medical knowledge, the ANSM will ensure the security of the message which must not induce bad prescribing or a danger to the public. Vector of proper use, advertising must also present the medicine objectively, and ensure compliance with the standards in force such as the MA** and the therapeutic strategies recommended by the HAS***.

Regarding advertising aimed at health professionals, in order to enable them to form their own personal idea of ​​the therapeutic value of the medicine, the ANSM ensures that the target population and the benefit-risk ratio are clearly perceptible, particularly in the documents used by persons carrying out a promotional information activity. Numerous guidelines, which are mandatory in practice, have been drawn up by the authorities to assist pharmaceutical companies in this delicate task.

Concerning advertising to the general public is only permitted for certain medicines:

• Medicinal products not subject to compulsory medical prescription, non-reimbursable and not including in their marketing authorization a ban on advertising due to a risk to public health, in particular when the medicinal product is not suitable for use without medical supervision;
• Certain vaccines included on a list from the Ministry of Health;
• Smoking cessation products.

It should also be noted that control of advertising is also exercised a priori for certain categories of medical devices presenting a significant risk to human health, the list of which is defined by a ministerial order. As with medicinal products, advertising for these devices is therefore subject to prior authorization in accordance with the French Public Health Code.

An Immutable Authorization Schedule

But the real constraint lies in respecting the timetable governing this control, implying for pharmaceutical companies to anticipate and plan their needs well in advance. Advertising is indeed subject to strict filing periods (4 per year for documents for healthcare professionals, and 8 per year for advertisements targeting the general public), and files are processed by the authorities within a regulatory time limit of 2 months.

Outside of these periods called the “deposit slot”, it is forbidden to apply for a visa. Only medicinal products that have been subject to an advertising ban during a reassessment of the benefit/risk ratio can derogate from this principle, and be the subject of a visa application outside the determined periods.

At the end of the evaluation period, the request will result in the granting of a prior authorization called the GP visa for advertising aimed at the public and the PM visa for advertising aimed at healthcare professionals, for a duration of 2 years. However, in the event of breaches of the requirement criteria on the content or presentation of the communication tool, the ANSM may issue a refusal. The applicant will then have no choice but to make a new request during the next slot. Each year, more than 10,000 visa applications are generally submitted to the ANSM (including both GP and PM visas), and this number tends to increase over time. Among these applications, approximately 15% are rejected (according to the ANSM’s 2022 and 2023 activity reports), a percentage that also appears to be rising each year.

It should be noted that it is possible to submit visa applications before the final decision on an initial marketing authorization (MA) or a modification of an existing MA, in the following cases: for an initial European MA obtained through the centralized, decentralized, or mutual recognition procedures, after the end of the European phase and based on the draft translation of the MA; for an initial national MA, based on the draft MA; and for MA modifications resulting from the above-mentioned European procedures, once the European phase is completed, also based on the draft translation. Naturally, the visa will only be valid if the MA itself is granted. The MA holder must ensure that the advertising strictly complies with the annexes of the approved MA.

The dematerialization of applying

Accelerated by the COVID-19 health crisis, the ANSM has implemented the dematerialization of visa applications via the national platform demarches-simplifiées.fr. The ANSM is thus temporarily opening a specific form for each filing period, and requests sent in paper format must now be exceptional. The applicant must then complete by scrupulously following the notice made available to users of the platform, by attaching a receipt of €510 previously issued after payment to the tax authorities.

ATESSIA supports laboratories throughout the entire review process of both promotional and non-promotional external communication materials : from communication strategy to the validation and submission of dossiers.

Article written by Mathilde ISRAEL, Regulatory Affairs and External Communication Advisor.

* ANSM : Agence Nationale de Sécurité du Médicament et des produits de santé (ANSM is the French Authority in charge of assessing and surveying pharmaceutical products) 

** MA : Marketing Authorization

*** HAS : Haute Autorité de Santé (HAS is taked for the French Government with the evaluating of health products from a medical and economic perspective and recommending best practices)

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