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Quelle substitution des médicaments biologiques en France?

Biological medicinal products substitution in France?

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Biological medicinal products are used in the treatment of numerous pathologies, such as diabetes, cancer and autoimmune diseases. Any biological medicinal product whose patent has fallen into the public domain can be copied: this is known as a “biosimilar”. A biosimilar is a medicinal product which, like any biological medicinal product, is produced from or derived from a cell or living organism, and whose efficacy and side effects are equivalent to those of its reference biological medicinal product. By February 2022, 67 biosimilar medicinal products had been authorized in the European Union. 

The marketing authorization of a biosimilar medicinal product must meet strict regulatory requirements to demonstrate that its pharmaceutical quality, efficacy and safety are clinically equivalent to those of the reference biologic medicinal product. 

The availability of biosimilar medicinal products has a dual benefit:  

– Public health, by facilitating access to care: increasing the number of biologics available helps to limit supply tensions and prevent stock-outs and/or production accidents. This guarantees patients continued access to their treatments.  

– Economic: stimulating competition and lowering the price of biological medicinal products, while guaranteeing the safety and quality of treatments. 

Since biosimilar medicinal products are derived from living organisms, they cannot be strictly identical to reference products. Consequently, the substitution principle, which applies to chemical medicinal products and their generics, cannot be applied automatically. 

However, in the light of advances in knowledge, interchangeability and substitution during initial prescription or treatment can now be envisaged under strict conditions and within the framework of the indications, dosage regimens and routes of administration common to the reference product. 

In order to guarantee proper use and safety during substitution, this substitution must be introduced gradually, initially for a limited number of medicines. The right of substitution for biosimilars is decided at national level by each member state. In France, the order of April 12, 2022 sets out the first two groups of biosimilars that can be substituted in pharmacies within a specific framework: filgrastim and pegfilgrastim (immunostimulant-cytokine agents). To date, only these two active substances are eligible for substitution in pharmacies. 

What’s the latest on biosimilar substitution in France? 

Pharmacists may substitute biologics under certain conditions: 

– The similar biological medicinal product dispensed belongs to the same similar biological group as the biological medicinal product prescribed, within the reference list of similar biological groups published by ANSM, 

– This similar biological group is included in a list established by a joint order of the ministers responsible for health and social security, issued after consultation with the ANSM (the consolidated order of April 12, 2022), 

– The prescriber has not excluded the possibility of this substitution by expressly stating so on the prescription, 

– The pharmacist must indicate the name of the medicinal product dispensed on the prescription and inform the prescriber and patient of the substitution. 

The gradual introduction of substitution will make it possible to : 

– evaluate in real-life situations the prescribing and dispensing circuit following substitution of biologics by the pharmacist; 

– guarantee the proper use of biosimilar medicinal products and appropriate clinical monitoring of patients (traceability, reporting and assessment of adverse events) in the same way as the reference medicinal product, 

– and to improve information and support for patients and healthcare professionals. 

The reference list of similar biological groups is automatically completed when a new biosimilar MA is granted. It is regularly updated on the ANSM website. It should be noted that this list is not intended to present substitutable or interchangeable biological medicinal products. In this respect, ANSM will make available the list of substitutable biological medicinal products on its website. 

Glossary : 

– Biological medicinal product (article L.5121-1, paragraph 14 of the French Public Health Code): “any medicinal product whose active substance is produced from or extracted from a biological source and whose characterization and quality determination require a combination of physical, chemical and biological tests as well as knowledge of its manufacturing process and control”. 

– Biosimilar” medicinal product (article L.5121-1, paragraph 15 of the French Public Health Code) “any biological medicinal product with the same qualitative and quantitative composition in active substance and the same pharmaceutical form as a reference biological medicinal product, but which does not meet the conditions laid down in 5° of this article to be considered as a generic, due to differences linked in particular to the variability of the raw material or the manufacturing processes, and requiring the production of additional preclinical and clinical data under conditions determined by regulation”. 

– Reference medicinal product: biological medicinal product approved in the EU that a company developing a biosimilar medicinal product chooses as a reference point for direct comparison of quality, safety and efficacy. 

– Interchangeability: refers to the possibility of replacing one medicinal product with another that is intended to have the same clinical effect. Interchangeability can be achieved in two ways: 

– Permutation: when a prescriber substitutes one medicinal product for another with the same therapeutic intent. 

– Substitution: the practice of dispensing a medicinal product in place of another equivalent and interchangeable medicinal product, without reference to the prescriber. 

This article was written by Leslie Gorge.

Ouvrir votre établissement pharmaceutique

How to open a pharmaceutical establishment in France?

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  1. What status for my establishment? 

In France, the Public Health Code (PHC) defines different status: 

Status Authorised activities 
Manufacturer Manufacture of medicinal products, products or objects referred to in Article L. 4211-1 of the PHC 
Importer Import, storage, quality control and release of batches of medicinal products, products or objects referred to in Article L. 4211-1 from: States not members of the European Community or parties to the Agreement on the European Economic Area Or other Member States of the European Community or parties to the Agreement on the European Economic Area when the medicinal products, products or articles have been manufactured by an establishment not authorised under Article 40 of Directive 2001/83 of 6 November 2001 on the Community code relating to medicinal products for human use. 
Exploitant Exploitation of medicinal products other than investigational medicinal products, generators, kits and precursors mentioned in 3° of article L. 4211-1. 
Depositary Storage of medicinal products, products, objects or articles of which it is not the owner, with a view to their wholesale distribution and as is for the order and on behalf of: – one or more Exploitant of medicinal products, generators, kits or precursors mentioned in 3° of article L. 4211-1; – or of one or more manufacturers or importers of dressing objects or articles presented as complying with the Pharmacopoeia mentioned in 2° of article L. 4211-1 of the PHC. 
Wholesaler Purchase and storage of medicinal products, other than investigational medicinal products, with a view to their wholesale distribution as such 
Wholesale distributor of pharmaceutical products other than medicinal products Purchase and storage of intermediate products intended for further processing by an authorised manufacturer or of products, objects, articles, generators, kits or precursors referred to in 2° and 3° of Article L. 4211-1, with a view to their wholesale distribution and as such 
Export Wholesale Distributor Purchase and storage of medicinal products other than experimental medicinal products, products, objects, articles, generators, kits or precursors referred to in 2° and 3° of Article L. 4211-1, medicinal plants referred to in 5° of Article L. 4211-1, with a view to their export as such 
Humanitarian wholesale distributor Acquisition, free of charge or against payment, and storage of medicinal products other than investigational medicinal products, with a view to their wholesale distribution or export 
Distributors of investigational medicinal products Storage of investigational medicinal products manufactured or imported by companies or organisations defined in 1° or 2° of this Article (R.5124-2), with a view to their distribution as such for the order and on behalf of one or more sponsors defined in Article L. 1121-1 
Wholesale distributor of medicinal plants Storage and controls and operations necessary for the wholesale and bulk distribution, in sachet-doses, fragments or in a fresh or dried state of medicinal plants mentioned in 5° of Article L. 4211-1 
Wholesale distributor of gases for medical purposes,  Purchase and storage of packaged gases for medical use, with a view to their wholesale distribution and as such 
Wholesale distributor of the Armed Forces Health Service Wholesale distribution of the medicinal products, products or objects referred to in Article L. 5124-8; 
Pharmaceutical establishment for the protection of the population in the face of serious health threats Purchase, manufacture, import and export of products necessary for the protection of the population against serious health threats, with a view to their distribution. 
Pharmaceutical purchasing centre  Purchase and storage of medicinal products other than experimental medicinal products, with the exception of medicinal products reimbursed by compulsory health insurance schemes, with a view to their wholesale distribution as such to pharmacists who are the owners of a dispensing service either in their own name and on their own behalf, or in order and on behalf of pharmacists who are members of a dispensing or the structures mentioned in Article D. 5125-24-16 

Some status are cumulative for all or part of an activity related to its status for the same legal institution. Example: a pharmaceutical establishment may be granted Exploitant status and may be granted manufacturer status limited to batch certification. 

  1. Who issues the opening authorisation? 

The Public Health Code specifies that the authorisation to open a pharmaceutical establishment is issued by the Director General of the National Agency for the Safety of Medicines and Health Products (ANSM). This opening authorisation is made public on EudraGMP. The start of the activity therefore requires prior authorisation from the ANSM to ensure that the project complies with the regulations and to verify that the necessary resources are available and that they will be implemented. This can be a challenge, for example when early access is about to start, or when a drug is being launched. Indeed, the Exploitant must be designated. 

The opinion of the competent central council of the National Order of Pharmacists is required within 2 months for any opening of a pharmaceutical establishment, except for a pharmaceutical establishment dependent on the central pharmacy of the armed forces or the health supply establishments of the armed forces health service. At the end of the 2 months, the Director General of the ANSM can make a decision. 

  1. How to compile your file?  

For the opening of a pharmaceutical establishment, the ANSM website has 3 types of files available depending on the desired status:  

  • Manufacturer/Importer file 
  • Exploitant’s file 
  • Distributor file 

In the event of a combination of activities, as in our example above for example, 2 files must be completed. 

The application to be submitted must comply with the decision of 1 October 2019 on the submission of applications for authorisation to open and amend the initial authorisations of the pharmaceutical establishments mentioned in Article R. 5124-2 of the Public Health Code, except for establishments under the authority of the Minister for the Armed Forces (cf. Article R. 5124-5 of PHC). 

Such a project includes essential areas of vigilance to carry it out. The constitution of the file requires defining the appropriate status according to the desired activity, anticipating the implementation of the desired organization to write a file that is as compliant as possible with what will be carried out in the future establishment as well as with the regulations in force. The ANSM is particularly attentive to the aspects of pharmaceutical liability, compliance with GxP and security of the premises. Identifying the pharmacist in charge upstream is a crucial point. 

  1. What is the processing time? 

No pharmaceutical operation may be carried out within the establishment until the authorisation to open has been obtained.  

Depending on the desired activity, the applicant submits an application for authorisation to open a site to the ANSM via the dedicated secure platform “Démarches Simplifiées”. 

Under the Public Health Code, the Director General of the ANSM is required to notify his decision within 90 days. 

Once the file has been submitted by the Responsible Pharmacist in charge of the future establishment via « Démarches Simplifiées », the Responsible Pharmacist receives an email acknowledging receipt of the file. 

The admissibility period begins. It lasts for 30 days from the date on which the application is received by ANSM, and allows the content of the application to be analysed: missing documents, incorrect naming of documents, etc. If the ANSM does not receive any requests within 30 days, the application is considered “admissible” and the processing can begin. 

The ANSM may ask the applicant for any additional information. The 90-day period is then suspended from the date of notification to the Responsible Pharmacist of the request for additional information by the Director General of the ANSM, until receipt of the information requested. 

The ANSM may also carry out an inspection during the processing period to ensure the accuracy of the information provided by the applicant. 

If ANSM does not respond within 90 days, this is equivalent to: 

  • refusal of authorisation for manufacturer and importer applications.  
  • tacit authorisation for other establishments. 

In recent years, Atessia has opened, modified or relocated more than a dozen pharmaceutical establishments. 

This article was written by Isabelle BARBIEUX, Senior Quality Assurance Consultant. 

The Jardé Law and Research Involving Human Subjects (RIPH): How Are Pharmaceutical Companies Affected? 

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Medical research is essential for the development of new treatments and the improvement of healthcare. 

In France, this research is governed by strict regulations designed to protect participants and ensure the integrity of human subjects. The Jardé Law, adopted in March 2012 and enforced since November 2016, is the legal framework for research involving human subjects (RIPH). 

It should be noted that clinical trials involving medicinal products are primarily regulated by the EU Clinical Trials Regulation (EU) 536/2014 (CTR), which came into effect on January 31, 2022. This regulation replaces Directive 2001/20/EC. As a reminder, any clinical trial with at least one active investigative site in France as of January 31, 2025, must be transitioned to the Clinical Trials Information System (CTIS) by its sponsor before this date. For clinical trials involving medicinal products, the Jardé Law introduces additional requirements to be considered. Other provisions include compliance with CNIL (GDPR), and procedures related to the use of medicinal products composed wholly or partially of genetically modified organisms (GMOs). 

Depending on whether the research concerns a medicinal product or another health product, such as medical devices (clinical investigation) and in vitro diagnostic medical devices (performance study), cell therapy preparations, tissues, organs, labile blood products (LBPs), or even research on dietary supplements or cosmetics, the applicable regulations vary. 

What is the Jardé Law? 

The Jardé Law, named after Deputy Olivier Jardé, is a regulation that governs the conditions under which research involving human participants can be conducted. It replaces the Huriet-Sérusclat Law of 1988 and aims to enhance the protection of participants while facilitating the conduct of clinical research. 

The main reference texts include: 

– The Jardé Law, Law No. 2012-300 of March 5, 2012, relating to research involving human subjects. 

– The ordinance, known as the “modified Jardé Law,” relating to research involving human subjects. 

– Decree No. 2016-1537 of November 16, 2016, relating to research involving human subjects. 

– The Public Health Code (Articles L1121-1 to L1126-11), which details the specific obligations for different categories of research. 

Classification of RIPH 

Research organized and conducted on human beings with the aim of developing biological or medical knowledge is referred to as “research involving human subjects” (RIPH). There are three types of RIPH: 

Category Legal Provisions Framework 
Category 1 Interventional research involving a risk to participants Articles L1121-1 and L1121-3 of the Public Health Code (CSP) These studies require prior authorization from the ANSM (French National Agency for Medicines and Health Products Safety) and a favorable opinion from a Committee for the Protection of Persons (CPP). 
Category 2: Interventional research with minimal risks and constraints Article L1121-2 of the CSP These studies require a favorable opinion from a CPP, but not authorization from the ANSM. 
Category 3: Non-interventional research Article L1121-1-1 of the CSP These involve observational studies where the risks are absent or negligible. A favorable opinion from a CPP is necessary, but these studies do not require authorization from the ANSM. 

What Are the Implications for the Industry? 

Participant Information 

The objective of the Jardé Law is to ensure the safety of participants. Special attention is given to the notions of informed consent and clear information. 

Manufacturers must ensure that participants fully understand the stakes, procedures, risks, and potential benefits of the study. These requirements are detailed in Articles L1122-1-1 to L1122-2 of the Public Health Code (CSP). 

Information for the ANSM 

Manufacturers must determine the category of their research during the design phase and ensure they obtain the necessary authorizations. Notably, for RIPH involving medicinal products, they cannot be classified as RIPH 2. An order specifies the criteria to remain within the scope of RIPH 2. For category 1 RIPH, this involves submitting a complete dossier to the ANSM and obtaining a favorable opinion from a CPP (Article L1121-4 of the CSP). Since 2022, for clinical trials on medicinal products, the CTR requires submission through the CTIS platform. Proper classification of your RIPH is a prerequisite for any procedure. 

Interactions with CPPs and the ANSM 

CPPs are French ethics committees. Interactions with CPPs and the ANSM are essential for the validation of research projects. Good communication and submission of complete dossiers are necessary, in accordance with Articles L1123-6 and L1123-7 of the Public Health Code. 

Procedures 

Before submitting the authorization request dossier (initial authorization and substantial modification) and/or human research opinion request, or routine care research, sponsors must obtain an IDRCB registration number for the research. This number identifies each research conducted in France. For a biomedical research authorization and opinion request concerning a medicinal product for human use, sponsors must obtain a research registration number in the European CTIS database (formerly: EudraCT). 

Subsequently, sponsors will electronically submit the biomedical research authorization and/or opinion request dossier to the ANSM and/or CPP, in accordance with the current orders setting the dossier formats for each type of research. Various “Notices to Sponsors” guide these procedures according to the situation. 

Conclusion 

The Jardé Law thus ensures the safety of participants in clinical research in France. 

For health manufacturers, understanding and complying with these regulations is not only a legal obligation but also a guarantee of the quality of the data generated, particularly for use in a Marketing Authorization Application (MAA) dossier. 

By integrating the requirements of the Jardé Law into their processes, manufacturers contribute to the development of innovative treatments while ensuring high ethical standards, in accordance with French regulations on this matter. 

Atessia can assist you in implementing these processes with its expertise in clinical trials. 

Article written by Zarine RAMJAUNY, Legal Consultant 

What are Good Manufacturing Practices (GMP) ? 

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Definition 

Good Manufacturing Practices are a set of principles and guidelines. The first GMPs were published in France in 1978. These guidelines are regularly updated to incorporate regulatory changes. 

The WHO defines Good Manufacturing Practices as “one of the elements of quality assurance, ensuring that products are manufactured and controlled in a uniform manner and to quality standards appropriate to their use and specified in the marketing authorization”. The aim is to guarantee the quality, safety and efficacy of medicinal products. 

These Good Manufacturing Practices provide an understanding of the requirements of European regulations relating to the manufacture of medicinal products. They are one of the standards applicable to health products with marketing authorisation for the European market, as well as to experimental medicinal products. 

The application of GMP by pharmaceutical establishments is verified by the competent authorities during inspections. 

GMP compliance certificates issued by the ANSM following these inspections are published in the European EudraGMDP database. 

Organisation of Good Manufacturing Practices 

The standard is made up of 4 different parts plus appendices and guidelines. The 4 parts are as follows:  

  • Part I: GMP for medicinal products for human use 
  • Part II: GMP for active substances used as starting materials in medicinal products 
  • Part III: GMP-related documents  
  • ICH Q9: “quality risk management” guideline 
  • ICH Q10: “pharmaceutical quality system” guideline 
  • Part IV: GMP specific to innovative therapy medicinal products 

The 10 Principles of Good Manufacturing Practice 

There are 10 fundamental principles applicable to pharmaceutical operations which are taken from these chapters and which must be applied in order to guarantee the compliance of medicines:  

  • Creating procedures: writing operating procedures and instructions to provide a “road map”; 
  • Documentation: provide a precise description of the work in progress to ensure compliance with procedures and traceability; 
  • Validation: proving the correct operation of the systems in place by ensuring validation circuits; 
  • System design: integrating processes, product quality and staff safety right from the design phase of buildings, systems and equipment; 
  • Maintenance: regular and efficient maintenance of systems, installations and equipment; 
  • Skills: developing and clearly demonstrating skills at the workplace; 
  • Contamination prevention: adopting regular and systematic hygiene and cleanliness practices; 
  • Quality first and foremost: regular checks on raw materials and processes (manufacturing, packaging, labelling, etc.); 
  • Quality audits: planning and carrying out regular audits to ensure GMP compliance and the effectiveness of the quality system. 

Conclusion  

Compliance with Good Manufacturing Practices is essential. It is a regulatory obligation for pharmaceutical establishments. It is crucial to ensure product compliance and safety. Furthermore, during inspections by the health authorities, failure to comply with these standards may result in decisions of varying severity, depending on the non-compliance observed. The consequences of inspections can range from administrative warnings to sanctions.