Clinical trials are a critical part of drug development and medical research, ensuring that new treatments are safe, effective, and improve patient outcomes. In the European Union (EU), the regulation and oversight of clinical trials are conducted in accordance with specific EU laws and standards. These measures are designed to safeguard the well-being of participants while upholding the principles of scientific integrity. Clinical trials provide the fundamental basis for the approval of new drugs and medical devices allowing for eventual approval and commercial introduction as authorised medicines. They can even be used where a specific therapeutic claim is made in other products such as nutraceuticals. This week, I want to delve into the processes involved in conducting clinical trials in the EU with a brief introduction to what clinical trials are and then to give an overview of the main guidelines and legislation. I will focus on regulatory frameworks, ethical considerations, and the steps taken to ensure public safety and trust.

What are Clinical Trials?

The most basic definition of a clinical trial is a research study conducted on human volunteers to assess the safety, efficacy, and side effects of a new treatment, intervention, or drug.  They typically follow a series of stages or “phases” that progress from small-scale studies in healthy volunteers to large-scale trials involving patients with the specific health condition(s) to be treated. The main aims of a clinical trial is to gather data that supports the potential benefits of a treatment and to identify any risks or adverse outcomes associated with its use. These clinical trials are critical in turning promising laboratory data on potentially useful molecules into practical, life-saving therapies.

The Phases of Clinical Trials

All of the main regional regulatory bodies follow the same model for conducting clinical trials, with four main phases:

• Phase I: This is the first step in testing a new molecule, bio-drug or other treatment in humans. It involves a small number of healthy volunteers (usually 20–100) and focuses on safety, determining the appropriate dosage, and identifying side effects.
• Phase II: After Phase I confirms initial safety, the drug advances to Phase II, where it is tested on a larger group of patients (100–300) with the targeted disease or condition. This phase assesses the drug's effectiveness and continues to monitor its safety profile.
• Phase III: Phase III involves an even larger group of patients (1,000–3,000 or more) and aims to confirm the treatment’s effectiveness, monitor side effects, and compare it with existing therapies. Successful Phase III trials are a key component of marketing authorization applications.
• Phase IV: Once the drug is approved and introduced to the market, Phase IV trials are conducted to continuously monitor its real-world performance and evaluate its long-term safety and effectiveness.

EU Clinical Trials Regulation (CTR) - Regulation of Clinical Trials in the European Union

The primary legislation that regulates clinical trials in the EU is the EU Clinical Trials Regulation (EU CTR 536/2014). The EU CTR is a well-defined legal framework that governs the authorisation, conduct, and oversight of clinical trials. This framework aims to ensure high standards of quality, safety, and reliability in clinical research while protecting participants.

It replaced the earlier Clinical Trials Directive (2001/20/EC), which was inifficent and costly due to the different national approaches to implementation across the EU member states. The new CTR regulation, which came into effect in January 2022, harmonises the process for conducting clinical trials across all EU countries. It introduces several important reforms:

• Centralised Application Process: Under the new regulation, researchers or sponsors can submit a single application for approval of a clinical trial, that is valid across all member states. This centralised method addresses the regulatory burden, as the previous system required needed approvals in each country where the trial was carried out.
• Single Decision Process: Member states involved in a clinical trial can be nominated as either the Reporting Member State (RMS) or as a concerned Member State (CMS) and they must collaborate to reach a joint decision on whether the trial can proceed. This promotes consistency and ensures the trial meets EU-wide safety and scientific standards.
• Increased Transparency: The EU CTR stipulates that clinical trial results, whether positive or negative, must be made publicly available. This includes publishing trial protocols and detailed results on the EU Clinical Trials Information System (CTIS), ensuring transparency and trust in the research process.
• Informed Consent: The regulation emphasises the necessity of providing clear and understandable information to participants before obtaining their informed consent. This ensures that participants are fully aware of the potential risks and benefits associated with the trial.

The Role of Ethics Committees

Ethical oversight is a fundamental part of regulating clinical trials in the EU, with each member state having ethics committees responsible for reviewing and approving the ethical aspects of a clinical trial before it can commence. They make sure that the trial is compliant with ethical standards, especially in protecting the rights, safety, and well-being of the participants. They also establish the risk-benefit ratio of the drug and ensure that participants are not exposed to unnecessary risks.

Ethics committees operate independently from the sponsors conducting the trial, ensuring that the well-being of participants takes precedence over any commercial interests. Trials on vulnerable populations, such as children or patients unable to give consent, require additional safeguards and ethical considerations.

The Conduct of Clinical Trials in the EU

Sponsor and Investigator Responsibilities

The company responsible for initiating, managing, and financing a clinical trial is defined as the clinical trial sponsor. The sponsor plays a pivotal role in ensuring the adherence of the trial to regulatory standards, including the guidelines of Good Clinical Practice (GCP). GCP is an international ethical and scientific quality standard for designing, conducting, and reporting clinical trials.

The sponsor is also responsible for selecting qualified investigators, ensuring that clinical trial sites are adequately equipped, and providing the necessary resources for conducting the trial. The investigator, typically a physician, is responsible for the day-to-day management of the trial and the safety of participants.

Safety Monitoring

Safety monitoring during clinical trials is crucial. Sponsors and investigators must establish systems for continuous safety evaluation and reporting of adverse events. Any serious adverse event (SAE) or suspected unexpected serious adverse reaction (SUSAR) must be reported to the relevant authorities within a specific time frame. This allows for real-time monitoring of any potential risks to participants and, if necessary, intervention to halt the trial or amend the protocol.

Data monitoring committees (DMCs) or independent safety monitoring boards (SMBs) are often established for large-scale or high-risk trials. These committees regularly review data from the trial to ensure participants are not exposed to undue risk.

Clinical Trial Approval: Marketing Authorisation

After successfully completing clinical trials, a company or sponsor must submit a dossier containing all the data gathered from preclinical studies and clinical trials to the European Medicines Agency (EMA) or national authorities for marketing authorisation. The EMA plays a central role in the evaluation of medicines, ensuring that they meet the necessary safety, efficacy, and quality standards before being approved for use in the EU.

The EMA's Committee for Medicinal Products for Human Use (CHMP) reviews the submitted data and provides a recommendation on whether the drug should be granted marketing authorization. If approved, the medicine can be sold throughout the EU and European Economic Area (EEA). In some cases, conditional or accelerated approvals may be granted for drugs that address unmet medical needs, allowing patients quicker access to potentially life-saving treatments.

The EU's robust framework for conducting and regulating clinical trials plays a crucial role in ensuring the development of safe and effective therapies for patients. The EU Clinical Trials Regulation, combined with strict ethical oversight and rigorous safety monitoring, provides a comprehensive system that protects participants while promoting scientific innovation. By streamlining processes and ensuring transparency, the EU is fostering a collaborative and efficient environment for clinical research, ultimately benefiting public health and the global medical community. As medical research continues to evolve, these regulations will remain vital in supporting the safe and ethical advancement of healthcare across Europe.

If your company is a sponsor or CDMO supporting clinical trials and would like assistance with accessing the EU for sourcing or clinical release, or if you need Clinical QPs or SMEs to support you with consulting and advice, then Orion GXP Consulting would be happy to assist.

To discuss your needs further, please email admin@oriongxp.com or call +353 7198 10101 (IRL) or +44 203 4750375.