What future for therapeutic cannabis in France?

A bit of history

In September 2018, a multidisciplinary scientific committee made up of ANSM, healthcare professionals and patients was set up to review scientific knowledge and foreign experience on medical cannabis. 

In December 2018, this committee concludes that the use of cannabis is appropriate for patients in certain clinical situations, and wishes to set up an experiment.

As of January 2019, a temporary specialized scientific committee (CSST) is being set up with the aim of assessing the relevance and feasibility of making therapeutic cannabis available in France. This CSST is tasked with issuing an opinion on:

  • the therapeutic value of cannabis in the treatment of certain pathologies;
  • the modalities for making cannabis available for medical use. 

At the same time, the committee had to define specifications for:

  • The drugs used during the experiment;
  • The content of training for doctors and pharmacists and information for patients;
  • The content of the patient follow-up register.

Launch of the experimental framework

On October 25, 2019, the French National Assembly gives the go-ahead for an experiment in the use of medical cannabis.

Decree no. 2020-1230 of October 7, 2020 on the experimentation of the medical use of cannabis defined in particular: 

  • the duration of the pilot (2 years), 
  • the status of medical cannabis as a narcotic drug,
  • the number of patients who may be included,
  • the conditions of treatment,
  • the setting up of a register to monitor adverse events.

The Order of October 16, 2020 set out the specifications for cannabis-based medicines used during the experiment provided for in Article 43 of Law no. 2019-1446 of December 24, 2019 on the financing of social security (LFSS) for 2020, together with the conditions for making them available and the therapeutic indications or clinical situations in which they will be used.

This order defined:

  • The indications for which medical cannabis products entered the trial,
  • The authorized pharmaceutical forms: 
  • form for inhalation by vaporization, such as dried flowering tops or granules;
  • oral form in capsule or equivalent form
  • oral or sublingual oil form
  • as well as specifications for the free supply and distribution of cannabis-based medicines for patients taking part in the experiment in the medical use of cannabis. 

The call for applications launched on October 19, 2020 by ANSM closed on November 24, 2020. Applications were examined on the basis of strict and demanding specifications in terms of compliance with good cultivation and manufacturing practices, drug quality and securing the distribution circuit as defined in the decree. This examination was carried out by the ANSM, and in particular by its control laboratories, and by experts from the Temporary Specialized Scientific Committee (CSST).

In all, six supplier/operator pairs were selected for the trial. 

First patient – Start of the trial

On March 26, 2021, the medical cannabis trial officially began with the inclusion of the first patient at Clermont-Ferrand University Hospital. The experiment will run for 2 years. 

In June 2021, a CSST was set up to monitor the medical cannabis experiment. It is made up of 16 members, including 4 patients and healthcare professionals, general practitioners, specialists in the therapeutic indications selected for medical cannabis, pharmacists and representatives of the Centre Régional de Pharmacovigilance (CRPV) and the Centres d’Evaluation et d’Information sur la Pharmacodépendance-addictovigilance (CEIP-A).

This committee is involved in monitoring the progress of the experiment and must issue an opinion on the evaluation data collected and on the framework for the marketing and use of medical cannabis.

2023: the first turning point

Decree 2023-202 of March 25, 2023, amending Decree 2020-1230 of October 7, 2020: 

  • extends the trial period for the medical use of cannabis by one year; 
  • indicates that medicines with a THC content of over 0.30% are subject to the narcotics regime; conversely, those with a THC content of less than or equal to 0.30% are now subject to the regime for medicines covered by lists I and II of poisonous substances.

At the same time, various decrees dated March 25, 2023 specify that:

  • Pharmacovigilance and addictovigilance will now be handled in the same way as for other drugs; 
  • Inhalation granules have been discontinued;
  • The ANSM is no longer responsible for selecting suppliers and operators of cannabis for medical use. The Direction Générale de la Santé (DGS) is now the competent authority in this area, via a public procurement contract. The medicines used will therefore no longer be supplied free of charge by participating companies.

End of the experiment

Article 78 of the Social Security Finance Act of December 26, 2023 puts an end to the experiment.

As of March 26, 2024, no new patients can be included. Patients included before this date will still be able to benefit from their treatment, with the exception of inhaled forms.

Other patients will have to wait until a medicine is authorized and available “no later than December 31, 2024” before they can benefit from a cannabis-based treatment for therapeutic use.

What’s next? 

Article 78 creates an ad hoc status for cannabis for medical use: pending the granting of marketing authorizations (MA) in due form, the use of cannabis-based medicines may be authorized by the ANSM in the form of temporary MA, for a temporary period of 5 years, renewable. Such authorization may only be granted if the use of these products meets the special needs of a given patient, and there is no suitable pharmaceutical packsize available, including due to the absence of effective marketing, with, for example, a marketing authorization (article L5121-1 4° of the CSP).

Article written by Isabelle BARBIEUX, Senior Quality Assurance Advisor

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Therapeutic patient education versus learning programs: what is role for the pharmaceutical industry?

> Definition and content

Therapeutic patient education (TPE) can be defined in several ways.

The World Health Organization (WHO) gave the following definition in 1996: “Therapeutic patient education aims to help patients acquire or maintain the skills they need to manage their lives with a chronic disease”.

In 2007, the French National Authority for Health (HAS) clarified the specific aims of therapeutic education:

– The acquisition and maintenance by the patient of self-care skills;

– The mobilization or acquisition of coping skills”.

Under the French law no. 2009-879 of July 21, 2009 on hospital reform and patients, health and territories (known as the HPST law), TPE is defined as being “[…] part of the patient’s care pathway. Its aim is to make patients more autonomous by facilitating their compliance with prescribed treatments and improving their quality of life. It is not enforceable against the patient and cannot condition the rate of reimbursement for his or her treatment or for drugs related to his or her illness”.

ETP, as provided for in the French Public Health Code, is divided into three distinct actions:

Therapeutic patient education programs, which comply with national specifications, are implemented at local level after registration with regional health agencies (ARS). They are proposed to the patient by a healthcare professional and lead to the development of a personalized program;

Accompaniment programs, which comply with national specifications, are designed to provide assistance and support to patients and their families in managing their disease;

Learning programs are designed to help patients acquire the technical skills they need to use a medicine/Auto-administration. These programs are implemented by healthcare professionals working on behalf of an operator who may be financed by the company exploiting the medicine. The learning program is proposed by the prescribing physician to the patient. In this case, the ANSM authorizes their implementation, after consulting an approved patient association To this end, the manufacturer submits a training application, justifying the expected benefits for the patient.

> ETP objectives

ETP is based on an individualized approach, considering the specific characteristics of each patient. It involves close collaboration between the patient, healthcare professionals and often the patient’s family and friends. The aim is to foster an in-depth understanding of the disease, its implications and associated treatments. This approach encompasses not only the medical aspects, but also the psychological, social and environmental aspects of health.

– Understanding the disease: ETP enables patients to understand the mechanisms of their disease, their symptoms, treatments and effects. Better knowledge helps patients adhere to treatment and prevent complications.

– Skills acquisition: Patients learn to manage their treatment, recognize the early signs of complications and adopt healthy lifestyle habits.

– Autonomy and decision-making: ETP aims to reinforce patients’ autonomy by giving them the tools they need to actively participate in decisions concerning their health.

> Who can set up this type of program?

Healthcare professionalsOthersLegal entities
> Doctors and specialists: They play an essential role in defining therapeutic objectives and validating educational content;
> Nurses: They are often on the front line in delivering education and educational follow-up to patients;
> Pharmacists: They can help explain treatments and their dosage;
> Psychologists or psychiatrists: They help patients manage the stress and psychological impact of their illness.
> Specialized educators: They are specifically trained to deliver TVE;
> Expert patients: people living with the same pathology can share their experience and provide invaluable support.
> A healthcare establishment (public or private);
> A collective practice structure (health center/health home/health cluster);
> A health network;
> An association;
> The Assurance Maladie (health insurance) for health examination centers and the Sécurité Sociale Agricole (agricultural social security);
> A mutual or other complementary insurance company;
> A foundation;
> A municipality.

> Manufacturers and their medicines, at the heart of TVE… but with less room for manoeuvre:

– Ever more innovative medicines

– Pathologies requiring increasingly advanced patient knowledge/technical gestures

– Image and communication issues, as well as the promotion of public health, may lead the laboratory to wish to support an ETP program especially when self-administering drugs.

In order to remain compliant, it is essential for manufacturers wishing to leverage the benefits of ETP to be aware of the roles and levels of involvement they are allowed to play.

Finally, implementing a TVE program without being authorized to do so is punishable by a fine of up to 30,000 euros.

> Conclusion

Therapeutic patient education represents a major evolution in the way we approach health and illness. In a world where it is becoming commonplace for patients to become experts in their own disease, they are a tool for them to understand, actively participate in their treatment and adopt health-promoting behaviors, while contributing to comprehensive, personalized care.

However, the role of the operator of a medicine is regulated and requires a case-by-case analysis of each project.

In such a context, manufacturers have a role to play, while considering the regulatory complexity imposed by the system and the need to steer clear of the multiple risks associated with their highly regulated field of activity (promotional requalification, contact with patients, granting benefits to patients or healthcare professionals).

Article written by Zarine RAMJAUNY, Legal Advisor

What is the Requirement for Transparency of Conflicts of Interest with Healthcare Professionals in France?

Following the “Médiator” case and inspired by the Sunshine Act in the United States, the law of December 29, 2011, concerning the strengthening of health safety, known as the “Bertrand Law,” was passed.

This law establishes systematic transparency of links between health industries on one hand, and other actors in the health field on the other. This primarily includes healthcare professionals, but also students, learned societies, associations, media, etc.

The “transparency of links” system, which provides the general public with information on the relationships between health industries and members of the health system, is in line with the “regulation of benefits” system, which aims at the ethics of healthcare professionals. These two legislations interact with each other, with some subtle specificities that distinguish them.

Who is Affected by the System?

The following actors are concerned:

Types of Declaration and Publication

It is appropriate to publicly disclose retrospectively:

  • Agreements: publication of all contracts made between laboratories and a health actor (for example: agreements with coverage of hospitality expenses (catering, transport, accommodation, registration fees at a congress));
  • Service provision contracts (for example: remuneration for clinical expert work);
  • Benefits exceeding 10 euros including taxes (for example, the granting of health product samples);
  • Remunerations awarded (for example: remuneration of a healthcare professional for speaking at an event).

Commercial contracts are excluded.

The typology of benefits and agreements responds to precise definitions that have been clarified by the authorities.

The system requires that pharmaceutical companies, in particular, are obliged to publish information on the public database, according to the following frequency:

  • Publication twice a year:
  • First calendar semester, i.e. from January 1st of year N to June 30th of year N: submission on the “transparency-health” website by September 1st of year N.
  • Second half of the calendar year, i.e. from 1 July of year N to 31 December of year N: submission on the “transparency in health” website no later than 1 March of year N+1.

Thus, the general public can access the work links and professional relationships maintained between health industries and actors in the French healthcare system.

In parallel, the European Federation of Pharmaceutical Industries and Associations (EFPIA) has also adopted the “EFPIA code of practice” to frame collaboration with Healthcare Professionals or their Organizations when conflicts of interest exist. This text is applicable to member companies.

ATESSIA supports its clients on all these questions.

Article written by Zarine RAMJAUNY, Junior Legal Consultant

ATESSIA Life Science Advisors, a Catalyst for Regulatory Innovation: Collaborating with UBAQ, ATESSIA Sets a New Standard to Facilitate the Management of Regulatory Challenges in the Health Sector

An alliance capable of moving mountains.

ATESSIA and UBAQ jointly pave the way for health sector players.

The health sector, constantly evolving and in the spotlight, requires wisely chosen partnerships.

ATESSIA, a consulting and expertise firm in regulatory and pharmaceutical affairs, and UBAQ, a recognized expert in SaaS solutions for Health Tech, naturally meet at the crossroads of their paths.

Their collaboration aims to simplify and strengthen the regulatory management of health industries, each contributing their expertise: ATESSIA with its deep knowledge of the regulatory field, distinctive know-how, and disruptive approach to consulting, and UBAQ with its sharp technological skills and fresh perspective on sector challenges.

Together, they offer a value proposition that combines innovation, expertise, and accessibility.

With this partnership, ATESSIA offers tailored support, deeply focused on quality customer experience, aiming to meet diverse needs and expectations at every interaction level.

“We were looking for a technical solution with an innovative approach to offer our clients. Having been in contact with UBAQ for several years, we now fully trust them and share the same values and ambitions: to support the Health Industries in their regulatory issues, always placing patients at the heart of our solutions.”

Géraldine BAUDOT-VISSER, Doctor of Pharmacy, founder of ATESSIA, and AMARYLYS.

A Tailored Partnership for the Health Industries

Always seeking to add value for health industry players, ATESSIA has teamed up with UBAQ to offer tailored support. This collaboration revolves around implementing an innovative technical tool designed to ease the daily life of health industry professionals. Indeed,

UBAQ aims to provide its clients with regulatory support that goes beyond its SaaS solution, choosing to partner with one of the most renowned firms in this field.

Both companies share a key priority: placing the customer, their experience, and satisfaction at the heart of each solution.

In addition to tool implementation, ATESSIA offers 360° support, covering all business and regulatory issues health industries may face.

This partnership provides an integrated solution, combining ATESSIA’s sharp expertise with an intuitive digital tool to ensure optimal regulatory compliance.

“Partnering with a regulatory affairs firm was obvious for us and is in line with the continuous support we offer our clients. ATESSIA breaks the mold and stands out with a very flexible and innovative approach: this is exactly what we were looking for.”

François CANCELLONI, General Manager and co-founder of UBAQ.

ATESSIA Life Science Advisors: The Strategic Partner in Pharmaceutical Regulatory Navigation

Founded in 2017 by Géraldine BAUDOT-VISSER, Doctor of Pharmacy, ATESSIA Life Science Advisors is an essential player in guiding health industries through regulatory landscape challenges.

With a team of experts and a client-centered approach, ATESSIA ensures compliance and relevance through personalized technical and strategic development support and health product commercialization.

ATESSIA positions itself as a market leader, with its insightful regulatory monitoring service, ATESSIA INTELLIGENCE, handling French and European regulatory subtleties.

ATESSIA’s renown highlights its expertise and commitment to assisting clients in successfully navigating the rigorous and complex world of regulatory and pharmaceutical affairs.

Key Points:

  • Expertise in 6 main areas: Pharmaceutical Affairs, Regulatory Affairs, Quality System Management, Health Product Promotion, Pharmacovigilance, Medical Devices, Regulatory Monitoring.
  • 126 companies subscribed to the regulatory monitoring tool, ATESSIA INTELLIGENCE.
  • Extended presence in Paris, Lyon, Luxembourg, Nice, Bordeaux, Lille, Auxerre, Orléans, and other locations.
  • 98% retention and satisfaction rate, according to the ISO indicator.

UBAQ, European Leader in Health Tech

Founded in 2023 from the merger of Qairn and Clardian (formerly BMI System), UBAQ supports the digital transformation of health industries with a suite of SaaS software.

These software solutions help dematerialize and simplify the application of the particularly strict and constantly evolving regulatory framework. UBAQ offers two solutions:

  • UBAQ DocPromo, which aims to comply with promotional documents.
  • NAYACT Transparency by UBAQ, focusing on the Law of Benefits Framework and transparency of interest links.

What Are the New Rules for Influencers on Social Networks?

Law No. 2023-451 dated June 9, 2023, which aims to regulate commercial influence and combat abuses by influencers on social media platforms, not only defines the concept of an “influencer”, but also introduces the notion of an “influencer’s agent”.

What is an Influencer?

Influencers are any “(…) natural or legal persons who, for a fee, mobilize their reputation among their audience to disseminate content to the public via electronic means. Their goal is to promote either directly or indirectly, goods, services or any cause. They engage in the activity of commercial influence through electronic means” (Article 1).

Examples include a patient, a healthcare professional or a person with a strong reputation.

What is an Influencer Agent?

” I. – An influencer agent’s role is to represent, for a fee, either natural or legal persons engaged int the activity of commercial influence through electronic means as defined in Article 1. This representation involves liaising with other natural or legal persons, and if relevant, their representatives, to promote goods, services or any cause, also for a fee.

II. – Individuals who undertake the activity defined in Section I of this article must take all necessary measures to safeguard f the interests of those they represent, to avoid situations that might lead to conflicts of interest and to ensure their actions align with the stipulation of the current law  (Article 7).

What are the Law’s Obligations?

Supervision of Sponsored Content:

This law creates an obligation for influencers to report any sponsored content. Specifically, any promotion of goods, services or a cause of any kind carried out by an influencer must systematically include the mention “Advertising” or “Commercial collaboration”. This mention must appear clearly, legibly and identifiably on the influencer’s image or video, whatever its format and for the entire duration of its broadcast.

  • Supervision of Published Visuals:

Images should be labelled as “Retouched Images” if they undergo processing to slim or thicken a silhouette or modify face appearance.;

Images should be labelled as “Virtual images” if any artificial intelligence process has been used to generate or modify a face or silhouette.

  • Supervision of Dropshipping Activities:

Influencers are obliged to provide the buyer with all pre-contractual information related to a distance sales agreement. This includes the identity of the supplier and confirmation of product availability. Failure to provide this information can result in influencers being held accountable.

What is Prohibited?

Direct or indirect promotion of the following products and services is prohibited:

  • Aesthetic procedures, processes, techniques, and methods referred to in Article L. 1151-2 of the French Public Health Code, as well as interventions referred to in Article L. 6322-1 of the same code (including aesthetic medical devices (DMs) listed in Annex XVI of Regulation 2017/745 MDR);
  • Procedures, processes, techniques, and methods presented as comparable to, preferable over or substitutes for therapeutic procedures, protocols, or prescriptions;
  • Products considered as nicotine-based that can be consumed and are made, even partially, of nicotine.

What are the Penalties?

Violators may face a fine of up to 300,000 euros and a prison sentence of up to 2 years. To ensure consumer protection, a dedicated team has been set up within the DGCCRF (a French authority, Direction Générale de la Concurrence, de la Consommation et de la Répression des Fraudes), and reports can be submitted via the Signal conso website.

Existing sanctions are reinforced and graduated. The following acts are punishable:

  • Failure to indicate the advertising nature of a video or photo posted by an influencer is now considered a misleading commercial practice;
  • Promotion of a prohibited or regulated product carries the same penalties as online advertising;

Additionally, the authorities have been granted a new power of injunction with penalties. This allows them to compel an influencer to remove non-compliant content or for platforms to suspend the influencer’s account promptly.

Judges and supervisory authorities will tailor penalties according to the severity of the act.

What About Drugs and Medical Devices?

The promotion of medicines to the general public is regulated by the French Public Health Code. With the exception of class I or IIa medical devices, the promotion of a drug, medical device or IVDD to the general public based on a recommendation from people who, through their reputation, can encourage the consumption of the product in question, such as influencers on social networks, is already prohibited by the Public Health Code.

Need assistance in managing influencer communication under contract with your laboratory? Our expert consultants are available to discuss your concerns.

Article written by Zarine RAMJAUNY, Junior Legal Consultant

The mysterious thing that an Exploitant is

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

If you’ve ever worked in a pharmaceutical company that has a subsidiary in France, there’s almost 100% chances that you haveheard about this absolutely unique-in-Europe status for a pharmaceutical establishment. So what does this mean and why are requests coming from French affiliates always so weird?

What is an Exploitant?

The term itself is so difficult to translate in a satisfactory way that it is almost always referred as “Exploitant” (with French accent, please).

The Exploitant is a distinct status from the MA Holder (however, they can be the same company) and cannot be defined as a distributor as well. Proof is, that WDAs issued by ANSM will not mention procurement/selling, but rather “Other – Exploitation”.

As long as there is a Marketing Authorization or an early access program in place (such as Early Access or Compassionate Use), no medicinal product can be distributed in France without an Exploitant being responsible for it.

The exploitant’s scope of activities covers:

  • Wholesaling – This means that the Exploitant is the one allowed to sell products to the rest of the distribution chain
  • Promotional activities – The Exploitant is the only entitled to use advertising material (under strict rules anyway)
  • Medical information – The Exploitant is responsible for providing necessary information to requestors, mainly prescribers, under stringent rules.
  • Pharmacovigilance – The Exploitant in the main contact for French agency
  • Batch follow-up and, if necessary, batch recall
  • Storage, if applicable

After this listing you may think that the Exploitant is responsible for almost everything, but the MA Holder still has certain responsibilities, and some are shared, like pharmacovigilance for example.

Some of the Exploitant duties (although not all) can be partly of completely subcontracted, but still fall under its supervision and responsibility. In case of subcontracting, the Exploitant will have to ensure that everything is done right.

In addition, the Exploitant is also the key when it comes to Market Access, Sales Reps Certification and pharmaceutical taxes.

Exploitants need to be authorized by ANSM prior to opening, and are regularly inspected, potentially financially sanctioned and can be closed by ANSM decision if any risk for Public Health.

Who’s the Responsible Pharmacist?

No matter how you call him/her (Chief Pharmaceutical Officer, and most often PR for “Pharmacien Responsable” in Molière’s language), he/she is the master person of an Exploitant. The one that personally undertakes all responsibilities, all sanctions.

The PR is necessarily a French Pharmacist, residing and working in France with a special level of experience that has to be recognized by the Order for Pharmacists.

How to enter the French Market and get your products “exploited”?

Securing a Marketing Authorization in France is a good start and an obvious prerequisite for entering the French Market indeed, but the having your product “exploited” is another key step.

You could either open your own Exploitant as your French subsidiary or rely on an already existing structure for exploiting your product.

Opening an Exploitant requires expertise in the following areas:

  • Describing the future Quality Management System. The QMS must be sufficiently described in order for ANSM to understand precisely enough how the Exploitant will operate and how it will handle a series of pharmaceutical operations like promotion, batch follow-up, pharmacovigilance;
  • Finding premises, and presenting related documentation as well as physical and IT securities in a way that will meet ANSM’s requirements;
  • Hiring a Responsible Pharmacist;
  • Managing all of the above in French, as the application file and relationships with the Authority can only be done in French;
  • Contracting Quality Agreements with partners (e.g. MAH) and sus-contractors (e.g. wholesaler) that meet French & EU regulation;
  • Certifying promotional activities within 9 months after the beginning of promotion.

Whatever the scenario, ATESSIA opened several Exploitant in France and can help you in defining your strategy, building you Exploitant opening file, or arranging third-party exploitation.

Article written by Raphaël DAUVERGNE, Regulatory and Pharmaceutical Affairs Advisor

Registering gene therapy medicinal products

The regulatory requirements for the pharmaceutical development of gene therapy medicinal product are described in Annex I, part IV of Directive 2001/83/EC applied to advanced therapy medicinal products. The following definition is included:

“Gene therapy medicinal product means a biological medicinal product which has the following characteristics:

a) it contains an active substance which contains or consists of a recombinant nucleic acid used in or administered to human beings with a view to regulating, repairing, replacing, adding or deleting a genetic sequence;

b) its therapeutic, prophylactic or diagnostic effect relates directly to the recombinant nucleic acid sequence it contains, or to the product of genetic expression of this sequence.”

Both of these two conditions must be met so the product can be classified as a gene therapy medicinal product.

According to Regulation (EC) No 1394/2007, gene therapy medicinal products must be regulatory approved under an European centralised procedure, like all other advanced therapy medicinal products (ATMPs).

This procedure includes an in-depth evaluation of the marketing authorisation application file submitted by the pharmaceutical company, which is carried out by the EMA and involves various specific committees and working groups that provide recommendations. The EMA website provides procedural and guidance documents to help companies applying for a marketing authorisation for ATMPs.

In the following paragraph we discuss the main elements of the registration procedure for a gene therapy medicinal product.

As with “conventional” medicinal products, the marketing authorisation dossier is based on three main aspects: the quality, safety and efficacy of the medicinal product, in order to determine its benefit/risk ratio. The eCTD dossier is composed of five modules to which certain technical adaptations are added.

In particular, if the product is a gene therapy medicinal product containing genetically modified organism (GMO), Module 1 must also include an assessment of the possible risks that the medicinal product may pose to the environment, both in regards to its use and its disposal. Information on the risk related to the release of GMO should be annexed to this module and should be presented in accordance with the provisions of Directive 2001/18/EC on the deliberate release into the environment of genetically modified organisms.

The three main EMA committees involved in the evaluation of gene therapy medicinal products are the Committee for Advanced Therapies (CAT), the Committee for Medicinal Products for Human Use (CHMP) and the Pharmacovigilance Risk Assessment Committee (PRAC).

The CAT is a multidisciplinary committee within the EMA. Its main responsibility is to assess the quality, safety and efficacy of ATMPs. The CAT also provides scientific recommendations on the classification of ATMPs. The CHMP will then adopt a positive or negative opinion on the marketing authorisation of the medicinal product concerned.

During the evaluation of the marketing authorisation application, the CHMP chooses from among its members a “rapporteur” State and a “co-rapporteur” State, responsible for coordinating the evaluation of the dossier and drawing up evaluation reports for the other Member States (MS) in the procedure. The MS comment on these reports within the timeframe set out in the procedure’s timetable, which has a total duration of 210 days.

At the end of the procedure, the CHMP issues an opinion, which may be positive or negative. The CHMP’s opinion is then forwarded to the European Commission (EC). On the basis of this opinion, the final decision is taken by the EC, which has 67 days to take the administrative decision on whether or not to grant marketing authorisation.

During the pre-submission phase of the marketing authorisation dossier, the Committee for Orphan Medicinal Products (COMP) may also be called upon if the applicant wishes to obtain orphan designation for its product. Indeed, most medicines with ATMP status also claim orphan drug status. However, to obtain this status, which is associated with many advantages, certain conditions must be met. These conditions are defined in Regulation (EC) No. 141/2000 on orphan medicinal products.

The growing interest in obtaining orphan drug status is due to the significant advantages that industry can enjoy, in particular:

– Smaller-scale clinical trials (due to small populations), which are less costly;

– Accelerated marketing authorisation process;

– 10-year marketing exclusivity from the time of marketing.

The Paediatric Committee (PDCO) also intervenes at an early stage in the centralised procedure to ensure that the pharmaceutical company meets the requirements requested of it in terms of paediatric development.

In parallel, all of these committees are also supported within the EMA by advisory bodies, both technical and scientific, divided by area of activity. The EMA’s Gene Therapy Working Party (GTWP) supports the CAT and the CHMP in the scientific evaluation of this category of medicines.

In the event of questions from applicant laboratories, the EMA and the ANSM are able to provide scientific advice. In fact, a laboratory can call on the advice of the EMA (Scientific Advice Working Party (SAWP)) and/or that of the competent national authorities, either during the initial development of the medicinal product, or before the submission of a marketing authorisation application. In France, the industry can also apply to the ANSM’s guidance and innovation desk.

In addition, in March 2016, the EMA set up a special status called PRIME (meaning “Priority Medicines”) to improve the development and marketing of innovative products. The PRIME regulatory process is designed to allow for an accelerated assessment of these priority therapies, but it also aims to support laboratories in their development, as well as to help them use other systems for early access to treatments.

It should be noted that in order to meet unmet medical needs of patients and in the interest of public health, it may be necessary to grant marketing authorisations on the basis of less complete data than is normally required. In such cases, the granting of a conditional marketing authorisation may be recommended subject to certain specific obligations to be reviewed annually. The provisions for the granting of such an authorisation are laid down in Commission Regulation (EC) No 507/2006 on conditional marketing authorisations for medicinal products for human use. 

It should be noted that the various regulatory measures taken in recent years have proved to be effective and promote the development of gene therapy medicinal products. However, these measures still need to be adjusted in order to achieve their main objective of making safe and effective gene therapy medicinal products available to patients. This is the purpose of the ongoing revisions of the European pharmaceutical legislation.

Article written by Blandine LATROBE, Regulatory and Pharmaceutical Affairs Advisor

How to manage a non-GMP raw material in your MA files?

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

The substances used in a medicinal product intended for the European market, including for export, are defined as raw materials for pharmaceutical use (RMP). They can be active (active substance) or inert (excipients).

Whether the medicinal products are intended for human or veterinary use, only active substances manufactured and distributed in accordance with European Good Manufacturing Practices (GMP – Part II) and Good Distribution Practices (GDP), introduced by article L.5138-3 of the French Heath Code, can be used.

Thus, when applying for a marketing authorization or for certain applications to modify the marketing authorization, the notice to applicants requires the submission of a signed QP declaration by the qualified person of the manufacturing site and/or of the certification of the batches of the finished product attesting that the active substance used is manufactured in accordance with good manufacturing practices.

Concerning the excipients used in medicinal products for human or veterinary use, there is no enforceable standard in the national or European regulations and they are not subject to the QP declaration in the marketing authorization file. It is up to the manufacturer or distributor of the finished product to define its quality system the applicable standard(s) for the manufacture or distribution of the excipient, according to its/their intended use(s). This exercise will be carried out in consultation with pharmaceutical users on the basis of the results obtained during a formal quality risk assessment (GMP point 5.29). It should be noted that ANSM recommends, at a minimum, the IPEC/PQG GMP & GDP reference systems.

However, it is recognized that for some raw materials, their pharmaceutical use may represent only a minor fraction of their other industrial uses (agri-food, cosmetics or others). Thus, their producers may not have the objective of meeting the specific requirements of pharmaceutical customers.

The EMA’s Q&A Part 1 reaffirms that compliance with the above-mentioned standards is a legal obligation and that, in the event of difficulties in guaranteeing a supply of satisfactory quality, alternative GMP sources must be sought out, qualified and, if necessary, registered. In the case of a source identified on European territory, the establishment must apply for authorization or registration from the competent authority of the Member State in which it is established. In case of import from a third country to the European territory, the source of the identified active substance will be conditioned by the provision of a written confirmation from the competent authority of the exporting third country.This document attests that the applicable standards are at least equivalent to the GMP defined by the European Union.

In exceptional circumstances these same EMA Q&A Part 1 introduces the possibility for manufacturing authorization holders (of the finished product) to assess and document the extent to which GMP is met, and to provide a risk-based justification for the acceptance of any deviation. At the MA level, the QP declaration should detail the rationale for stating that the standards applied provide the same level of assurance as GMP.The EMA will collect the experience gained with this approach, which can be used as a basis for discussion of possible future related changes to the guidelines.

However, at the national level, the ANSM does not, for example, explicitly provide for derogations or for exceptional circumstances, unlike the EMA for centralized MA. When informed in advance of a particular context (such as medicinal products of major therapeutic interest or the absence of a therapeutic alternative), the competent authorities could then request additional information or carry out an inspection to ensure that the establishment complies with the standards in force in the Union. Thus, this situation can only be transitory, since these alternative sources (in the EU or in third countries) and/or their principals can request an express request for an inspection of the raw materials from a competent authority of one of the member states in order to obtain a certificate of conformity.

The control of the supply chain is the key word. Deficiencies in the qualification and monitoring process of suppliers and/or manufacturers of raw materials are regularly the subject of injunctions issued by the ANSM against pharmaceutical establishments (2 for the year 2020 and 3 for the year 2021). For the alternative identified source, this may be a hindrance (compulsion to comply with the opposable standards) or an opportunity (to comply with them in order to enter the EU market for UPMPs). A mutualization of supplies (and on-site audits) can also be an interesting approach to encourage the source to seize this opportunity.

Article written by Lorraine BALIN, Senior Regulatory and Pharmaceutical Affairs Advisor

How to proceed with non-pharmacopoeial excipients in the formulation of a medicinal product for human use?

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

– Excipients – inherently inactive – have a wide range of applications and are essential components in the formulation of medicines. However, few of these components are manufactured exclusively for pharmaceutical use. Often, the pharmaceutical use of an excipient represents only a minor fraction of its other industrial uses (food, cosmetics or others). However, the quality of excipients is crucial to ensure the quality, safety and efficacy of medicines.

– There is no registration or authorisation procedure prior to its use in a medicinal product. Implicit agreement for the acceptability of an excipient can only be obtained on the basis of a complete marketing authorisation dossier. Excipients used in the formulation of medicinal products can be classified into two main categories: known excipients (i.e. described in the literature, e.g. Handbook of Pharmaceutical Excipients, in the regulations, e.g. (EU) Regulation n°231/2003, or previously screened for risk/safety by an international organisation, e.g. JECFA, FAO, WHO) and unknown excipients, so-called “new excipients” (i.e. used for the first time in a medicinal product or via a new route of administration according to ICH M4Q).

– Among the known standard excipients used, the European guidelines of the EMA provide for two categories: those described in a pharmacopoeia (e.g. European, American, Japanese, French, British, etc.), and those not described in a pharmacopoeia. The latter are then subject to “in-house” control specifications, generally based on the excipient manufacturer’s own specifications, which may be consolidated by the MA holder depending on the use of the excipient in its formulation. It should be noted that in the case of mixed and co-processed excipients, a combination of one or more excipients described or not described in a pharmacopoeia may be considered.

– In Europe, the European Pharmacopoeia is the binding reference for substances for pharmaceutical use. Nearly 200 monographs for excipients are included. Increasingly, they include additional pharmaco technical specifications depending on the use of the excipient. The aim of the European Pharmacopoeia excipient monographs is to provide authorities and patients with a guarantee of acceptable quality. The national pharmacopoeias of the EU Member States are also considered as reference documents that can be used without providing a specific justification in the marketing authorisation dossier. A reference to the “current edition” of the European/national pharmacopoeia in the marketing authorisation dossier is expected to avoid subsequent maintenance changes to the marketing authorisation dossier.

For the same excipient, depending on its various possible origins and uses, different additional requirements may also be necessary: e.g. with regard to a chemical risk (residual solvents according to ICH Q3C, elemental impurities according to ICH Q3D, nitrosamine impurities, etc.), with regard to a bacteriological risk (mycotoxins, endotoxins, sterility, etc.), or with regard to a viral risk (TSE/BSE).

– Although also accepted in Europe under certain conditions, references to monographs described in other pharmacopoeias (i.e. outside Europe and considered as third country or unofficial pharmacopoeias) must be duly justified in the marketing authorisation dossier. In this case, a copy of the monograph accompanied, if necessary, by the validation of the analytical procedures contained in this monograph and, if necessary, a translation should be provided in the marketing authorisation dossier. Updates to these monographs should be declared via the submission of MA variations to the authorities.

– In cases where the excipient used in the formulation is known but has no control monograph in a pharmacopoeia (e.g. surfactant for a skin solution), specifications should be set by the supplier to ensure that the quality of the raw material is maintained on a continuous basis, and reflects both the inherent properties of the excipient and its manufacturing process. These specifications are usually taken over by the user of the excipient and consolidated where appropriate. Consideration of the following parameters is recommended in establishing these internal control specifications: physical characteristics, identification tests, purity tests, assay and other relevant tests that may influence the performance of the pharmaceutical form. In addition, it should again be demonstrated that the methods used provide accurate, reproducible and repeatable results for the characteristic tested and are therefore validated.

– It should be remembered that it is the responsibility of the drug product manufacturer to ensure the quality of all raw materials used in the manufacture of a medicine. By regularly auditing the excipients producer, the end user is able to determine whether adequate controls are in place to ensure that the producer is capable of producing a product of appropriate quality. It should be noted that several guidelines and practical guides are available to manufacturers and users of pharmaceutical excipients from IPEC (The International Pharmaceutical Excipients Council) on the following topics: excipient compositional profiling, excipient qualification, excipient safety, development of certificates of analysis, determination and auditing of Good Manufacturing Practices (GMP) for manufacturers, development of technical agreements/specifications, etc.

– Finally, since 2015, the European regulation imposes on excipients manufacturers the obligation to comply with the appropriate GMP determined by the drug product manufacturer on the basis of a formalised risk assessment (reference document to be provided in case of inspection). An ANSM doctrine, currently being finalised, will soon explain the inspection procedures for excipient manufacturers with regard to the provisions of Article L.5138-3 of the Public Health Code.

ATESSIA assists you in the drafting of your MA and variation files in the context of your activities related to all types of pharmaceutical excipients.

Article written by Isabelle MOUVAULT, Pharmaceutical Affairs Advisor

Advertising for medicines: the keys to obtaining a visa in France

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

Prior control of advertising

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

Regarding the content of promotional documents, in application of the Public Health Code and taking into account the state of scientific and medical knowledge, the ANSM will ensure the security of the message which must not induce bad prescribing or a danger to the public. Vector of proper use, advertising must also present the medicine objectively, and ensure compliance with the standards in force such as the MA** and the therapeutic strategies recommended by the HAS***. Finally, so that health professionals can form a personal idea of ​​the therapeutic value of the medicine, the ANSM checks that the target population and the benefit-risk ratio are clearly perceptible, in particular in the documents used by persons carrying out a promotional information activity. Many guidelines, which are mandatory in practice, have been drawn up by the authorities to help pharmaceutical firms in this delicate exercise.

Furthermore, advertising to the general public is only accessible for certain medicines:

– medicinal products not subject to compulsory medical prescription, non-reimbursable and not including in their marketing authorization a ban on advertising due to a risk to public health, in particular when the medicinal product is not suitable for use without medical supervision;

– certain vaccines on a list from the Ministry of Health;

smoking cessation products.

It should also be noted that control of advertising is also exercised a priori for certain categories of medical devices presenting a significant risk to human health, the list of which is defined by a ministerial order.

An Immutable Authorization Schedule

But the real constraint lies in respecting the timetable governing this control, implying for pharmaceutical firms to anticipate and plan requests up to 6 months before the launch of a new medicine. Advertising is thus subject to strict filing periods (4 per year for documents for healthcare professionals, and 8 per year for advertisements targeting the general public), and files are processed by the authorities within a regulatory time limit of 2 months.

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

At the end of the evaluation period, the request will result in the granting of a prior authorization called the GP visa for advertising aimed at the public and the PM visa for advertising aimed at healthcare professionals, for a duration of 2 years. However, in the event of breaches of the requirement criteria on the content or presentation of the communication tool, the ANSM may issue a refusal. The applicant will then have no choice but to make a new request during the next slot. Each year, out of the 10,000 visa applications processed by the ANSM, around 10% are rejected in this way, and around two thirds of GP visas are modified before they are issued.

The dematerialization of applying

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

Article written by Gismonde PLAN, Senior Regulatory Affairs Advisor

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

** MA : Marketing Authorization

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