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 supports its clients daily in the practical modalities of implementing the French early and compassionate access system, whose subtleties require some explanations. 

On July 1, 2021, the new early and compassionate access system was introduced through 2 decrees, supplemented by 4 orders, with immediate effect. This new system is based on 2 mechanisms for access and coverage by health insurance: 

  • Early Access (AAP)  

Firstly, early access, which targets medicinal products that meet an unmet therapeutic need and may be innovative. The laboratory submits a request for early access authorization (AAP) to the High Authority for Health (HAS) and, for medicinal products not yet authorized under a Marketing Authorization (AMM), to the National Agency for the Safety of Medicines and Health Products (ANSM).  

These authorizations can apply to: 

  • A medicinal product prior to obtaining the AMM in the considered indication (Pre-AMM AAP = AP1), 
  • A medicinal product that already has an AMM in the considered indication, prior to common law coverage by health insurance (Post-AMM AAP = AP2) Interestingly, the product may or may not have an AMM for another indication. As per HAS doctrine, granting early access authorization is reserved for certain specialties meeting the following 5 cumulative eligibility criteria: 

1. Strongly presumed efficacy and safety in the considered indication. 

2. The disease to be treated is severe, rare, or disabling. 

3. There is no “appropriate treatment.” 

4. The implementation of treatment cannot be delayed. 

5. The medicinal product is presumed to be innovative.  

The authorities examine each of these criteria separately, in a relatively strict manner. 

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

  • From a REGULATORY standpoint: the laboratory must commit to filing an AMM request within 2 years for an AAP1 or a request for registration within the month following the AMM’s approval for an AAP2. Thus, the timing of the filing is crucial in the project. 
  • From a LOGISTICAL standpoint: the laboratory makes the product available within 2 months following the granting of the AAP (PUI) and ensures it can supply the product to allow continuity of treatments initiated during the entire AAP, for a minimum period of one year (including 3 months of coverage). 
  • From a FINANCIAL standpoint: the laboratory implements a PUT-RD, for data collection and transmission of periodic summary reports. The laboratory finances this data collection (cf. agreement to be signed with health establishments). 
  • The pharmaceutical laboratory is also required to assist prescribers in entering and monitoring the collection of real-life follow-up data of the medicinal product, providing them with the necessary means. 

Two types of compassionate access: 

This system targets two distinct cases, both involving a medicinal product to treat patients with diseases without appropriate treatment in a given therapeutic indication, without being intended to obtain an AMM in France. The requests are managed only by the National Agency for the Safety of Medicines and Health Products (ANSM). 

  1. Either this compassionate access is requested for an unauthorized and unavailable medicinal product in France by a hospital prescriber for a specifically named patient, provided that the ANSM can presume a favorable benefit/risk ratio for a severe, rare, or disabling disease: this is an individual and nominative compassionate access authorization (AAC). 
  1. Or it involves the regulation of a practice, initiated by the ANSM, to secure an off-label prescription practice of a medicinal product available in France, with an AMM for other indications, when it is subject to a well-established off-label prescription on French territory: this is a compassionate prescription framework (CPC).  

Exemptions to compassionate access have been foreseen in the following cases: 

  • Allowing nominative access to medicinal products in development for the indication: this is a “very early” compassionate access. 

The grant by the ANSM is subject to several eligibility conditions, which brings this system closer to early access and can be the gateway to it: 

  • The implementation of the treatment cannot be delayed; 
  • The patient cannot participate in any ongoing research; 
  • The company marketing the medicinal product must commit to filing an early access request within 12 months following the first “pre-precoce compassionate” authorization (18 months for rare diseases). 

For these mechanisms, the designation of a laboratory operating a medicinal product may be necessary, to ensure, if necessary, the import/distribution, pharmacovigilance, quality complaints, or medical information. 

The laboratories now have several years of experience with these new systems, and the emerging trends show the authorities’ willingness to make innovative medicinal products available to French patients and to respond to the personal situations of patients in therapeutic dead ends. 

Article written by Caroline LECUELLE, Consultant in Regulatory Affairs & Pharmaceuticals 

What are the differences between the Mutual Recognition Procedure and the Decentralized Procedure ? 

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

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

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

1/ The Mutual Recognition Procedure (MRP) 

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

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

Timetable 

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

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

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

The MA (including the SPC, package leaflet and labeling) is recognized by the CMS. 

This period is followed by a 30-day national closing phase to issue the national MA. 

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


2/ The decentralized procedure (DCP) 

This procedure differs from the MRP in two main points :  

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

In this case, the laboratory asks a member state to act as reference state (“RMS”) for the evaluation among the states in which it wishes to authorize its medicinal product. 

Timetable 

The RMS draws up a preliminary assessment report on the dossier submitted and the draft summary of product characteristics (SPC), package leaflet and labeling. 

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

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

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

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

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

The DCP therefore lasts a maximum of 210 days. This period is followed by a 30-day national closing phase to issue the national MA. 

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

To sum up: 

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

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

Article written by Fabien MEDINA, Pharmaceutical and Regulatory Affairs Senior Advisor. 

*ANSM : Agence Nationale de Sécurité du Médicament et des produits de santé (competent authority for medicines and health products) 

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