Carole Souchaire, co-founder of Alhena Consult, puts it bluntly: this nine- to twelve-month timeframe is almost impossible to shorten. It is precisely this discrepancy between the advertised timeframe and the actual timeframe that causes delays in the opening schedules of exploitant sites for foreign laboratories or start-ups.

What it means to ‘open an exploitant site in France

Many marketing authorisation holders only discover this French-specific requirement at a late stage. A European marketing authorisation grants the right to market medicines on the European market, but this is not sufficient to gain access to the French market under the conditions laid down by the Public Health Code. In France, in accordance with the ANSM’s recommendations, market access is primarily granted through an exploitant site, which must have a Chief Pharmaceutical Officer.

It is important to emphasise that this Chief Pharmaceutical Officer is not merely an administrative manager responsible for placing products on the market. They hold a corporate office, are involved in the company’s decision-making and bear personal liability in the field of pharmaceutical activities. The French Chief Pharmaceutical Officer puts their professional qualifications, their professional independence and their ability to say ‘no’ on the line.

This independence is not merely theoretical, and the health authorities regularly emphasise this in memos or during inspections. Despite pressure from finance departments or international parent companies – in a context where the financial stakes can be considerable – the Chief Pharmaceutical Officer has the authority to refuse the commercial release of a non-compliant product.

The actual timetable: three phases that add up

In practice, the actual timetable is divided into three stages. The first stage is the preparation of the ANSM dossier. This takes three to four months. This phase depends entirely on the laboratory and can be optimised depending on its internal organisation.

The second stage is the assessment by the ANSM. At this stage, a minimum of three months is required for the processing and approval of the application for authorisation to open an exploitant site. This is the only timeframe over which the pharmaceutical company has no control.

The third phase involves setting up the quality system (also known as the QMS – Quality Management System), organising outsourced pharmaceutical activities and drawing up contracts with service providers. Here too, three to four months are often required, even though some of the work is carried out in parallel with the assessment. Distribution, pharmacovigilance, medical information, on-call systems, quality documentation, organisation of pharmaceutical operations: none of these can be improvised.

The classic mistake, therefore, is to assume that the duration of phase 2 is the total duration.

What the ANSM application package contains

This is where the second unpleasant surprise comes in. The application package for opening an exploitant site is not simply an administrative form. It is a detailed application, a comprehensive demonstration of your ability to handle medicines in accordance with the Public Health Code (CSP) and the requirements of the French National Agency for Medicines and Health Products Safety (ANSM).

The ANSM assesses whether an organisation is well-structured and efficient. The standard application dossier must demonstrate that the pharmaceutical establishment is properly established in terms of its resources, responsibilities, workflows and procedures. Documentation must be provided on the layout of the offices (including the office dedicated to the Chief Pharmaceutical Officer), IT security, the lease agreement, the qualifications and appointment of the Chief Pharmaceutical Officer and the deputy Chief Pharmaceutical Officer, the quality system, the supply chain, pharmacovigilance, medical information, the on-call system and relations with service providers.

This is precisely why three to four months of preparation are required. The application dossier is not simply the final draft of a project that is still vague. It is a comprehensive audit carried out even before the ANSM begins its assessment or comes to check the systems during an inspection.

Read also: How should interactions with health agencies be managed?

Actual costs: set up your own business or use a temporary exploitant site?

The real issue, particularly for a start-up, is also a financial one.

On paper, opening your exploitant site may seem the more logical option. In practice, however, the cost is not insignificant. You need to factor in around 200,000 euros in costs for a Chief Pharmaceutical Officer, around 50,000 euros for outsourcing the preparation of the application dossier, plus the cost of the quality management system and the necessary service providers: distribution, pharmacovigilance, medical information, and sometimes other functions depending on the product portfolio and healthcare products.

In light of this, a temporary exploitant site often appears to be a more sensible solution initially. For around 450,000 euros a year (depending on the number and types of specialties to be operated), the start-up can rely on an existing structure, with a Chief Pharmaceutical Officer in post, established procedures, an opening authorization and a quality system already in place. The cost gap may close after two or three years, but in the short term, the temporary option is often cheaper than laboratories had anticipated.

The mistakes that foreign laboratories fail to anticipate

Foreign laboratories almost always underestimate the operational realities of the French market.

First mistake: believing that a single Chief Pharmaceutical Officer is sufficient. In reality, a Chief Pharmaceutical Officer cannot manage an exploitant site on their own. At the very least, they must be supported by a deputy Chief Pharmaceutical Officer and other service providers for the activities they wish to outsource.

Second mistake: thinking that the release procedure carried out elsewhere in Europe is sufficient for France. However, the French Chief Pharmaceutical Officer carries out a specific commercial release procedure, which involves checking the batch file, storage conditions, transport documents, temperature deviations and the conformity of packaging materials, amongst other things. If a batch is non-compliant, it will not be placed on the market.

Third mistake: believing that the parent company’s overall quality system can simply be copied and pasted. This is not the case. A quality management system must be established that is tailored to French requirements, particularly with regard to medical information, pharmacovigilance, supply and the pharmaceutical operations specific to the exploitant site.

Conclusion

Setting up an exploitant site in France cannot be planned in just three months. The actual timeframe is nine to twelve months, as it involves three phases: preparing the application, the ANSM assessment, and then setting up the quality system and agreements with service providers. The actual cost also requires a clear decision between two options: setting up your own organisation or using a temporary exploitant site.

If you are preparing to open an exploitant site on the French market, Alhena Consult can assist you with both the application process and the strategy best suited to your timetable, your portfolio of medicines and your market launch requirements.

Contact our team for bespoke support.

Sources

ANSM — Application package for the opening of an exploitant site
Legifrance — Public Health Code, articles relating to the Chief Pharmaceutical Officer
ANSM — Management of pharmaceutical establishments
ANSM — Submission of applications for opening authorisation

Implementing Regulation (EU) 2025/1466, adopted by the Commission in July 2025, addresses this shortcoming. This Implementing Regulation does not alter the underlying principle: Marketing Authorization Holders remain responsible for their systems. However, it provides a clear legal basis for requirements that have hitherto been dealt with primarily in contracts and inspections. For a Chief Pharmaceutical Officer or a local QPPV in France, the message is clear: contracts must be reviewed, third parties identified, and the audit checklist adapted ahead of the next ANSM inspection.

The aim of the European Regulation of July 2025

The text forms part of a wider drive to strengthen the safety of medicines for human use in Europe. The Commission starts from a simple observation: pharmacovigilance activities are increasingly being outsourced, sometimes on a global scale, involving direct subcontractors and then subcontractors of subcontractors. The purpose of these regulations is therefore to provide a clearer framework for the responsibilities, audits and inspections relating to activities entrusted to third parties.
For pharmaceutical companies, this is a familiar challenge. The parent company sometimes signs a single contract covering several European countries, whilst the French subsidiary remains legally responsible for local operations. The regulation aims to clarify this grey area. It enhances consistency between marketing authorization, the pharmacovigilance system, data security and the operational management of service providers.
This text does not create an entirely new obligation. It makes requirements that were already expected in audits, in dealings with the European Medicines Agency and in national inspections legally enforceable. In practice, the text significantly clarifies supervisory responsibilities.

The three major changes for your PV service providers

The right to audit is now enshrined in the regulations

Until now, the right to audit was mainly set out in contracts. When the clause was vague or incomplete, the laboratory found itself in a vulnerable position. The regulation changes this: the service provider can no longer use the weakness of the contract wording to limit an audit. The right to audit is now enshrined in the text.

The practical impact is immediate. Existing contracts must be reviewed to ensure that roles, scopes and delegated activities are described unambiguously. This also applies to more complex organizations, covering clinical trials, post-marketing activities and product surveillance.

Service providers must make themselves available for inspections by the authorities

The second change is just as significant. When an authority, such as the ANSM in France, initiates an inspection, the service provider must agree to take part. This requirement is no longer merely a matter of best practice; it is now a statutory obligation.

For an exploitant, this changes the way supplier audits are prepared: team availability, access to data and the ability to respond promptly to the regulatory authority. This issue directly affects healthcare professionals involved in pharmacovigilance (PV) quality, as well as those involved in the reporting, analysis and monitoring of adverse events. Contracts should therefore provide for participation in inspections, the availability of contact persons and access to the summary of product characteristics where necessary.

Cascading audits are becoming a key governance issue

The third change is often the most significant. The Chief Pharmaceutical Officer can no longer limit their oversight to their direct service provider. If that service provider subcontracts part of the work, the laboratory must be able to identify this chain, assess it and, where necessary, audit it.

A master agreement signed outside France may cover local activities of which the subsidiary is only partially aware. However, it is the marketing authorization holders and the exploitant who bear regulatory responsibility. The new legislation therefore requires the actual subcontracting arrangements to be mapped out, including where secondary parties handle sensitive data, adverse events or tasks related to the pharmacovigilance system.

Why this regulation addresses a recurring issue in the field

The globalization of outsourcing has profoundly changed the way pharmacovigilance activities are managed. In many groups, the approach is straightforward: a single contract, a centralized organization, and a single global provider for several countries. In practice, this model often creates a disconnect between the contracting party and the local manager who will be held accountable to the ANSM.

This is precisely what the regulation is designed to address. It does not call into question the international structure of parent companies. It clarifies who controls what, who is authorized to audit what, and who must be able to produce evidence during an inspection. For a laboratory in France, this clarification is essential. It operates within a framework shaped by the Public Health Code, European requirements, the European Medicines Agency and, more broadly, the regulations governing the safety of medicines and healthcare products.

How to incorporate these changes into your next PV audit

The first step is to map the supply chain down to the second tier. You need to identify direct service providers, less visible subcontractors, the activities carried out, data flows and the countries involved. Without this overview, the audit will remain incomplete.

The second stage concerns contractual governance. The local Chief Pharmaceutical Officer must be a signatory to, or at the very least the recipient of, the framework agreements covering local activities. They must also be able to verify that these agreements comply with the requirements of the regulation and with the French obligations relating to marketing authorization.

The third step involves updating the audit checklist. It must explicitly include the right to audit, participation in inspections, cascade management, proof of written consent prior to re-subcontracting, and access to critical documentation.
The fourth step is more difficult to implement: revising the audit clauses without delay. A laboratory that delays this update risks incurring an avoidable non-conformity.

See also: Everything you need to know about managing regulatory changes to a product’s marketing authorization

Key takeaways

The 2025 European Pharmacovigilance Regulation transforms vague expectations into enforceable obligations. Audit rights, participation in inspections, cascade audits, transparency regarding contracts and control over third parties: these issues must now be reflected in your contracts, your risk mapping and your audit program.

For a Chief Pharmaceutical Officer in France, the question is now a practical one: are your service providers, your contracts and your audit trail already in line with what the Commission and the ANSM may require? If not, you need to rectify this now.

Would you like to assess the impact of Implementing Regulation (EU) 2025/1466 on your subcontracting agreements and pharmacovigilance audits? Contact Alhena Consult for a pharmacovigilance audit tailored to your organization.

In response, the parent company asks the expected question: ‘Which legislation provides for this?’. It is precisely on this point that the FAQ (frequently asked questions) published by the ANSM on 9 January 2026 provides clearer written guidance. It does not introduce any new obligations. Instead, it sets out in writing the expectations already identified during inspections and in the June 2022 guidelines on good pharmacovigilance practices. This FAQ was eagerly awaited, as the last version dated from 2018 but was linked to the previous version of the French guidelines on good pharmacovigilance practice.

For a French subsidiary, the benefits are immediate. What was previously merely a record of a discrepancy or a verbal reminder now becomes a dated, published and legally binding document. The BPPV FAQ 2026 does not introduce any new requirements. It provides the Chief Pharmaceutical Officer and th elocal qualified person responsible for Pharmacovigilance (local QPPV) of the exploitant site with a reference document to draw upon.

What the FAQ on good pharmacovigilance practices actually sets out

The 2026 FAQ on Good Pharmacovigilance Practices does not replace the 2022 BPPV, the European GVP (Good Pharmacovigilance Practices) or the Public Health Code. It clarifies Chapter 4 of the Good Pharmacovigilance Practices, which deals with the role of the marketing authorisation holder and the exploitant. Its scope is therefore primarily practical: it sets out in black and white requirements that already existed within the French pharmacovigilance system, but which were sometimes difficult to enforce within an international group.

In this regard, it sets out several key points. The ANSM states that the local QPPV must be appointed as soon as possible after Marketing Authorisation has been granted and, at the latest, before the medicinal product is placed on the market; that they must reside and practice in France; and that their employer must ensure they possess the necessary knowledge of pharmacovigilance at national level. The FAQ also states that the local QPPV must be able to access the European PSMF if the local PSMF refers to it, and that it may obtain it on request in order to understand the overall structure of the pharmacovigilance system.

The same reasoning applies to safety reports, local signal detection, data flow, updates to the SPC (Summary of Product Characteristics), the RMP (Risk Management Plan) or labelling, and, more broadly, to pharmacovigilance activities entrusted to the parent company, the Marketing Authorisation Holder or service providers. The benefit of this is that it transforms expected practices into a written reference that can be used by the exploitant.

Aurélia Bidant, co-founder of Alhena Consult, sums it up clearly: “These clarifications do not introduce any real changes, but they do reinforce the role of the exploitant and the local QPPV. For a subsidiary, this is more a matter of operational support than a major legal change.”

Why the FAQ redefines the relationship between subsidiaries and parent companies

Within an international pharmaceutical group, the parent company almost always requires an explicit regulatory basis to justify a local requirement. This approach is legitimate: it seeks to harmonise practices, contracts, systems and processes across the group. In this context, the French subsidiary regularly found itself in difficulty. Whenever it requested access to certain reports, transparency regarding subcontracting, or support in identifying local issues, the only evidence it could provide to support its case were the discrepancies identified during inspections by the ANSM.

An inspection report does not carry the same weight in discussions with a parent company as a formal document, dated and published by the regulatory authority. It is precisely this gap that the FAQ fills. It does not create a new obligation, but it finally provides the subsidiary with a written text on which to rely when justifying French requirements that are not always shared by other countries.

As Aurélia Bidant points out, the problem was clearly identified: prior to January 2026, certain expectations existed in the practice of inspections, but these were not set out in a formal document. Without written guidance, parent companies were reluctant to adapt their organisational structures or documentation. The FAQ therefore changes the nature of the exchange: the subsidiary no longer relies solely on inspection feedback; it can now cite a legally binding document from the ANSM.

Read also: Setting-up an exploitant site in France: timelines, costs, and regulatory requirements

Access to safety reports: a practical example

Access to safety reports is a prime example of the practical value of the FAQ. In some international groups, PSURs are prepared and submitted at group level. The French subsidiary therefore has only partial, or even no, insight into their content, conclusions or the follow-up measures envisaged. Yet it remains responsible in France for the safety of the medicines it markets. It is precisely this disconnect that the FAQ helps to address.

The local QPPV cannot properly fulfil its obligations if it is unaware of the findings of the periodic reports, the issues identified, or the measures that may result from them within its territory.

As Aurélia Bidant points out, this problem still exists in some laboratories: pharmacovigilance reports are managed at head office level, even though the local subsidiary should be able to access them and be aware of their findings. The FAQ provides practical guidance on this matter.

It enables the Chief Pharmaceutical Officer and the local QPPV to formalize their request to the parent company on the basis of a written document from the ANSM, rather than solely on the basis of expected usage or a previous inspection.

In practice, this strengthens the subsidiary’s ability to gain access to PSURs, their conclusions and, more broadly, the safety data required for the local monitoring of products marketed in France.

How to use the FAQ in your internal discussions

The first step is to use the FAQ as a reference document. If the parent company does not work in French, it must be translated accurately, attached to written requests and incorporated into the local quality system. This formalisation already provides practical support for internal decision-making.

The second stage involves document structuring. The FAQ is intended to be incorporated as a reference document into applicable procedures, relevant contracts and communications with the Marketing Authorisation Holder, the exploitant’s parent company or service providers responsible for certain activities. The principles set out in the policy must also be reflected in the local PSMF, in particular through the description of responsibilities, access to security data and the interfaces between the subsidiary and the group entities. It may also be cited in discussions concerning critical computerised systems and the management of computerised systems – in terms of governance, validation and maintenance of a validated state – where such systems support pharmacovigilance activities.

The third step is about building relationships. The aim is not to use the FAQs as a means of opposing the parent company, but as a tool for clarification and alignment. The approach must remain collaborative. The subsidiary must explain what the ANSM expects from an exploitant in France, from the local QPPV and from a pharmacovigilance system managed at local level.

See also: Pharmacovigilance: the new 2025 European requirements for quality systems

Conclusion

FAQ 2026 on good pharmacovigilance practices does not introduce any new regulatory requirements. It formalizes expectations already identified during inspections and provides French subsidiaries with a written document to support their requests to the parent company, the Marketing Authorisation Holder or the group’s head office. For the Chief Pharmaceutical Officer and the local QPPV, it provides a practical tool for ensuring access to the information needed to manage drug safety at a local level.

Do you find yourself having to advocate for French requirements with your parent company? Contact our team for pharmacovigilance support tailored to your situation.

The challenges of presenting to health authorities

A successful scientific presentation to the authorities is a major investment for a pharmaceutical group or a start-up. These meetings provide an opportunity to compare the scientific vision with the evaluators’ expectations, before development costs become prohibitive. The role of agencies such as the EMA or the ANSM is therefore to ensure patient safety whilst promoting medical innovation.

There are various types of regulatory meetings in Europe, ranging from Scientific Advice to pre-submission meetings. These discussions may also cover the Paediatric Investigation Plan (PIP) or the process of obtaining Orphan Drug Designation.

When it comes to cutting-edge therapies, it is useful to keep a close eye on approval timelines so that the overall market launch strategy can be adapted accordingly. Each meeting should therefore be seen as an opportunity to build a relationship of trust with the authorities.

Understanding the expectations of the regulatory agencies: EMA and ANSM

To succeed in this task, it is essential to adapt to the specific characteristics of each audience. Both the EMA and the ANSM have clear objectives: to validate the relevance of pharmaceutical, preclinical and clinical data and to ensure that the risk-benefit balance is favourable to the patient. The formats required are, therefore, strictly codified and must be based on scientific documentation of the highest quality.

Clarity and transparency are key when preparing technical documents and presentation slides. An effective presentation should not just look good. Above all, it must serve as factual evidence. Experts therefore expect complete consistency between the data presented in each visual and the substantive dossier already submitted. Any inconsistency can become a major sticking point and delay the product’s planned marketing process by several months. This rigour in presentation ensures a robust procedure for obtaining a Marketing Authorisation (MA).

The key steps to a successful presentation

Preparing and planning the presentation

Preparation is the first step towards success. It is essential to plan ahead for the meeting. To do this, drawing up a detailed reverse schedule helps to gather the relevant data, as well as to identify the most suitable in-house experts to contribute. This collaborative phase should result in the development of a clear message, in which every chart and every idea serves to support the main argument.

Team preparation and mastering the audition

Preparing the team is the second key step. It is not enough simply to have the data; you must also be able to present it confidently and manage the stress inherent in this type of hearing. Organising rehearsals that simulate the actual hearing helps to refine the language used and ensures that everyone in the group knows their role. A well-structured and consistent Q&A training session helps to answer the authorities’ most technical questions without hesitation.

D-Day session and strategic follow-up phase

On the day of the oral presentation, time management and a professional demeanour are crucial. At this stage, it is important to be factual and concise, and to maintain eye contact with the agency members to hold their attention. Finally, the follow-up after the presentation is all too often overlooked. However, it is essential to write a detailed report after the meeting. This is to analyse the agency’s feedback and adjust the development plan accordingly. This adjustment phase is critical, as it determines the project’s long-term viability. Regardless of the laboratory’s objective (national or European marketing), this stage finally confirms the prerequisites required to market a medicinal product in France and/or Europe.

A successful presentation does not end when the presentation is over. Follow-up is the stage that turns a verbal exchange into concrete regulatory decisions.

Mistakes to avoid when securing your project

One of the most common mistakes is to approach the agency with an unclear message or without having reached an internal consensus beforehand. If the company’s own experts cannot agree on the interpretation of a clinical result, the health authority will spot this immediately. This will seriously undermine its credibility. Similarly, providing unverified or incomplete data poses a significant risk and may slow down the consultation process with the agency and, ultimately, the approval of the medicinal product.

Underestimating the importance of communication and presentation is another common mistake. Even excellent scientific expertise risks not being fully appreciated if it is poorly presented. It is also important to pay attention to logistical matters, such as meeting submission deadlines and preparing supporting documents. The selection of service providers is a further risk factor.
Choosing the right partners for preclinical and clinical development ensures an unbroken data chain.

Finally, for drug candidates in the final stages of development, planning for post-marketing pharmacovigilance obligations in Europe must be considered from the dossier submission stage onwards.

The importance of expert support

Delivering a successful presentation to national or European agencies requires a thorough understanding of the subject matter and regulatory requirements. The company’s commitment to public health must be evident through flawless professional preparation. Seeking support from a regulatory affairs expert, such as Alhena Consult, is an invaluable service that can significantly improve your chances of success.

The impact of a favourable scientific opinion or a successful pre-submission is then measured in terms of time saved and faster market access. In addition to the approval of the main dossier, these meetings provide an opportunity to discuss specific schemes, such as early and compassionate access in France, in order to meet the needs of patients awaiting treatment. By managing every stage of the submission process effectively, the company is able to turn stringent regulatory constraints into genuine drivers of strategic development.

Sources

• ANSM (French National Agency for Medicines and Health Products Safety): framework for Scientific Advice and pre-submission meetings for the submission of Marketing Authorisation applications.
• EMA (European Medicines Agency): guidelines on interactions with the committees (CHMP/PRAC) under the Centralised Marketing Authorisation procedure.
• HAS (French National Authority for Health): guidelines on exceptional access schemes (early and compassionate access) in France.
• ICH (International Council for Harmonisation): international standards (M4) for the structure of technical and safety dossiers for healthcare products.

Regulatory anticipation to break the linearity of the timetable

Rapid market access depends above all on the company’s ability to stop viewing the stages sequentially and instead bring them together. Historically, Marketing Authorisation Applications (MAA) were only submitted once the clinical files had been completely closed. Today, industry leaders favour a proactive approach, consulting agencies as soon as pivotal studies are designed. The use of early access mechanisms is a major lever in this regard. In Europe, the European Medicines Agency’s (EMA) PRIME programme provides enhanced support and early dialogue, often paving the way for Accelerated Assessment. At the same time, in the United States, the FDA offers statuses such as Fast Track or Breakthrough Therapy, which can radically transform the submission timetable. It is also essential to understand the key differences in the approval of innovative therapies in order to choose the most favourable territory for a priority launch.

To save time, the aim is to reduce approval times through this accelerated assessment. In very specific contexts of public health emergencies or major unmet medical needs, the EMA may also authorise a “rolling review”. This mechanism, although less common outside of health crises, allows experts to evaluate quality modules and non-clinical data well before the results of the final clinical study are available. By anticipating the review of data in this way, this method makes it possible to obtain a scientific opinion much more quickly after the completion of phase III.

Industrial synchronisation: CMC at the service of marketing

The success of a therapy depends not only on its medical validation, but also on the laboratory’s ability to produce on a large scale according to the strictest standards. The CMC (Chemistry, Manufacturing and Controls) component often represents the insidious bottleneck of post-development. Anticipating industrial challenges means that the development of manufacturing processes must progress in tandem with clinical phases. The validation of sites and production lines must be initiated well before final authorisation is obtained. For innovative medicines, this step is critical. Particular attention must be paid to compliance manufacturing requirements. Even the slightest change in the process after clinical trials may require the company to prove bioequivalence, which would delay market launch by several months.

This forward planning also extends to logistics and raw materials. By securing stocks and anticipating packaging and labelling specific to the various European Union member countries, the healthcare industries ensure that the first launch units can be shipped as soon as the European Commission gives its approval. This reverse planning must incorporate all GMP (Good Manufacturing Practices) compliance requirements so that no inspection by the ANSM or any other national authority can block the product’s launch at the last minute.

Operational cross-functionality to break down internal silos

Real acceleration cannot happen without seamless coordination between internal teams. Too often, the regulatory affairs, production, quality and market access departments work in isolation, only sharing information at the end of each stage. To increase efficiency, it is essential to establish a culture of collaboration from the middle of the clinical development process onwards. Early integration of the constraints of each profession makes it possible to identify risks before they become insurmountable obstacles. For example, involving pharmacovigilance experts from the outset of the marketing authorisation application process makes it possible to structure a robust risk management plan that will meet the expectations of the authorities without requiring multiple back-and-forth exchanges.

This cross-functional approach also makes it easier to anticipate post-marketing pharmacovigilance obligations. By forming a multidisciplinary launch team, the company ensures that its commercial strategy is consistent with scientific promises and regulatory realities. This synergy is all the more valuable when it comes to choosing the right partners.

Anticipating availability through the new early access framework

In France, the early access system represents an exceptional opportunity for innovative medicines. This system, which followed the major reform of ATUs (Temporary Use Authorisations) in France, makes it possible to make a treatment available to patients who have reached a therapeutic impasse. This can be done even before the marketing authorisation has been officially granted. Beyond the ethical aspect and the immediate benefit to public health, early access is a key strategic tool. It allows financial coverage by health insurance to begin much earlier and enables the collection of extremely valuable real-world data. This data will then support the assessment by the Transparency Commission of the Haute Autorité de Santé (HAS) during negotiations on price and reimbursement rates.

Mastering the mechanics of early access requires meticulous preparation. It is necessary to demonstrate that the drug offers real therapeutic progress and that its implementation is safe. This system bridges the gap between the end of research and full commercialisation, enabling a smooth transition to the common market.

Preparing the commercial ground and perception of value

While obtaining marketing authorisation is a unified European step, effective patient access to treatment depends on decision-making processes specific to each Member State. Pricing and reimbursement decisions remain a national competence, requiring specific applications to be submitted to each local health authority as soon as marketing authorisation is granted.

This crucial step must be prepared well in advance of the EMA’s opinion so as not to delay the availability of the treatment. This involves building a solid case demonstrating the therapeutic and medico-economic value of the product according to the specific requirements of each country. In France, for example, the dossier must demonstrate the medical benefit and the improvement in medical benefit in order to justify the cost of the treatment to the Ministry of Health and Social Security. Only a detailed understanding of how a drug is marketed allows the strategy to be adapted to the specific regulatory and economic characteristics of each territory.

Accelerating the arrival of a drug on the market is a high-precision exercise. There is no room for improvisation when managing key stages, making it strategically essential to rely on an expert partner. Alhena Consult supports you in transforming these challenges into opportunities for growth. Thanks to our operational support and expertise in regulatory affairs, we ensure that your strategy is consistent so that your innovations achieve their ultimate goal: treating patients effectively and quickly.

In this competitive environment, complete internalization of the value chain has become rare. Outsourcing is now an essential operational lever. Choosing the right partner goes beyond a simple customer-supplier relationship. It is above all a strategic decision that directly impacts data quality, meeting deadlines, and ultimately obtaining regulatory approval.

Understanding needs: from early stages to patient administration

Before entering into any collaboration, it is essential to precisely define the technical and regulatory requirements, which vary considerably depending on the stage of development.

The preclinical phase: proof of concept and safety profile

This stage marks the transition from fundamental research to human trials. Its objectives are to demonstrate proof of concept (efficacy) and assess the toxicity of the drug candidate. The partnership requirements here focus on cutting-edge scientific expertise: screening and selection of candidates, relevant animal models, and pharmacokinetic (ADME) and toxicology studies.

The clinical phase: methodological requirements and patient safety

From the start of phase I (first administration to humans) through to phase III, the challenges evolve. Beyond the scientific aspect, the priority extends to logistics, the protection of individuals and strict compliance with ethical and regulatory standards. This cycle does not end with the granting of authorisation: it continues with post-marketing pharmacovigilance.

Each of these phases requires specific skills and structures.

Identify key outsourcing stakeholders

The R&D services market is segmented. Distinguishing the roles of each partner is a prerequisite for building an effective project team.

CROs (Contract Research Organisations)

These are the central partners in outsourcing. A CRO can take on all or part of the operations.

• Preclinical CROs: these have the infrastructure and equipment necessary to conduct regulatory pharmacokinetic and toxicology tests.
• Clinical CROs: these orchestrate the operational implementation of trials: submission and obtaining approval for clinical trials, site selection, monitoring, data management and biostatistical analysis.

The choice between a global organisation (present in America, Europe and Asia) and a niche CRO (specialising in oncology or gene therapy, for example) will depend on the size of the trial and the resources allocated.

Specialised analytical laboratories

Some tests require specific expertise that generalist CROs do not always possess. This is the case for sample bioanalysis (pharmacokinetics/toxicology), the development of complex biomarkers, immunogenicity, and certain genomic analyses. These state-of-the-art laboratories are therefore essential for obtaining robust biological data.

Regulatory experts and consultants

Although they are not directly involved in experimental operations, their role is crucial. They anticipate the requirements of agencies (EMA, FDA) in order to prevent costly data from being rejected for non-compliance. A solid regulatory strategy then makes it possible to secure the process and reduce development time.

Patient associations and research centres

These stakeholders are essential, particularly in the field of rare diseases. Collaborating with an association at an early stage helps to optimise the protocol design to ensure its feasibility for patients and thus facilitate recruitment. Similarly, the selection of investigation centres (hospitals, networks such as Unicancer or research institutes) determines the speed of inclusion. In this regard, there are specific challenges, particularly for low-prevalence diseases.

Read our analyses on the development of medicines for rare diseases.

Selection criteria: prioritising long-term value

Selecting a service provider based solely on economic criteria represents a major risk. This can impact the viability of the marketing authorisation application. Here are the fundamental criteria to evaluate.

Technical expertise and therapeutic experience

Has the partner already conducted a similar trial? Do they have expertise in the specific biomarkers for your therapeutic area? A CRO with expertise in cardiology will not necessarily be effective for a vaccine or cell therapy.

Regulatory compliance: the distinction between GLP and GCP

Mastering this framework is crucial.

• In preclinical trials: it is important to note that not all studies require GLP (Good Laboratory Practice) certification. Exploratory discovery or early pharmacology studies may be conducted in a ‘non-GLP’ manner (with scientific rigour). However, pivotal safety studies (regulatory toxicology) must comply with GLP.
• In clinical trials: at this stage, compliance is mandatory. Compliance with GCP (Good Clinical Practice) is mandatory for all clinical research. To ensure the compliance of your future trials, it is essential to understand the requirements of the EMA (European Medicines Agency).

Communication and transparency

In a complex development project, unforeseen circumstances will inevitably arise. A reliable partner is one who immediately reports difficulties and proposes a corrective solution. Transparency regarding progress, deviations from protocol and budget management is a key indicator of trust.

Financial and operational stability

For a biotech company, ensuring the financial stability of its CRO throughout the entire Phase III trial is vital. Similarly, it is important to verify their IT capabilities and GDPR compliance (Health Data), issues that are increasingly monitored by the authorities.

The importance of centralised regulatory coordination

The multiplicity of stakeholders creates fragmentation that can hinder the project. This compartmentalised approach often leads to inconsistencies in the final dossier.

It is in this context that the support of a consulting firm with expertise in regulatory affairs guarantees overall consistency:

• Roadmap: support for establishing regulatory requirements and the type of studies to be conducted, consultation for scientific advice (when, how and where, depending on the stage of development, the type of molecule and the pathology).
• Strategic alignment: verifies that the protocols proposed by the CRO adequately address the scientific questions raised by the EMA or FDA.
• Smooth communication: liaises between the raw data from the laboratories and the drafting of the CTD (Common Technical Document)* modules.
• Compliance control: ensures that practices comply at all times with the requirements of agencies, in particular the EMA (Europe) and the FDA (US).
• Anticipation: prepares the final stages from the start of the trials.

* Standardised structure, agreed upon by international regulatory authorities, for the submission of marketing authorisation applications (MAAs).

To visualise the outcome of this work, understand the process for obtaining marketing authorisation (MA) for a new drug.

This coordination is also essential for preparing for the post-MA phase. The data collected during clinical trials form the basis of the future monitoring system. Inadequate management of safety data during the clinical phase will complicate the implementation of future obligations, particularly with regard to post-MA pharmacovigilance obligations.

Conclusion

The choice of partners for preclinical and clinical development requires in-depth analysis. The aim is to build a network of complementary skills capable of transforming scientific innovation into medical reality. Regulatory coordination therefore provides strategic direction for development. Without an integrated view of regulatory requirements, technical excellence alone does not guarantee market access. Alhena Consult positions itself at this critical interface to secure your choices and streamline the path of your innovation to patients.
Would you like to structure your development plan and secure your choice of service providers? Our experts are available to audit your strategy.

Establishing early dialogue with these authorities is therefore the solution to guaranteeing patient access to care while securing investments. When managed well, these interactions make it possible to align strategy with the expectations of evaluators. They therefore offer significant time savings and accelerate development.

Effective management of these exchanges is also a key lever for accelerating a drug’s market entry by securing regulatory milestones from the earliest phases of the project.

Understanding the role and scope of health agencies

In a globalised context, it is crucial to distinguish between the different stakeholders. While their common mission remains the protection of public health and the assessment of the benefit/risk ratio, their jurisdictions and operating methods differ.

The EMA and national regulatory agencies

The European Medicines Agency and national regulatory authorities coordinate the scientific evaluation of medicines developed for the European Union market. Its committees issue scientific opinions that are decisive for the authorisation of new medicines.

The FDA

In the United States, the Food and Drug Administration is the sole point of contact. It combines the roles of evaluator and decision-maker.

To better understand the nuances between these two giants, check out our analysis of their key differences.

The MHRA (Medicines and Healthcare products Regulatory Agency)

Since Brexit, the British agency has been operating independently. It remains an influential player, often pioneering innovation mechanisms.

Poor communication with these entities can have serious consequences: requests for additional clinical studies, suspension of trials, or even refusal of registration.

Different types of interactions: from concept to market

Opportunities for exchange vary depending on the stage of product maturity and the therapeutic area concerned.

Early stage interactions

Even before entering clinical trials, experimentation must be rigorously supervised. This is a critical phase in order to avoid taking the wrong direction during the preclinical development of a drug.

• In Europe (EMA): for highly innovative technologies or new methods, the ITF Briefing Meeting (Innovation Task Force) provides an informal discussion platform. Scientific Advice then provides a formal opinion on quality, preclinical or clinical development plans.
• Some European national agencies, such as those in the Netherlands, also offer early dialogue mechanisms, allowing for discussion with the authorities from the very early stages of development.
• In the United States (FDA): the informal equivalent for breakthrough innovations is often the INTERACT meeting. The key formal step is the Pre-IND Meeting (Investigational New Drug), which is essential before launching the first human trials across the Atlantic.

During clinical development

Once trials have begun, dialogue must remain fluid. Key moments include End-of-Phase Meetings (particularly at the end of phase II in the United States). These are crucial for validating the design of future pivotal phase III studies and securing investment. However, interim discussions may be necessary during the study. These interactions help to avoid deviations and reduce development time.

In addition, the EMA, through Scientific Advice, offers structured support for clinical development and supports project leaders throughout the drug development cycle.

Pre-MA (Pre-submission) interactions

Just before submission, pre-submission meetings and follow-up meetings are held to ensure that the format of the dossier is compliant. This is the time to check that the dossier is appropriate for the marketing authorisation (MA) process.

Post-authorisation: a continuous cycle

Product lifecycle management requires regular interaction to ensure that new safety requirements are implemented. After authorisation, the relationship continues through periodic safety update reports (PSURs), marketing authorisation variations for new indications, and regulatory on-site inspections. Compliance remains a priority in order to scrupulously meet post-marketing pharmacovigilance requirements.

Best practices for successful interactions

A meeting with an agency cannot be improvised. It is a high-stakes exercise that requires meticulous preparation.

Define a clear regulatory strategy

You should never approach a health agency without a precise battle plan. The interaction should aim to validate a specific approach. It is therefore essential to anticipate the authorities’ questions. But you should also prepare the exact objectives of the meeting and define the key messages to be conveyed in advance. This strategic preparation will help you avoid distractions.

Building a credible case

Data quality and clinical consistency are paramount. A clear narrative and transparent information reinforce the credibility of the application, especially with regard to compliance requirements.

Prepare the internal team

Effective preparation involves reviewing likely questions and aligning positions. Assigning roles during the meeting ensures a professional image.

Manage the meeting professionally

Establishing effective communication helps build trust. The aim is to encourage dialogue to facilitate data validation through clear and substantiated responses.

Making effective use of feedback

It is essential to analyse recommendations and update the development plan. In the case of rare diseases, among others, this ability to adapt is vital.

Why seek support from a specialist partner?

The process of coordinating with the authorities requires expert resources in order to avoid common pitfalls. The support of a specialist partner provides cross-functional expertise:

• Multi-agency expertise: having a global vision makes it possible to harmonise the often divergent requirements of the EMA and the FDA.
• Knowledge of ‘unwritten rules’: beyond the letter of the law, experience of past interactions provides an understanding of the implicit expectations of assessors and current trends.
• File structuring: an expert consultant knows how to present arguments to maximise their impact and reduce the risk of blocking questions. This is particularly relevant when navigating complex frameworks such as clinical trials.
• Support during meetings and post-meeting follow-up: the presence of expert consultants during direct discussions with agencies helps to moderate debates and ensure that technical responses are formulated in the best possible way.
• Reduced risk of additional requests: expert advice helps to anticipate sticking points in order to avoid requests for additional studies and secure approval deadlines.
• Comprehensive operational support: from medical expertise to pharmacovigilance management, the use of specialist consultants enables continuous improvement of the dossier and contributes significantly to the success of the marketing authorization.

Conclusion

The relationship with health agencies is a common thread that runs through the entire life cycle of a medicine. It is not a mere administrative formality, but a demanding collaboration which, when mastered, becomes a catalyst for success.

Identifying the right moment to communicate. Preparing a flawless dossier. Demonstrating professionalism during exchanges. All these steps are the pillars of a winning strategy.

Surrounding yourself with experts who can decipher regulatory expectations and coordinate these interactions is often the most profitable decision for your development. Alhena Consult positions itself as your strategic partner to ensure this link with agencies, providing you with the operational support and regulatory expertise you need to successfully navigate each step.

Orphan drug designation: criteria and procedure

The “orphan” designation is the first hurdle to overcome. It does not equate to marketing authorization, but it is the key that unlocks access to incentives.

Strict eligibility criteria

For a product to obtain this designation from the Committee for Orphan Medicinal Products (COMP) and the European Commission, the sponsor must prove:

• Prevalence: the condition must affect no more than 5 in 10,000 people in the EU.
• Severe condition: the condition must be life-threatening or cause chronic serious disability.
• No alternative or significant benefit: if an authorized treatment already exists, the new drug must offer a “significant benefit” to patients.

The application dossier submitted to the EMA

The application is evaluated by the EMA’s Committee for Orphan Medicinal Products (COMP). This dossier requires absolute scientific rigor, combining bibliographic data and preliminary results. The schedule is strict: once the application has been administratively validated, the procedure lasts 90 days.

Interactions with the COMP (questions/answers, oral hearings) are frequent and decisive. The possibility of requesting a meeting/teleconference prior to submission is also strongly recommended: the EMA strongly encourages sponsors to request this meeting as it allows for an initial regulatory assessment of the application and provides advice on possible improvements to the application that will be submitted.

Validation steps and average timeframes

Once the evaluation is done, the COMP gives its opinion. If it’s positive, the European Commission then has 30 days to approve the decision and add the product to the Community list of orphan designations.

Regulatory and financial benefits

Once designation has been obtained, the benefits are tangible:

• 10-year marketing exclusivity after marketing authorization;
• Protocol assistance: scientific advice at reduced cost or free of charge;
• Reduction in administrative fees charged by the EMA;
• Access to specific funding for European research.

Regulatory stages of development

The development of an orphan drug does not follow a conventional straight line. The scarcity of available data means that each stage must be optimized.

Preclinical and clinical: adapting to rarity

From the preclinical development stage of a drug, it is necessary to anticipate the transition to human trials. In the clinical phase, the small number of patients affected makes large randomized trials difficult. The EMA therefore encourages innovative study designs. It is therefore crucial to be aware of the EMA’s requirements for clinical trials so as not to invalidate years of research with a protocol that does not comply with European regulatory standards.

Strategic interactions with the EMA

To ensure a smooth process, dialogue with agencies is based on several key mechanisms:

• Scientific Advice: a major risk mitigation tool. It allows developers to submit questions to the agency regarding quality development.
• Protocol Assistance: a version of Scientific Advice dedicated to orphan drugs. It allows the relevance of planned studies to be validated with the EMA.
• PRIME (PRIority MEdicines) program: if the drug meets a major unmet medical need, it can benefit from enhanced support and accelerated assessment.

Documents to prepare and recommendations for each phase

Regulatory success depends largely on anticipating the documentation required, which acts as validation milestones.

• Early phase (ODD designation dossier): this stage requires the compilation of a solid scientific argument proving medical plausibility and compliance with prevalence criteria.
• Preclinical and clinical development; protocol assistance, PRIME if applicable.
• Clinical development: even for a rare disease, a PIP (Pediatric Investigation Plan) must be submitted to the EMA, usually after the first pharmacokinetic studies. If the disease only affects children, the EMA may also request that the PIP be submitted at the end of the preclinical phase before clinical studies begin.
• Marketing authorization application: the final dossier (Common Technical Document¹) compiles all the modules.

Evaluation and authorization procedures (MA)

Unlike conventional medicines, which can sometimes go through national procedures, orphan drugs must follow the centralized procedure with the EMA. A single MA opens the doors to all 27 EU countries.

Assessment by the CHMP and COMP

The MA application is reviewed by the CHMP (Committee for Medicinal Products for Human Use) for a benefit/risk assessment. At the same time, the COMP reassesses whether the orphan designation criteria are still met at the time of authorization. These committees rely on internal expert groups for in-depth data analysis.

To understand the complexity of the application, it is useful to refer to the basics: how to obtain marketing authorization (MA) for a new drug.

Conditional marketing authorization and exceptional circumstances

In the field of rare diseases, waiting for complete data is not always ethical or possible. Conditional marketing authorization therefore allows approval based on less complete data, if the benefit of immediate availability outweighs the risk inherent in the lack of data. Marketing authorization under exceptional circumstances applies when the rarity of the disease makes it impossible to obtain complete data, even in the long term.

These procedures have a direct impact on the EMA’s approval times for new drugs, which can be shortened to speed up access to care.

Post-authorization monitoring and obligations

Obtaining marketing authorization does not mark the end of regulatory oversight. For orphan drugs, monitoring is even more rigorous.

Pharmacovigilance and risk management

Any uncertainties accepted at the time of marketing authorization must be resolved after the drug is placed on the market. The Risk Management Plan (RMP) is therefore particularly detailed. Laboratories must strictly comply with post-marketing pharmacovigilance obligations in Europe. These often include post-authorization safety studies (PASS) or patient registries².

Reassessment of orphan status

The granting of orphan status confers on the holder ten years of market exclusivity from the date of marketing authorization. However, this exclusivity may be lifted after five years if the COMP considers that the drug has become sufficiently profitable to cover all research and development investments.

The “orphan” designation may also be reassessed at any time if the initial conditions are no longer met, particularly in the event of a change in the prevalence of the disease, or if the significant benefit of the product is called into question.

The arrival of a competing drug does not automatically result in the loss of exclusivity, unless it is demonstrated that it provides a superior clinical benefit or that the existing drug no longer meets medical needs.

The role of expert regulatory support

Developing an orphan drug is a race against time. Every regulatory error results in months of delay, or even refusal of approval. The complexity of the dossiers, the specific nature of the arguments to be provided for “significant benefit,” and the management of interactions with EMA require a 360° view.

Alhena Consult supports biotech companies and pharmaceutical laboratories. We help transform scientific innovation into regulatory success. We do this in several ways:

• Strategic structuring: analysis of eligibility for orphan designation and drafting of a well-argued dossier for the COMP.
• Interactions with agencies: preparation and support during Scientific Advice or Protocol Assistance (PIP) meetings.
• Operational drafting: handling of regulatory modules (CTD) for marketing authorization applications.
• Post-marketing authorization support: pharmacovigilance management and maintenance of authorizations.

In a sector where regulations evolve as quickly as science, surrounding yourself with experts allows you to secure your most valuable asset: time to market.

Are you developing a molecule for a rare disease? Do you want to secure orphan status for your drug? Contact Alhena Consult for an audit of your regulatory strategy.

¹ Common Technical Document (CTD): internationally standardized mandatory format used to submit a Marketing Authorization Application.

² Specific obligation required in the Risk Management Plan (RMP) to collect, over the long term and in real-world settings, the safety and effectiveness data that were lacking at the time of Marketing Authorization.

During this phase, the mechanism of action of the drug candidate is validated, and its safety (toxicity) and activity in the body are evaluated. A preliminary pharmacokinetic and pharmacodynamic profile is then established. All of this data is then used as a basis for calculating, with safety margins, the initial dose and route of administration for the first clinical study in humans.

Definition and objectives of preclinical development

Preclinical studies mark the first stage in the life cycle of a drug. Conducted on non-human systems (cell models followed by animal models), these studies identify the drug’s efficacy, mechanism of action, adverse effects, toxic doses, and target organs. They therefore include the analysis of pharmacodynamics, pharmacokinetics (ADME), and toxicology, in accordance with GLP requirements and ICH¹ guidelines. Preclinical development is essential for compiling the regulatory dossier for the clinical trial application (CTA) and the marketing authorization application.

Please note: this article does not detail the clinical phases that follow the preclinical phase. However, it is important to note that the design of the first study in humans, particularly the choice of dose, route, and frequency of administration, is determined by the preclinical results of toxicology and pharmacokinetics. Similarly, the toxicology program continues in parallel with clinical development to monitor long-term safety.

The main stages of preclinical development

The preclinical phase comprises a series of pharmacological and toxicological studies conducted in a progressive manner.

In vitro studies (pharmacology and screening)

Tests conducted on cells or biochemical models confirm the targeted mechanism of action. They then enable promising candidate molecules to be quickly identified. This phase therefore provides early pharmaceutical proof of concept before progressing to more complex trials.

In vivo studies (efficacy and toxicology)

The selected candidates are then tested on animals to assess both efficacy and systemic toxicity. These experiments provide a preliminary safety profile: acute toxicity (single dose), subchronic and chronic toxicity (repeated doses), and reproductive toxicity.

Pharmacokinetics (ADME)

The fate of the drug in the body is then studied (Absorption, Distribution, Metabolism, Excretion). This step measures blood concentration over time, identifies metabolites, and evaluates how the compound is eliminated. It therefore defines, in particular, the appropriate route of administration and frequency in humans.

Pharmacodynamics

During this phase, the dose-response relationship is quantified using dose-response curves and parameters such as the median effective dose (efficacy threshold) and median lethal dose (toxicity threshold). It then validates the activity of the active ingredient at the cellular and organic levels.

Toxicology and safety pharmacology

These specific tests detect any potential adverse effects on vital systems. “Safety pharmacology studies” evaluate, for example, the effects of the candidate at doses higher than therapeutic doses on heart rate, blood pressure, brain function, etc. They follow the principles of the ICH S7A “Core Battery” and must meet GLP² (Good Laboratory Practice) standards.

Specificities according to molecule type

The preclinical study plan varies depending on the nature of the candidate: small chemical molecules, biological molecules, or cell therapy or gene therapy drugs. Biological drugs, for example, require immunogenicity and binding stability testing. Gene therapies involve biodistribution and targeted genotoxicity studies. Additional recommendations are provided depending on the type of therapeutic entity, according to specific regulatory guidelines (EMA for Europe, FDA for the United States).

Preparation of the regulatory dossier

All preclinical results must be compiled in the regulatory development dossier. As part of a clinical trial application, data from preclinical studies are included in the Investigational Medicinal Product Dossier (IMPD) and/or summarized in the investigator’s brochure for a clinical trial application dossier. These elements are then included in the Common Technical Document (CTD), particularly modules 2 (syntheses) and 4 (non-clinical reports) for the marketing authorization application (MAA).

These detailed preclinical data are required by all health authorities in Europe and the United States. This is required even before clinical trials begin. To this end, it must comply with international standards (ICH guidelines). It must also demonstrate that the drug candidate is reasonably safe for initial testing in humans. This same data will be included in the marketing authorization application (MAA).

Challenges and issues in preclinical development

Several challenges arise during preclinical development.

Long duration and high cost

Preclinical development involves complex studies (in vitro, in vivo, toxicology, pharmacokinetics) over several years. Conducting these studies in accordance with GLP requires significant technical and financial resources. These early investments, with no guarantee of success, further increase the overall cost of drug development.

See also: Reducing drug development time

Very high failure rate

More than 90% of drug candidates fail during development. According to a Forbes study cited by PharmAnalyses, the failure rate for candidates is as high as 95%.

Strict regulatory constraints

Studies must comply with numerous standards. To this end, they follow a testing program tailored to each therapeutic indication. The required reports, which must be comprehensive and traceable, significantly increase the regulatory burden.

Ethical constraints related to animal testing

Animal testing, which is essential for preclinical studies, raises major ethical issues. Regulations therefore impose strict protocols, governed by GLP. Alternative approaches (organoids, organs on chips) are being developed in parallel to limit the use of animals.

Prediction limitations and health risks

Certain adverse effects remain difficult to detect in the preclinical phase. This structural risk therefore often requires a margin of safety (safety doses) to be built in. It also requires the continued collection of safety data (pharmacovigilance) well after the preclinical phase, when the drug is used in clinical trials.

Conclusion

Despite these limitations, preclinical development remains essential for the creation of safe and effective drugs. It serves not only to rule out dangerous candidates as early as possible, but also to deepen understanding of the drug. This must be done before taking the risk of administering it to humans for the first time.

¹ ICH (International Council for Harmonization) is an international organization that develops harmonized guidelines to ensure the quality, safety, and efficacy of drugs in the world’s major regulatory markets.
² GLP (Good Laboratory Practice) refers to an international regulatory framework that guarantees the quality, traceability, and reliability of non-clinical studies submitted to health authorities.

Sources:

• Pharmacomedicale: “Drug development and monitoring”
• Interpharma: “Preclinical phase”
• Leem: “Preclinical development or initial evaluation”
• Inserm: “Drug development: from test tube to pharmacy”

This article explores the regulatory framework, the main challenges encountered, and the solutions being implemented to advance research and facilitate access to appropriate therapies.

Definition and key data

A rare disease is a condition that affects a small number of people and requires specialized care. In France, there are approximately 7,000 rare diseases, affecting more than 3 million patients, or nearly 4.5% of the population. Half of these diseases appear before the age of 5 and are responsible for around 10% of deaths between the ages of 1 and 5.

Nearly 80% of rare diseases are genetic in origin. In half of all cases, they cause motor, sensory, or intellectual impairment, and in 9% of cases, total loss of independence.

The term “orphan disease” applies to rare diseases for which there is no effective treatment.

Challenges in developing drugs for rare diseases

Small population size and methodological difficulties

The small number of patients affected by a rare disease is a major obstacle to research. It limits scientific visibility, access to funding, and the ability to conduct robust clinical trials. Prevalence of sometimes fewer than a few hundred cases complicates identification and inclusion. Clinical heterogeneity and the lack of data on natural history hinder the definition of relevant endpoints and weaken protocols.

The methodology of clinical trials is often based on small sample sizes, which limits the scope of the results and increases uncertainty about efficacy in real-world conditions.

Patient-specific issues and limitations of clinical trials

Many rare diseases affect children, which impose specific constraints in terms of ethics, protocols, and appropriate formulations. Clinical trials conducted on small populations do not always allow for the prediction of long-term effects or real-world efficacy at the time of Marketing Authorization. These methodological limitations complicate development and slow down access to treatments. They also undermine the economic attractiveness of the field, as companies have to bear high costs for an uncertain return on investment. This situation justifies the use of specific regulatory and financial support.

Role of stakeholders and need for collaboration

Approximately 61% of clinical trials are sponsored by the pharmaceutical industry, compared to 39% by non-commercial stakeholders, mainly academic institutions. Basic research provides scientific foundations, while companies are responsible for clinical and regulatory development. However, for many rare diseases, the knowledge base remains insufficient, which limits investment. Furthermore, information remains fragmented across different institutions, reducing its usefulness to stakeholders.

These constraints make structured collaboration between researchers, clinicians, patients, funders, and authorities essential. The combination of multidisciplinary skills is a prerequisite for advancing the development of orphan drugs.

The European regulatory framework

An incentive framework to encourage innovation

In order to support the development of drugs for rare diseases, the European Union introduced Orphan Drug Designation (ODD) in 2000. This applies when the prevalence is less than 5 per 10,000 inhabitants and the disease is serious or debilitating.

This designation provides access to several benefits: ten years of market exclusivity, tax reductions, subsidies, and free scientific advice. The EMA also offers the PRIME procedure, which facilitates early exchanges with the authorities. Finally, Marketing Authorization Applications (MAAs) may benefit from accelerated assessment or result in conditional Marketing Authorization or Marketing Authorization under exceptional circumstances, when not all clinical data can be provided.

Persistent constraints and the need for monitoring

While these measures speed up access to treatment, they do not remove regulatory requirements in terms of benefit/risk. Orphan drugs must demonstrate sufficient efficacy and safety despite sometimes limited clinical data. The authorities therefore impose enhanced risk management plans, post-authorization monitoring and, in some cases, additional real-world studies.

These constraints are intended to compensate for the uncertainties associated with small sample sizes and the difficulty of predicting efficacy in real-world conditions. Furthermore, the regulatory framework remains complex for project leaders, who must adapt their development strategy to the specific characteristics of each disease. This complexity justifies the need for specialized regulatory support, capable of anticipating the expectations of agencies, optimizing the choice of procedures, and securing interactions with health authorities.

Collaborative initiatives and the role of patients

Beyond the regulatory framework, the European Union has set up several collaborative programs designed to strengthen research and pool resources.

Among them, the European Joint Program on Rare Diseases (EJP RD) promotes the transition from basic research to clinical application, while the European Reference Networks (ERN) bring together more than 900 specialized units in 26 member states.

The ERICA consortium coordinates the clinical research activities of the ERNs, and infrastructures such as EATRIS and ECRIN support preclinical development and multinational trials.

Platforms such as Orphanet centralize knowledge and facilitate access to information, while the IRDiRC and EURORDIS strengthen international cooperation and the voice of patients.

These initiatives demonstrate the importance of a collective approach to overcoming data fragmentation and optimizing the development of orphan drugs.

Available solutions and levers

Natural History Studies (NHS)

Natural History Studies (NHS) describe the progression of a disease throughout the patient’s life in the absence of treatment. They trace the different phases of the disease, from the pre-symptomatic period to the advanced stages, and incorporate genetic, clinical, and environmental variables.

They play an essential role in rare diseases, enabling the characterization of phenotypes, the identification of patient subgroups, and the definition of appropriate endpoints for clinical trials. However, conducting these studies remains complex due to the small number of patients available and the dispersion of data.

Patient registries

Patient registries complement these studies by collecting clinical and epidemiological information in a structured manner. There are currently more than 700 rare disease registries in Europe (Orphanet). These tools facilitate recruitment for clinical trials, enable post-treatment follow-up, and document phenotypic variability and genotype-phenotype correlations.

They are therefore an essential tool for meeting regulatory requirements and strengthening research by providing a consistent and usable database at the European level.

The importance of strategic and regulatory support

The development of treatments for rare diseases relies on appropriate organization. Collaboration with patient associations provides essential data on disease progression, unmet needs, and therapeutic priorities, which can be incorporated into the design of clinical trials.

Early identification of reliable biomarkers is also crucial to understanding the disease, refining patient stratification, and guiding therapeutic strategies.

Finally, setting up a multidisciplinary team combining researchers, regulatory experts, market access specialists, and patient representatives helps to enhance the quality of development and optimize interactions with health authorities.

Conclusion

Rare diseases collectively affect millions of patients but lack therapeutic solutions. The constraints associated with low prevalence and lack of data are mitigated by a specific regulatory framework, including Orphan Drug Designation and accelerated procedures.

The use of registries, Natural History Studies, and international collaborations is now the preferred route for advancing research and accelerating the availability of treatments.