EU Drug Approval Process

Introduction:

The EU drug approval system includes several routes that pharmaceutical companies can utilize to get their products approved across the 27 member states. These pathways are designed to accommodate the diverse nature of medicinal products and their intended uses:

1. Centralised Procedure (CP)

2. Mutual Recognition Procedure (MRP)

3. Decentralised Procedure (DCP)

1. Centralised Procedure (CP):

The Centralised Procedure is the process used by the European Medicines Agency (EMA) for the evaluation and approval of medicines for human and veterinary use, intended to be marketed within the European Union. Here's a breakdown of the three main steps:

Step I: Pre-submission to Application

Pre-submission: Before an application is formally submitted, applicants can engage with the EMA to gain an understanding of regulatory requirements, submission processes, and timelines. Early dialogue is encouraged to ensure a clear and streamlined submission process.

Early Advice: Applicants may seek scientific advice or protocol assistance (especially for orphan medicines) from the EMA. This can cover clinical trial design, quality issues, and non-clinical aspects to optimize drug development.

Rapporteur/Co-rapporteur Appointment: The EMA appoints a rapporteur and a co-rapporteur from among its members to lead the evaluation. These individuals are responsible for coordinating the assessment of the application and preparing the assessment reports.

Assessment Team: An assessment team is formed, often including members from the rapporteur and co-rapporteur's national competent authorities, to evaluate the submission in depth.

Application: The company submits the application, including all required documentation such as results from clinical trials, manufacturing details, and proposed labeling.

Validation: The EMA verifies the application to ensure it is complete and meets the necessary criteria to enter the evaluation process.

Step II: Scientific Evaluation

Scientific Evaluation: The rapporteurs and assessment team conduct a detailed scientific review of the submitted data to evaluate the medicine's quality, safety, and efficacy.

Assessment Reports: The rapporteurs produce initial assessment reports which are circulated to the CHMP members and the applicant.

List of Questions (+ clock stop): The CHMP may have questions for the applicant, leading to a "clock stop" in the evaluation timeline, giving the applicant time to respond to the queries.

CHMP Opinion: The CHMP, after deliberation and considering the rapporteurs' assessments and the applicant's responses, adopts an opinion on whether the medicine should be authorized.

Possibility to Appeal: If the opinion is negative, the applicant has the right to request a re-examination of the decision.

Transfer to EU Commission: A positive CHMP opinion is then forwarded to the European Commission, which has the authority to grant marketing authorization.

Step III: Decision Making Process

Review by the European Commission: The European Commission reviews the CHMP's opinion and draft decision, considering any scientific or legal issues.

Consultation: The draft decision is usually subject to a consultation process with the member states.

Final Decision: The European Commission issues a final decision, which is legally binding in all EU member states.

Implementation: Following the decision, the company can begin marketing the medicine across the EU, and the decision is also communicated to the public.

The centralized procedure is designed to ensure that medicines are evaluated to the highest scientific and regulatory standards and that once approved, they can be made available to patients across the entire European Union efficiently.

2. Mutual Recognition Procedure (MRP):

The Mutual Recognition Procedure (MRP) is a regulatory pathway in the European Union for obtaining marketing authorization for a medicinal product in multiple EU Member States when the product is already authorized in one EU Member State (the Reference Member State, or RMS). Here's a step-by-step explanation:

Application to Reference Member State (RMS)

Initial Authorization: The pharmaceutical company first obtains a national marketing authorization from the RMS, which involves a full assessment of the product's quality, safety, and efficacy.

RMS Approval (Day 210)

Assessment Period: The RMS completes its evaluation within 210 days, providing a national marketing authorization for the product.

Submit Mutual Recognition (MR) Application to Member States

Application for Recognition: The company then applies for mutual recognition in other Member States, known as Concerned Member States (CMS), providing the assessment report from the RMS to support the application.

Closure of Procedure

Assessment Reports (AR): CMS review the assessment report and raise any concerns or agree to the mutual recognition.

Product Information Harmonization: The Summary of Product Characteristics (SPC), labelling, and Patient Information Leaflet (PIL) are harmonized across all involved Member States.

National Authorizations: If no objections are raised, the procedure is closed, and national authorizations are granted based on the RMS’s assessment.

Serious Objections Referral to CMDh

Objections and Referral: If any CMS has serious objections that could lead to a refusal of mutual recognition, the issues are referred to the Co-ordination Group for Mutual Recognition and Decentralised Procedures – human (CMDh).

Arbitration by CMDh (60 Days): The CMDh, comprising representatives from all EU Member States, has 60 days to reach a consensus or agreement, which is binding unless an appeal is made.

Serious Objections Referral to CHMP

Continued Dispute: If the serious objections are not resolved, the dispute can be referred to the Committee for Medicinal Products for Human Use (CHMP).

Arbitration by CHMP (Art 32, 33, 34): The CHMP, part of the EMA, then conducts its arbitration under Articles 32, 33, or 34 of Directive 2001/83/EC, depending on the type of issue at hand.

60 Days CHMP Opinion + 30 Days Commission Decision: The CHMP has 60 days to formulate an opinion, which is then sent to the European Commission. The Commission has an additional 30 days to make a final decision.

The MRP allows companies to efficiently extend their product's market reach within the EU based on an existing national marketing authorization, leveraging mutual recognition among Member States while ensuring that all have agreed upon the product's safety and efficacy. This process supports the EU's aim to facilitate access to medicines and protect public health while respecting the national sovereignty of each Member State's regulatory system.

3. Decentralised Procedure (DCP)

The Decentralised Procedure (DCP) is designed for the approval of non-centralized medicines in the European Union. It allows a pharmaceutical company to apply for the simultaneous authorization of a medicinal product in several EU Member States if the medicine has not yet been authorized in any EU country. Here's an explanation of the process:

Step 1: Submission and Evaluation (Day 1 to Day 120)

Submission of Dossier: The applicant submits a registration dossier to the selected Reference Member State (RMS) and Concerned Member States (CMSs).

RMS Evaluation: The RMS begins the evaluation process and drafts a preliminary Assessment Report (AR).

CMS Comments: The CMSs review the AR and provide comments.

Questions to Applicant: The RMS compiles a list of questions based on the comments from CMSs and sends them to the applicant.

Clock Stop: The procedure is paused (usually for a recommended three months) to give the applicant time to respond to the questions.

Step 2: Finalization and Approval (Day 121 to Day 210)

Draft Assessment Report: Once the applicant's responses are received, the RMS prepares the draft final AR, draft Summary of Product Characteristics (SPC), and draft labelling/packaging leaflet.

Closure of Procedure: If all CMSs agree with the RMS's assessment and the applicant's responses to the list of questions, the procedure can be closed, leading to national approvals.

Serious Objections Referral to CMDh: In case any CMS has a serious objection that cannot be resolved, the issue is referred to the CMDh.

Arbitration by CMDh (60 Days): The CMDh, consisting of representatives from all EU Member States, has 60 days to resolve the dispute.

Further Serious Objections Referral to CHMP: If the CMDh cannot reach a consensus, the issue is referred to the CHMP for arbitration.

Arbitration by CHMP (Art 32, 33, 34): Under the relevant articles of Directive 2001/83/EC, the CHMP has 60 days to formulate an opinion.

CHMP Opinion and Commission Decision: The CHMP’s opinion is then forwarded to the European Commission, which typically has 30 days to issue a final decision.

The DCP allows for simultaneous national approvals in multiple EU countries while ensuring that the medicinal product meets the necessary standards. The use of a single RMS for the initial assessment provides a unified approach, and the collaboration with CMSs ensures that the interests and regulations of individual Member States are taken into account. This procedure benefits both the applicant and the Member States by reducing duplication of effort and enabling a coordinated decision-making process.