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In Europe, changes to a marketing authorisation (MA) for a human medicine are covered by Regulation (EC) No. 1234/2008 of November 24, 2008. This regulation has been applicable since January 1, 2010 to MAs obtained in centralized, decentralized and mutual recognition procedures, and since August 4, 2013 to MAs obtained in national procedures. It presents multiple possibilities for classifying the modifications that can be made to a MA, including the Post-Approval Change Management Protocol (known by the acronym “PACMP”) which we will focus on in this article.

Origin and definition 

A PACMP is a regulatory tool providing predictability and transparency in terms of requirements and studies necessary for the implementation of a strictly CMC (for “Chemistry, Manufacturing & Controls”) change, because the approved protocol of the planned changes constitutes an agreement between the MA holder and the regulatory authority. This is a stepwise approach to evaluate modifications, initially allowing for an early evaluation of the modification strategy and, in a 2^nd step, a subsequent separate evaluation of the data produced after implementation of the planned changes on the basis of the agreed strategy.

The objective of this tool is to allow faster and more predictable implementation of modifications after approval, given that the MA holder will have previously obtained the agreement of the authorities on the proposed strategy and the tests allowing to check the effect of the modification on the quality of the product. Typically, the variation category designated for reporting changes under a PACMP is at least one category lower than it would normally be (e.g., Type IB instead of Type II). The implementation of the changes planned in an approved PACMP is therefore faster and less risky for the laboratories that request it, which ultimately benefits to the marketing of the drug and therefore to the patient.

In 2012, the EMA compiled a set of questions and answers regarding the PACMP in the document “Questions and answers on post approval change management protocols (EMA/CHMP/CVMP/QWP/586330/2010)”. This document was revised in December 2025 to reflect experience gained since its initial publication, the revision of the regulations on variations (2024), and the associated guidelines on variations (2025) applicable on January 15, 2026. The following topics are covered:

• Suggestions for PACMP content; 
• PACMP submission and evaluation mechanisms; 
• Implementation of the change(s) after finalisation of the studies described in the PACMP; 
• Types of changes that may be subject to a PACMP; 
• Multiple changes within the framework of a single PACMP; 
• Place of the PACMP in the Module 3 of the MA; 
• PACMP and development according to the traditional approach versus the improved approach (so called “QbD” for “Quality by Design”). 

In 2019, the ICH Q12 guideline “Technical and regulatory considerations for pharmaceutical product lifecycle management“, proposed in order to provide a framework to facilitate the management of changes to chemical properties, manufacturing and control measures after the authorisation, in a more predictable and efficient manner throughout the lifecycle of the product, has reinforced the place of the PACMP as an essential regulatory tool in the management of the lifecycle of medicines in Europe.

Scope of the PACMP use 

The PACMP concerns both CMC modifications relative to the drug substance (DS) and modifications relative to the drug product (DP). It applies to all medicinal products for human use, including biotechnological or biological products, whether a traditional or improved (“QbD”) approach was followed for the development of the product. However, its use is optional.

A PACMP can be applied to a single product, multiple products, or multiple products and multiple sites.

The presence of a PACMP in its MA file involves careful risk analysis and a full understanding of the different risk assessments to ensure that the quality, safety and efficacy of the medicine are never compromised.

It has to be noted that no modification described in a PACMP should result in additional risks to patient safety, product quality or efficacy. Also, a CMC modification that would require human efficacy, safety, or pharmacokinetic/pharmacodynamic data to evaluate the effect of the modification (e.g., certain formulation changes, clinical or nonclinical studies to evaluate new impurities, evaluation of immunogenicity or antigenicity) cannot be included in a PACMP.

Formalisation of the PACMP in the MA file 

The PACMP takes the form of one or more document(s) presented in section 3.2.R “Regional Information” of the MA file. It can be planned as soon as the MA application is made or during a MA variation application (Type II).

MA modifications linked to the PACMP 

The different variations linked to the introduction, deletion or modification of a PACMP in a MA file are presented in the table below. 

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