EU ATMP Legal Routes: Autorisations de mise sur le marché standard, accélérées et adaptatives: Thérapie moléculaire ◄ garantie santé entreprise

Rôle et responsabilités de l'agence de réglementation dans l'évaluation des ATMP

L'obligation pour l'ATMP d'évaluer les MAA dans le cadre d'une procédure CAT centralisée souligne le rôle de l'EMA non seulement dans l'évaluation des MAA, mais également dans les orientations scientifiques au stade du développement, parmi d'autres MAA qui relèvent de la seule compétence de l'EMA (par exemple, les noms d'orphelins et les PIP). Cependant, les demandes d'autorisation d'essais cliniques (CTA) sont approuvées au niveau national (généralement à moins qu'une procédure de réconciliation volontaire ne soit suivie) dans chaque État membre où la CTA est soumise. Les organismes de réglementation des États membres de l'UE sont connus sous le nom d'autorités nationales compétentes (ANC) et, bien qu'ils aient le pouvoir d'approuver l'autorisation de mise sur le marché de médicaments non soumis à la procédure centralisée (dans le cadre de la reconnaissance mutuelle, décentralisée ou nationale) dans leur État membre, , à part l'évaluation des demandes de CTA, comprennent des orientations scientifiques sur les plans d'essais cliniques. Pendant le développement clinique, des conseils scientifiques de l'EMA peuvent être obtenus ainsi que les conseils scientifiques de la NCA pour garantir que les exigences de la MAA sont respectées et que les approches réglementaires appropriées sont suivies. L'EMA fournit également des conseils scientifiques parallèles au réseau européen d'évaluation des technologies de la santé (EUnetHTA), qui permet aux développeurs de médicaments d'obtenir des commentaires des autorités réglementaires et des organismes d'ETS sur leurs plans de production de preuves, pour soutenir la prise de décision sur l'autorisation de mise sur le marché et le remboursement de nouveaux médicaments. En même temps.

Le comité principal de l'EMA est le comité des médicaments à usage humain (CHMP), qui est responsable de l'évaluation scientifique de la plupart des médicaments à usage humain (à l'exception des plantes), afin de déterminer leur qualité, leur innocuité, leur efficacité et leur rapport bénéfice / risque. équilibre. Cela se fait par l'évaluation des AAM et des variations post-autorisation des AMM approuvées (par exemple, pour introduire de nouvelles indications ou des changements dans les processus de fabrication). En outre, le CHMP et ses groupes de travail contribuent aux réunions de conseil scientifique et préparent des lignes directrices scientifiques pour fournir un soutien aux développeurs médicaux sur les exigences d'un plan de développement avant le MAA. For ATMPs, the CAT, rather than the CHMP, prepares the initial draft opinion on an ATMP-related submission (i.e., an MAA or a variation), with the CHMP responsible for final adoption of the CAT opinion. In addition to its primary roles in the evaluation of ATMP MAAs and execution of ATMP classification procedures, the CAT also contributes to other ATMP-related activities, including the provision of support to scientific advice procedures, advice on pharmacovigilance or risk management systems, evaluation of post-authorisation variation submissions, and preparation of scientific guidelines.

The CAT’s activities in pharmacovigilance and risk management are in support of another key EMA committee, the Pharmacovigilance Risk Assessment Committee (PRAC). The PRAC is responsible for assessing and monitoring the safety of human medicines, and it was established in line with the pharmacovigilance legislation (Directive 2012/26/EC) that updated Directive 2001/83/EC and came into effect in 2012 to help strengthen the safety monitoring of medicines across the EU. The PRAC is primarily responsible for assessing risk management plans (RMPs) submitted with MAAs and for evaluating post-authorisation safety studies (discussed later), among other responsibilities.

With respect to the designation of orphan medicinal products and evaluation of PIPs as discussed earlier, these activities are the responsibility of the Committee for Orphan Medicinal Products (COMP) and Pediatric Committee (PDCO), respectively. The two other EMA committees, the Committee on Herbal Medicinal Products (HMPC) and Committee for Medicinal Products for Veterinary Use (CVMP), are not involved in the regulation of ATMPs for human use.

A number of working parties and related groups support the EMA’s scientific committees on scientific issues relating to their particular field of expertise. For ATMPs, the key working party is the Scientific Advice Working Party (SAWP), which is composed of NCA members and executes scientific advice and protocol assistance procedures. Another EMA initiative with a key role in early development of ATMPs for human use is the Innovation Task Force (ITF), a forum for early dialogue with industrial and academic organizations on innovative aspects of medicine development, which recruits experts from relevant committees and working parties as needed. Unlike scientific advice and protocol assistance, which provide to medicine developers formal, documented feedback and recommendations that are intended to be MAA enabling, ITF meetings are for the informal exchange of information through which the EMA can (1) clarify at an early stage the route to market for innovative medicines, and (2) maintain an awareness of current developments on innovative medicines in preparation for their assessment.

Innovative medicines are defined by EMA as those medicines that contain an active substance or combination of active substances that has not been authorised before. ITF meetings are provided free of charge as an incentive to developers of innovative medicines—which include ATMPs—to engage in early dialogue with the EMA. Other incentives provided specifically for the development of ATMPs include the following: a 65% fee reduction for a scientific advice request (or 90% for organizations registered with the EMA as micro-, small-, and medium-sized enterprises (SMEs)); and, also for SMEs, a 90% fee reduction for the ATMP certification procedure, which involves the scientific evaluation by the CAT of non-clinical and quality data generated at any stage during the ATMP development process to identify any potential issues early such that they can be addressed prior to MAA submission.

The MA Procedure Ensures the Quality, Safety, and Efficacy of ATMPs through Clinical Development

Defining Quality, Safety, and Efficacy: The Role of Clinical Development

In accordance with the EU regulatory framework, medicinal products must be demonstrated to be safe, efficacious, and of suitable quality for use in humans. During clinical development (Figure 2), medicinal product safety (i.e., the tolerability of the product and the minimization and/or management of adverse events caused by it) and efficacy (i.e., the ability of the product to induce the desired therapeutic response) are addressed in progressive non-clinical studies (e.g., in animal models of disease) and human clinical trials. Concurrently, medicinal product quality is established through the development of a defined manufacturing process and its associated analytical and stability testing procedures, i.e., the so-called chemistry, manufacturing, and control (CMC) studies. The output of these CMC studies can be considered to be a controlled, commercial-scale process that enables routine production of a characterized product defined by a set of quality attributes that correlate with safe and efficacious use in patients.

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Manufacturing process development of ATMPs within a regulatory framework for EU clinical trial & marketing authorisation applications.

At the time of MAA, the safety and efficacy data generated during clinical development are reviewed with the intention of concluding on the benefit-risk balance of the product. A medicinal product may only be authorised if the benefit-risk balance is positive, i.e., the benefits outweigh the risks. The benefit-risk assessment may be quantitative or qualitative, depending on the therapeutic context and clinical study design, but the benefits are related to the key favorable effects based on the primary and most important secondary clinical endpoints, while the risks describe the incidence, severity, duration, reversibility, and dose-response relationship of unfavorable effects of the medicine, including adverse events. Benefits and risks also have limitations and uncertainties that are taken into consideration when concluding on the benefit-risk balance, e.g., sample size, representativeness of the target patient population, statistical modeling, and adequacy of monitoring. In all cases, the way in which a conclusion on the benefit-risk balance of a medicine is made is described in the assessment reports generated during the MAA review.