Wael HAYEK

Poisonous Substances: What Use within the Pharmaceutical Industry? 

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Poisonous substances are defined in French legislation (and only in this legislation!) and include certain substances classified as dangerous according to categories defined by the Public Health Code. This classification imposes a number of constraints on marketing authorization holders based on these active substances. 

The regulation of poisonous substances thus encompasses substances, preparations, plants and medicines. 

Definitions 

Poisonous substances correspond to all narcotic, psychotropic, or potentially harmful substances. These substances are classified on List I or List II. Their dispensation in pharmacies is subject to mandatory medical prescription written by a doctor, dentist, or midwife, and for narcotic drugs, to the presentation of a prescription meeting all security techniques. 

Lists I and II of poisonous substances mentioned in Article L. 5132-1 of the Public Health Code include: 

– Certain substances classified as harmful to health in accordance with Article L. 1342-2; 

– Medicines that may directly or indirectly pose a danger to health; 

– Human medicines containing substances whose activity or side effects require medical supervision; 

– Any other product or substance presenting direct or indirect health risks. 

Medicines can be listed on List I, List II, or the list of narcotics, with this classification accommodating scenarios based on their quantitative composition of poisonous substances. 

List I means that a medicine can only be dispensed in a pharmacy for the duration mentioned on the prescription and can only be renewed if mentioned by the prescriber and for a maximum of one year. 

Medicines belonging to List II cannot be dispensed multiple times from the same prescription within 12 months, unless otherwise indicated by the prescriber. 

Finally, narcotic drugs are subject to a secure prescription and cannot be dispensed for a period exceeding 28 days. Some non-narcotic medicines are required to comply with some or all of the rules applicable to narcotics: these are narcotics-like medicines. 

Regulatory Evolution and Impact on Industry 

Since the adoption of stricter regulations regarding poisonous substances, the pharmaceutical industry has faced a more stringent framework. 

The measures outlined in the Public Health Code aim to strengthen control over all operations related to these substances, from production processes to wholesale distribution, import, and export. 

According to the Public Health Code, the production, manufacturing, transport, import, export, possession, offer, transfer, acquisition, and use of plants, substances, or preparations classified as poisonous are subject to strict conditions defined by decrees in the Council of State. This regulation requires full compliance with precise standards governing each stage of the supply chain. 

Decrees in the Council of State, established with the advice of the National Academies of Medicine and Pharmacy, have the power to prohibit certain operations or prescriptions related to poisonous substances, thus emphasizing the importance of safety and pharmaceutical regulation. 

Until 1st June  2021, poisonous substances were classified by order of the Minister of health, upon the proposal of the Director General of the National Agency for the Safety of Medicines and Health Products (ANSM). 

Since the decree of 1st February  2022, the ANSM is now responsible for: 

– Classifying substances and medicines intended for human medicine on Lists I and II of poisonous substances defined in Article L. 5132-6 of the Public Health Code; 

– Setting any exemptions to the regulation of poisonous substances regarding medicines intended for human medicine. Indeed, certain poisonous substances, below dose or concentration thresholds and used for a brief treatment duration, may be dispensed without a prescription; 

– Classifying any substance, intended or not for human medicine, as narcotics or psychotropics. 

Industrial pharmaceutical establishments must adapt to the regulatory specifics of this status, covering activities such as manufacturing, import, wholesale distribution, and research. Any failure to comply with these regulatory requirements can lead to severe sanctions, requiring strict compliance. 

These measures also affect stakeholders operating in the field of veterinary medicines. 

Regarding labelling, the regulation of poisonous substances adds requirements for medicines based on these substances in terms of primary and secondary packaging. The labelling must notably include a green or red frame so that the pharmacist can indicate the dosage to be followed. 

Finally, regarding possession, specific rules must also be followed. Poisonous substances are not eligible for direct access requests. As a reminder, the ANSM defines the list of medicines that can be presented for over-the-counter access at the front of the counter in pharmacies according to criteria chosen to guarantee health and patient safety (self-medication). 

Article written by Zarine RAMJAUNY, Legal counsel 

What are the mechanisms for early and compassionate access in France?  

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Atessia assists its clients on a daily basis with the practicalities of implementing the French early access programs and compassionate use scheme, the subtleties of which require some explanation. 

This new system has been in place since 1st July 2021 and is based on 2 access and reimbursement mechanisms:  

  • Early access (AAP) 

The first is the early access scheme, dedicated to medicinal products that meet an unmet therapeutic need and are likely to be innovative. The pharmaceutical company submits an application for early access authorisation (AAP) to the French National Authority for Health (HAS) and, for medicinal products not yet authorised under marketing authorisation, to the French National Agency for the Safety of Medicines and Health Products (ANSM).  

These authorisations may apply to : 

– a medicinal product prior to obtaining marketing authorisation for the indication in question (Pre-marketing authorisation AAP = AP1),  

– a medicinal product which already has a marketing authorisation for the indication in question, prior to it being covered by the general health insurance system (Post-marketing authorisation AAP = AP2). 

Interestingly, the product may or may not have marketing authorisation for another indication. 

As indicated in the HAS doctrine, the granting of an AAP is reserved for specific medicinal products that meet the following 5 cumulative eligibility criteria: 

  1. Efficacy and safety are strongly presumed in the indication in question  
  1. The disease to be treated is serious, rare or disabling 
  1. There is no such thing as “appropriate treatment” 
  1. The treatment cannot be deferred 
  1. The drug is presumed to be innovative. 

The authorities examine all these criteria separately, and quite strictly. 

This system also requires concrete commitments from the laboratories, which should not be underestimated and which need to be weighed up with the parent company.  

  • REGULATORY: The pharmaceutical company must undertake to submit a marketing authorisation application within 2 years for an AP1 or a registration application within one month of obtaining the marketing authorisation for an AP2. The timing of the application is therefore crucial to the project. 
  • LOGISTICS: The pharmaceutical company makes the product available within 2 months of the granting of the AAP and ensures that it can supply the product to allow continuity of treatment for patients initiated throughout the AAP. At the end of the AP, the exploitant pharmaceutical company ensures the continuity of the treatments initiated for a minimum period of one year, of which 3 months are covered by health insurance.  
  • FINANCIAL: The pharmaceutical company sets up a PUT-RD for data collection and the transmission of periodic summary reports. It funds the data collection withing the framework of an agreement signed with health establishments. 
  • The pharmaceutical company is also required to support prescribers in entering and monitoring the collection of real-life monitoring data for the drug, by providing them with the necessary resources. 

Since the implementation of the AP scheme in July 2021, the HAS has published a positive report covering three years of application : 

  • Two types of compassionate access  

This system covers two distinct cases, which have in common the fact that they concern a medicinal product used to treat patients suffering from illnesses for which there is no appropriate treatment, in a given therapeutic indication, without it being intended to obtain marketing authorisation in France. Applications are managed solely by the ANSM. 

  1. 1st mechanism: this compassionate access is requested for an unauthorised drug not available in France by a hospital prescriber for a named patient, provided that the ANSM is able to presume a favourable benefit/risk ratio for a serious, rare or disabling disease: this is an individual and nominative compassionate access authorisation (AAC). 
  1. 2nd mechanism: it is a framework for a practice, at the initiative of the ANSM, with a view to securing the practice of off-label prescribing of a medicinal product available in France, which has marketing authorisation for other indications, when it is the subject of well-established off-label prescribing on French territory : this is a compassionate prescribing framework (CPC). 

Exceptions to compassionate access have been made in the following cases: 

  • Allowing nominative access to medicines in development for the indication: this is a “very early” compassionate access. 
  • The LFSS for 2024 also provides for the possibility of granting compassionate access authorisations in the event of a refusal for early access on the grounds that the drug is not considered innovative enough. 

There are a number of eligibility conditions attached to the ANSM grant, which bring this scheme closer to early access and can be the gateway to it: 

  • treatment cannot be postponed; 
  • the patient cannot take part in any ongoing research; 
  • the company responsible for exploiting the medicinal product must undertake to submit an application for early access program within 12 months of the first ‘compassionate pre-approval’ (18 months for rare diseases).  

Compassionate access schemes differ from early access programs in that their initiation does not rest with the manufacturer, who may be required to implement and fund a PUT-SP. 

Thus, the reform has brought greater predictability for manufacturers and continuity of access up to standard reimbursement. In return, pharmaceutical companies are bound by a number of commitments. 

According to the ANSM report, published in 2024, the use of compassionate access has been stabilising since the 2021 reform. In 2023, a relative decrease of 10% in compassionate access requests was observed. This decrease is partly linked to the granting of marketing authorizations for several Covid-19-related products, which had previously been the subject of numerous compassionate access requests. 

Moreover, the number of medicinal products available under this scheme has remained stable, with 373 made available in 2023. 

For these products, it may be necessary to appoint a pharmaceutical company to operate the medicinal product, in order to ensure import/distribution, pharmacovigilance, quality claims or medical information, as appropriate. 

Pharmaceutical companies now have several years’ experience of these new mecanisms, and the trends that are emerging show a willingness on the part of the authorities to make innovative medicines available to French patients and to respond to the personal situations of patients who have reached a therapeutic impasse. 

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

What about the classification of Marketing Authorization variations? 

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What about the classification of Marketing Authorization variations? 

When a holder wishes to register a medicine in a country, he submits a marketing authorization application (MAA) file to the health authorities. 

Once marketing authorization (MA) has been obtained, this file is not intended to remain unchanged. For each change impacting the product, whether (for example) a change in manufacturing, control, therapeutic indication, packaging, the holder must submit a variation request to the health authorities. 

A variation is therefore a modification of the marketing authorization. 

Modifications to the terms of an European marketing authorization are provided for by Directive 2001/83/EC and Regulation (EC) No 726/2004, and detailed by Regulation (EC) No 1234/2008 of November 24, 2008 concerning the examination of modifications to the terms of an MA for medicinal products for human use and veterinary medicinal products (hereinafter referred to as the “Modifications” regulation) 

This regulation has been applicable since January 1, 2010 to MAs obtained through centralized, decentralized and mutual recognition procedures, and since August 4, 2013 to MAs obtained through national procedures. 

There are 3 types of variations: 

– Type IA variations, also called minor. These are modifications whose repercussions on the quality, safety and efficacy of the medicinal product are considered minimal or non-existent. These modifications may be implemented by the holder without prior review by the authorities. However, not later than 12 months from the date of implementation, the holder must notify this modification simultaneously to all relevant Member States, the competent national authority or the EMA (as applicable) . 

Of note, there are type IAIN variations (IN = immediate notification). They can also be implemented by the holder without prior examination by the authorities. However, notification to the competent authorities must be made within 14 days of implementation. 

– Type IB variations. Also minor, they are defined as variations which are neither minor of type IA, nor major of type II, nor extensions. Within type IB variations, we also find the so-called “unforeseen” variations, which are not included in the initial regulation and which are mentioned in article 5. 

– Type II variations, called major. These are modifications which are not extensions of Marketing Authorization and which may have significant consequences in terms of quality, safety and efficacy. 

Modifications to the terms of a marketing authorization also include extensions of marketing authorization and urgent restriction measures for safety reasons. 

Variations are categorized according to the type of change by the Guidelines relating to the characteristics of the different categories of modifications, to the conduct of the procedures provided for in Chapters II, IIa, III and IV of Commission Regulation (EC) No 1234/2008 of 24 November 2008 concerning the examination of amendments to the terms of a marketing authorization for medicinal products for human use and veterinary medicinal products and the documentation to be submitted under these procedures. There are changes classified as administrative (A), relating to quality (B), or relating to safety, efficacy or pharmacovigilance (C). Changes D concern the plasma master records and the vaccine antigen master records. 

The aim is twice: correctly position each change according to its type and category. To benefit from the type indicated in the classification, you must be able to provide the required documentation and meet the conditions mentioned, otherwise the variation request is likely to be recategorized or even rejected. 

Once these definitions have been established, note that MA holders have the possibility of submitting several modifications concerning one or more MAs in a single request, under the conditions determined by the regulation. It is called a grouping. It is important to mention that not all variations can be “grouped” together. A regulatory strategy must be put in place. 

Finally, the worksharing or task distribution procedure is strongly recommended. It allows MA holders to submit, in a single application, the same type IB, type II modification or the same group of modifications corresponding to one of the cases referred to in Annex III of the regulation provided that it does not include a request for extension, when these elements relate to several MAs held by the same holder, whatever the type of procedure (all combinations being possible), or to several purely national MAs from the same holder in more than one Member State. It was established to avoid duplication of work to evaluate these modifications: they are examined by a single authority, called the “reference authority” and chosen from among the competent authorities of the Member States and the EMA, to on behalf of other authorities concerned. 

Do not hesitate to call on ATESSIA to support you in the development of the regulatory strategy and writing your variation request files, whatever the registration procedure. 

Article written by Véronique LEWIN, Senior Consultant in Pharmaceutical Affairs – CMC