Clinical trials are a type of clinical studies performed to investigate the safety and/or the efficacy of a medicinal product, here an Advanced Therapy Medicinal Product (ATMP), which is called an advanced therapy investigational medicinal product at this stage. Clinical trial is a crucial step to succeed for an advanced therapy medicinal product to obtain its marketing authorization. Although clinical trials of an ATMP falls under the general European regulation on clinical trials, ATMP’s characteristics have led the European legislator and regulator to elaborate regulatory adjustments, including Good Clinical Practice specific to ATMPs.
A clinical trial is the first step of the medicine’s research and development process that involves human volunteers. Therefore, it must be preceded by a discovery (proof of concept) and a pre-clinical phase including in-vitro and in-vivo experimentations.
Clinical trial is composed of four phases: the first one using healthy participants and each of the other phases having an increasing number of participants with the condition being treated (Detailed description of the phases or link to WHO Clinical trials). See also the EuroGCT Factsheet “What is the clinical trials process?”
Stakeholders
Subjects/participants: Individual patients and healthy volunteers: People volunteer to take part in clinical trials either as a control or as a recipient to test medical interventions including gene and cell therapy such as advanced therapy investigational medicinal products, cells and tissues used for therapeutic purposes, but also other biological products, surgical procedures, radiological procedures, devices, behavioral treatments, or preventive care.
Ethics Committees: Ethics Committees’ role is to verify that the research protocol of the clinical trials complies with all ethics principles. Ethics Committees are independent national or local bodies established by Member States in accordance with their national law and empowered to give opinions for the national competent authorities to authorise or not the start of clinical trials.
It should be noted that it generally exists other Ethics Committees under national laws, such as national ethics committees in charge of advising the policy and law decision makers, or universities’ research ethics committees in charge of reviewing research protocols for other studies than clinical trials.
Funders and Sponsors: A clinical trials’ sponsor is the individual, the company, the institution or the organization which takes the responsibility for the initiation, the management, and the setting up of the financing of the clinical trial. In the European Economic Area, 61% of clinical trials are sponsored by the pharmaceutical industry and 39% by non-commercial sponsors (academia, fund raisers…).
National Competent Authorities: National Competent Authorities, which are often national medicines agencies, are notably responsible for authorizing and oversighting clinical trials.
European Medicines Agency: The role of the EMA regarding clinical trials was mainly limited to the review of clinical trials data in the context of marketing authorisation application. It is now being strengthened with the entry into force of the new European regulation on clinical trials as the EMA has been in charge of setting up and maintaining the Clinical Trials Information System (CTIS). More information here.
Investigators: They are the individuals, researchers, who are responsible for the conduct of a clinical trial at a clinical trial site.
Principal investigator: is an investigator who has the responsibility to lead the investigators team conducting a clinical trial at a clinical trial site.
Definitions
Clinical study: “‘Clinical study’ means any investigation in relation to humans intended:
to discover or verify the clinical, pharmacological or other pharmacodynamic effects of one or more medicinal products;
to identify any adverse reactions to one or more medicinal products; or
to study the absorption, distribution, metabolism and excretion of one or more medicinal products;
with the objective of ascertaining the safety and/or efficacy of those medicinal products;” (article 2§2 (1), of European Regulation No 536/2014 on clinical trials on medicinal products for human use, and repealing Directive 2001/20/EC)
Clinical trial: “‘Clinical trial’ means a clinical study which fulfils any of the following conditions:
the assignment of the subject to a particular therapeutic strategy is decided in advance and does not fall within normal clinical practice of the Member State concerned;
the decision to prescribe the investigational medicinal products is taken together with the decision to include the subject in the clinical study; or
diagnostic or monitoring procedures in addition to normal clinical practice are applied to the subjects.”
(Article 2§2 (2), of European Regulation No 536/2014 on clinical trials on medicinal products for human use, and repealing Directive 2001/20/EC)
‘Low-intervention clinical trial’: “means a clinical trial which fulfils all of the following conditions:
the investigational medicinal products, excluding placebos, are authorised;
according to the protocol of the clinical trial,
the investigational medicinal products are used in accordance with the terms of the marketing authorisation; or
the use of the investigational medicinal products is evidence-based and supported by published scientific evidence on the safety and efficacy of those investigational medicinal products in any of the Member States concerned; and
the additional diagnostic or monitoring procedures do not pose more than minimal additional risk or burden to the safety of the subjects compared to normal clinical practice in any Member State concerned” (Article 2§2 (3), of European Regulation No 536/2014 on clinical trials on medicinal products for human use, and repealing Directive 2001/20/EC)
Advanced therapy investigational medicinal product: “‘Advanced therapy investigational medicinal product’ means an investigational medicinal product which is an advanced therapy medicinal product as defined in point (a) of Article 2(1) of Regulation (EC) No 1394/2007 of the European Parliament and of the Council.” (Article 2§2 (7), of European Regulation No 536/2014 on clinical trials on medicinal products for human use, and repealing Directive 2001/20/EC)
Subject: “‘Subject’ means an individual who participates in a clinical trial, either as recipient of an investigational medicinal product or as a control;” (Article 2§2 (17), of European Regulation No 536/2014 on clinical trials on medicinal products for human use, and repealing Directive 2001/20/EC).
Ethics Committee: ‘Ethics committee’ means an independent body established in a Member State in accordance with the law of that Member State and empowered to give opinions for the purposes of this Regulation, taking into account the views of laypersons, in particular patients or patients' organizations; (Article 2§2 (11), of European Regulation No 536/2014 on clinical trials on medicinal products for human use, and repealing Directive 2001/20/EC).
Protocol: “‘Protocol’ means a document that describes the objectives, design, methodology, statistical considerations and organization of a clinical trial. The term ‘protocol’ encompasses successive versions of the protocol and protocol modifications;” (Article 2§2 (22), of European Regulation No 536/2014 on clinical trials on medicinal products for human use, and repealing Directive 2001/20/EC).
Good clinical practice: ‘Good clinical practice’ means a set of detailed ethical and scientific quality requirements for designing, conducting, performing, monitoring, auditing, recording, analysing and reporting clinical trials ensuring that the rights, safety and well-being of subjects are protected, and that the data generated in the clinical trial are reliable and robust; (Article 2§2 (30), of European Regulation No 536/2014 on clinical trials on medicinal products for human use, and repealing Directive 2001/20/EC).
Challenges
Legal challenge:
Clinical trials’ regulation in the European Union was governed by the Directive 2001/20/EC of the European Parliament and of the Council of 4 April 2001 on the approximation of the laws, regulations and administrative provisions of the Member States relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use. But the lack of homogeneity in the implementation of the directive within Member States appears to be a burden on European research.
The way clinical trials are conducted in the European Union (EU) will undergo a major change when the Clinical Trials Regulation (Regulation (EU) No 536/2014) will come into application on 31 January 2022. The Regulation harmonizes the assessment and supervision processes for clinical trials throughout the EU, via a Clinical Trials Information System (CTIS). Clinical trials information system will contain the centralized EU portal and database for clinical trials called EudraCT foreseen by the Regulation. The European Medicines Agency sets up and maintains Clinical Trial Information System, in collaboration with the Member States and the European Commission.
Before the Clinical Trials Regulation fully come into force, a transitional period has been arranged. From 31 January 2022, a 3-years transition period is foreseen in which the clinical trials Directive will still apply. Initial clinical trials applications must be submitted under the new regime from the second year of application of the clinical trials Regulation; i.e. from 31 January 2024.
Initial 12 months after 31 January 2022: a clinical trial application may still be submitted in EudraCT and governed by the old Directive but also may be submitted in the new EU portal and be governed by the new regulation.
Next 24 months: All initial clinical trial applications must be submitted in the new EU portal and be governed by the new Regulation.
From 3 years after 31 January 2022: All clinical trials applications are governed by the new Regulation regardless of their date of submission.
Ethical challenge:
The conduct of a clinical trial involves several risks related to the experimental nature of medical research. One of the main ethical challenges is to find the balance between those risks to subjects and patients and the expected benefits produced by the research. The general principle which is legally establish is: “A clinical trial may be conducted only if:
the rights, safety, dignity and well-being of subjects are protected and prevail over all other interests; and
it is designed to generate reliable and robust data.”
(Article 3 of European Regulation No 536/2014 on clinical trials on medicinal products for human use, and repealing Directive 2001/20/EC).
Economical and societal challenge:
In medical research, it is well-known that developing and obtaining a marketing authorization for a medicine or medicinal product is a very long and expensive process in general, and even more when it comes to advanced therapy medicinal products. Indeed, the previous lack of harmonization in clinical trial national regulations and processes, which is now addressed by European Regulation No 536/2014 on clinical trials on medicinal products for human use that will come into force in 2022, raised the issue of the European competitiveness in medical research, especially concerning the unavoidable step of clinical trials. Moreover, European competitiveness in this field is not only an economical challenge but also a public health one. In fact, early access to medical innovations for European citizens also depends on researchers’ ability to perform clinical trials in European Union countries.
Scientific challenge:
Advanced Therapy Medicinal Products, because of the specific risks they pose, are subject to stricter rules than classical medicines to ensure patient protection. From a scientific and technical perspective, the characterization and manipulation of living cells and tissues for therapeutic use is problematic in terms of ensuring their long-term stability, particularly concerning their natural tendency to evolve and interact within the human body.
This leads to difficulties in ensuring the long-term safety and efficacy of these advanced therapy medicinal products, whether it is the risk of tumors, contamination of cells and tissues with infectious agents or immune rejection, or, in the case of gene therapies, the integration of genetic material in an unintended location. These difficulties have to be taken into account within the design of clinical trials of ATMPs, which is challenging as often specific to each ATMPs.
Opportunities and incentives
It exists specific rules concerning clinical trials of advanced therapy investigational medicinal products which provides supplementary delays (50 days more) as well as the possibility to consult experts (50 days more) for the assessment of their clinical trials applications in view of their specificities. (Articles 6§7 and 18§5 of European Regulation No 536/2014 on clinical trials on medicinal products for human use, and repealing Directive 2001/20/EC)
Clinical Trials Facilitation and Coordination group: Since 2004, the Heads of Medicines Agencies agreed to coordinate the implementation of the EU clinical trial directive 2001/20/EC across Member States. This group is, at the same time, a forum for discussion to agree on common principles and processes to be applied throughout the European medicines regulatory network and a promoter of harmonization of clinical trial assessment decisions and administrative processes across national competent authorities.
Acknowledgements
Published: 05/04/2023
Authors:
Edouard Habib, EuroGCT ELSI Legal Information Officer