Wael HAYEK

The conditions for prescription and dispensing (CPD) define how patients may access a medicine. The prescription and/or dispensing of a medicine may be restricted—meaning reserved for hospital use or to certain physicians (such as specialists), or subject to specific requirements (regarding treatment duration or additional examinations)—in the interest of patient safety.

The prescribing of healthcare products falls within the scope of physicians and certain healthcare professionals, within the limits of their professional practice: dentists, midwives, physiotherapists, podiatrists, nurses, and occupational therapists.

Medicines that present difficulties in use or risks in case of inappropriate use may only be obtained, depending on the case, with a prescription from a physician, dentist, or midwife. These are known as prescription-only medicines (PMO, Rx). They are classified into different categories based on their prescribing and dispensing rules:

• List I medicines (single dispensing with the same prescription unless otherwise specified by the prescriber) and List II medicines (renewals allowed for up to one month of treatment for a maximum of 12 months).
• Narcotics: around twenty medicines, including morphine and its derivatives, whose dispensing is subject to very strict rules (secured prescription, batch number and a micro-lettering box to prevent falsification, with quantities limited to 7, 14, or 28 days of treatment).

If a medicine is not included in these lists, it is considered “non-mandatory prescription” (PMF), or even OTC (available over the counter in pharmacies).

As an exception, community pharmacists are authorised to prescribe and administer, to certain populations, the vaccines included in the national immunisation schedule, as well as seasonal influenza and COVID-19 vaccines. They may also dispense, without a prescription, certain prescription-only medicines for the management of sore throats and cystitis in pharmacies, after performing a rapid diagnostic test (TROD).

Some prescription-restricted medicines may be dispensed to the public by a hospital pharmacy (PUI). These medicines are included on the “retrocession” list.

Medicines with Restricted Prescription

This term covers five categories of medicines belonging to List I:

• Medicines reserved for hospital use (RH): they may only be prescribed, dispensed, and used in hospitals.
• Hospital-prescription-only medicines: they may only be prescribed in hospitals. They are dispensed in any pharmacy or, in some cases, only in hospital pharmacies.
• Hospital-only initial prescription medicines: the initial prescription must be issued in a hospital, but renewal prescriptions may be issued by a community physician. Depending on the case, dispensing may occur in hospital or community pharmacies. In some situations, the number of renewals is limited, and a new hospital prescription is required after a set period (usually one year).
• Medicines restricted to certain specialists: these medicines are complex to use or treat complex diseases. They may be dispensed in hospital or community pharmacies.
• Medicines requiring special monitoring: patients treated with these medicines must undergo regular monitoring (blood tests, additional examinations, more frequent consultations). The prescription may only be renewed if these monitoring requirements are met.

Regulatory Framework – Directive 2001/83/EC

Directive 2001/83/EC includes articles dedicated to prescription and dispensing requirements.
According to Article 70:

“1. When granting a marketing authorisation for a medicinal product, competent authorities shall specify its classification as either:
— medicinal product subject to medical prescription,
— medicinal product not subject to medical prescription.
They shall apply the criteria set out in Article 71(1).

2. Competent authorities may establish subcategories for medicinal products that may only be supplied on medical prescription, referring to the following classification:
   a) medicinal products on prescription that may or may not be renewed;
   b) medicinal products subject to special medical prescription;
   c) medicinal products under ‘restricted’ medical prescription, reserved for certain specialised settings.”

These provisions are also reflected in French regulation (Article R5121-36 for prescription conditions and Articles R5121-77 et seq. for restricted-prescription medicines). According to Articles R5121-77 et seq. of the French Public Health Code, the marketing authorisation (MA) defines the prescription and dispensing conditions of a medicine.

The MA of a restricted-prescription medicine may require the prescriber to indicate on the prescription that the patient has been informed of the associated risks.
When the reference medicinal product of a generic is classified in a restricted-prescription category, the generic’s MA follows the same classification.

Evolving Toward Greater Access in Community Pharmacies

Law n° 2020-1525 of 7 December 2020 on accelerating and simplifying public action, integrated into Article L5123-2 of the Public Health Code, illustrates a desire to shift medicines towards community pharmacy distribution.
According to Article L5123-2, any request for inclusion on the hospital formulary of a medicinal product that is not classified as reserved for hospital use must be accompanied by a request for inclusion on the “community list”

Atessia’s Support

Atessia assists pharmaceutical companies in defining or modifying the prescription and dispensing conditions of their medicinal products.

This article was written by Estelle ICARD, Regulatory & Pharmaceutical Affairs Consultant.

In December 1999, the European Parliament and Council adopted Regulation (EC) No. 141/2000 on so-called “orphan” medicinal products. These are drugs developed to treat rare diseases. They are called “orphan” because the pharmaceutical industry has little interest in developing and marketing products that are only intended for a small number of patients.  

This Regulation established a Community procedure for designating certain medicinal products as orphan medicinal products and introduced incentives to promote the research, development and marketing of such designated medicinal products. A large proportion of advanced therapy medicinal products claim orphan drug status. This “orphan drug” designation can be granted at any stage of the drug’s development, prior to obtaining marketing authorization. 

However, certain conditions must be met. According to the regulations, in order to obtain orphan designation, the sponsor must demonstrate: 

> that the medicinal product is intended for the diagnosis, prevention or treatment of a life-threatening condition or chronic disability affecting no more than 5 in 10,000 people in the European Union;  

> or that, in the absence of incentives, the sale of this medicine in the EU is unlikely to generate sufficient profits to justify the necessary investment; 

> and that there is no satisfactory alternative method or, if available, that the treatment in question will provide a significant benefit. 

Once the “application” file is ready, the sponsor submits their application for orphan designation via the Regulatory & Scientific Information Management Platform (IRIS*).  

Applications for orphan designation are evaluated by a specific committee set up within the EMA, the COMP*. This committee is responsible for examining the applications for designation submitted, in order to issue an opinion to the European Commission within 80 days of receipt of the application. Subsequently, the Commission adopts its final opinion on an application for designation of a medicinal product as an orphan medicinal product within 30 days of receipt of the Committee’s opinion, in the light of the eligibility criteria set out in Regulation (EC) No 847/2000 laying down the provisions for implementation of the criteria for designation of a medicinal product as an orphan medicinal product and definitions of the concepts ‘similar medicinal product’ and ‘clinical superiority’. 

Orphan drug legislation offers sponsors an attractive opportunity to benefit from reductions in regulatory fees payable to the EMA. This incentive leads to reduced fees for protocol assistance, MA applications, pre-authorisation inspections and post-approval MA variation applications.  

Obtaining orphan drug status also brings many other significant advantages that manufacturers can benefit from, such as protocol assistance. This is scientific advice specific to orphan drugs that guides sponsors on the types of clinical studies needed to demonstrate the quality, significant benefits and risks of the drug.  

Another factor encouraging sponsors to apply for orphan designation is the 10-year market exclusivity of their drug after MA is granted. Authorized orphan drugs benefit from ten years of protection from competition on the market from drugs with similar indications. That is, each indication with an orphan designation confers ten years of market exclusivity for that particular indication.  

All of these incentives have proven successful since the implementation of orphan drug legislation in the EU in 2000. The ongoing revision of European drug legislation would retain most of the incentives, according to current discussions. 

Atessia supports its clients in their efforts to obtain orphan designation for their drugs.  

*IRIS: Integrated Regulatory Information System 

*COMP: Committee for Orphan Medicinal Products 

Article written by Blandine LATROBE, Regulatory & Pharmaceutical Affairs Consultant 

In France, certain drugs are covered by the National Health Insurance system. They are referred to as reimbursable drugs. Obtaining reimbursement is not based solely on a product’s therapeutic value. It involves a specific regulatory process, involving several authorities and affecting the price, prescription conditions, and patient access to the drug. 

The reimbursement request must be submitted by the pharmaceutical company that markets the drug. 

Assessment by the Transparency Committee 

The French National Authority for Health (HAS), through its Transparency Committee, assesses each specialty based on: 

• Actual benefit (Service Médical Rendu – SMR), which determines the applicable reimbursement rate (15%, 30%, 65%, or 100%). 

• Drugs whose SMR is considered insufficient are not reimbursable. 

The price of a reimbursable drug is then set by the Economic Committee for Health Products (CEPS), following negotiations with the pharmaceutical company, based on: 

• The Improvement in Medical Service Rendered (Amélioration du Service Médical Rendu – ASMR), which ranks the product in relation to comparators already available, with 5 ASMR levels : from I (major therapeutic progress) to V (no improvement). 

This price, combined with the reimbursement rate, subsequently determines the registration of the drug on the regulatory lists that allow it to be covered by Health Insurance : 

• List of specialties reimbursable to Social Security Insured (City list): drugs available in community pharmacies, covered by Social Security based on a price negotiated with the CEPS and a reimbursement rate determined according to the SMR. 

• List of pharmaceutical specialties approved for use by communities (Hospital list): drugs used in hospitals, covered through the standard hospital budget (GHS), without price negotiation with CEPS, as hospitals manage their own budgets and tenders. 

• Supplementary List (“Liste en sus”): expensive and innovative drugs administered in hospitals, excluded from the GHS budget, reimbursed on an invoice basis, with prices negotiated directly with CEPS, taking into account their therapeutic value and impact on hospital costs. 

A drug only becomes eligible for standard reimbursement after publication in the Official Journal. Note that some medicines are tacitly included on the hospital list. This is the case for medicines under compassionate use or early access programs. According to these prescription and dispensing conditions, the medication must be prescribed by a healthcare professional (doctor, midwife, dental surgeon, chiropodist, nurse) on a prescription in accordance with the regulations and within the limits of prescription rights. It is then dispensed to the patient either in community pharmacies or hospitals. 

Obtaining reimbursement is not just an administrative formality: it is a key step that determines access to the French market. The pharmaceutical company must prepare a solid dossier and anticipate the authorities’ expectations, while ensuring that the product is correctly positioned in relation to existing alternatives. An unfavorable reimbursement or reimbursement obtained within a restrictive framework can limit the drug’s adoption by prescribers and hinder its access to patients. 

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

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 Concerned Member State(s) (or “CMS”) in which the laboratory wishes to market its product. The Reference Member 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.

Source EMA

After a possible upgrade of the MA dossier, the RMS sends the MA dossier and its assessment report, including the Summary of Product Characteristics (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 CMS has no further comments.

Once the MA (including the SPC, package leaflet and labeling) is recognized by the CMS, this recognition is followed by a 30-day national closing phase to issue the national MA. Procedures successfully closed are published on the CMDh website.

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 requests a member state to act as reference state (“RMS”) in order to carry out the evaluation, among the states where it wishes to obtain authorization for its medicinal product.

Source EMA

* EEA = European Economic Area

MA = Marketing authorization

The RMS draws up a preliminary assessment report on the dossier submitted and the draft 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. Procedures successfully closed are published on the CMDh website.

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.

3/ To sum up:

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

Article written by Mathilde ISRAEL, Regulatory Affairs and External Communication Advisor.