Clinical trials in human medicines (2024)

Clinical trials are studies intended to discover or verify the effects of one or more investigational medicines.

The regulation of clinical trials aims to ensure that the rights, safety and well-being of trial participants are protected and the results of clinical trials are credible.

Regardless of where they are conducted, all clinical trials included in applications for marketing authorisation for human medicines in the European Union (EU) /European Economic Area (EEA) must have been carried out in accordance with the requirements set out in Annex 1 of Directive 2001/83/EC. This means that:

• clinical trials conducted in the EU / EEA have to comply with EUclinical trial legislation;
• clinical trials conducted outside the EU / EEA have to comply with ethical principles equivalent to those set out in the EEA, including adhering to international good clinical practice and the Declaration of Helsinki.

In the EU / EEA, approximately 2,800 clinical trials are authorised each year.

Approximately 60% of clinical trials are sponsored by the pharmaceutical industry and 40% by non-commercial sponsors, mainly academia.

For more information, seeClinical Trials Regulation.

• Accelerating Clinical Trials in the EU (ACT EU)
• Data submission on investigational medicines: guidance for clinical trial sponsors
• Reporting safety information on clinical trials
• Clinical Trials Regulation
• Clinical Trials Information System
• Clinical Trials Information System: training and support

EMA's Committee for Medicinal Products for Human Use (CHMP)is responsible for conducting the assessment of a human medicine for which an EU-wide marketing authorisation is sought. As part of its scientific evaluation work, the CHMP reviews the clinical trial data included in the application.

Clinical trial data is included in clinical-study reports that forma large part of the application dossiers submitted by applicants such aspharmaceutical companies and small and medium enterprisesapplying for a marketing authorisation via the Agency.

Assessments are based on purely scientific criteria and determine whether or not the medicines concerned meet the necessary quality, safety and efficacy requirements in accordance with EU legislation.

Furthermore, the Agency manages two clinical trial databases, EudraCT and the Clinical Trial Information System. EMA also co-leads the business change programme Accelerating Clinical Trials in the EU (ACT EU),together with the Heads of Medicines Agencies (HMA) and the European Commission.

For more information, see Clinical Trials Regulation.

Sponsors can adjust the way they run clinical trials that have been affected by the war in Ukraine using the experiencegained during the COVID-19 pandemic. They can also applythe approaches and flexibilities agreed in the context of the pandemic.

The European Commission, EMAand the Heads of Medicines Agencies (HMA)issued thisinitial advice for sponsors on 30 March 2022:

• Advice to sponsors on managing the impact of the war in Ukraine on clinical trials(30/03/2022)

Additional recommendations for sponsors are available fromthe Clinical Trials Coordination Group (an HMA groupuniting clinical trials experts):

• Heads of Medicines Agencies - Recommendation to sponsors on managing the impact of the war in Ukraine on clinical trials

Guidance is also available from EMA'sBiostatistics Working Partyon actionssponsors of affected clinical trials can take to help ensure the integrity of their studies and the interpretation of the study results while safeguarding the safety of trial participants as a first priority:

• Points to consider on the impact of the war in Ukraine on methodological aspects of ongoing clinical trials

EMA strongly encourages sponsorsto capture data affected and unaffected by the war, and to use the 'estimand framework'described in the ICH E9 (R1) guideline fordealing with events impacting the trial:

• ICH E9 statistical principles for clinical trials

Guidance on clinical trial management during the COVID-19 pandemic is available below.

• Guidance on clinical trial management during the COVID-19 pandemic
• Implications of Coronavirus disease (COVID-19) on methodological aspects of ongoing clinical trials

EMA advises sponsors to also check any guidance available at national level.

Sponsors with specific questions relating to EU guidance cancontact EMA using the Send a question form. Questions relating to national guidance should be addressed to the relevant national authority.

Sponsors can also contact either EMA or the national competent authorities for scientific advice on:

• methodological aspects relating to their trials;
• the use ofaffected clinical trial results for regulatory purposes.

Support in preparation for and during public health emergencies

EMA'sEmergency Task Force (ETF)can provide support to clinical trial sponsorsfor all medicines intended to target a potential or declaredpublic health emergency. This isin linethe Regulation on EMA's Reinforced Role (Regulation (EU) 2022/123).

This support includes:

• Setting up joint multinational clinical trials
• Acting as a sponsor or co-sponsor of a trial
• Deciding on which protocol to follow

Interested clinical trial sponsors should send their proposals to phesupportct@ema.europa.eu.

They should include the study protocol and specify in which Member State(s) they intend to run clinical trials, if already known.

The ETF works closely with EMA’s partner organisations in the EU to support study sponsors and the conduct of larger multinational trials.

These partner organisations include:

• Heads of Medicines Agencies' (HMA) Clinical Trials Coordination Group (CTCG);
• European Commission's Clinical Trials Advisory Group (CTAG);
• European Health Emergency Preparedness and Response Authority (HERA)

A report is availablerecommendingEU-level actions to improve the set-up and conduct of clinical trials during public health emergencies.

The recommendations seek toaddress issuesseen inthe COVID-19 pandemic andoutbreak of mpox disease with setting up large enoughclinical trials across multiple EU Member States. These are needed to rapidly gathersufficient high-quality evidence to support decision-making byhealth authorities.

The report results froma lessons-learned workshopon clinical trials in emergencies held by EMA'sETFand the European Commissionwith national competent authorities,ethics committeesand academic experts.

More information:

• European Medicines Agency / Emergency Task Force and European Commission workshop on lessons learned on clinical trials in public health emergencies(09/06/2023)
• Scientific advice and protocol assistance: Medicines intended for a disease causing public health emergency
• Public health threats

Guidance for clinical trial sponsors during the COVID-19 pandemic

Guidance has been available for clinical-trial sponsorson managingclinical trials and participants during the COVID-19 pandemic:

• Good clinical practice:Guidance on clinical trial management during the COVID-19 pandemic

This coveredhow todealwith the extraordinary situations that the pandemic presented andspecific advice on clinical trials for potentialCOVID-19 treatments.

Guidance has also been available forsponsorsof affected clinical trialsto help ensure the integrity of their studies and the interpretation of the study results while ensuring the safety of trial participants:

• Implications of Coronavirus disease (COVID-19) on methodological aspects of ongoing clinical trials

In line with this guidance, EMA has beenflexible and pragmatic during the assessment of affected clinical trial data submittedas part of marketing authorisation applications.

The Accelerating Clinical Trials in the EU (ACT EU) initiative aims todevelop the EU furtheras a competitive centre forinnovativeclinical research.

The initiative builds on theClinical Trials Regulation (CTR) and Clinical Trials Information System's (CTIS) launch on 31 January 2022. It aims to deliver onthe clinical trial innovation recommendations of theEuropean medicines agencies network strategy and the European Commission’s Pharmaceutical strategy for Europe.

For more information, see:

• Accelerating Clinical Trials in the EU (ACT EU)

Decentralised clinical trials aim to facilitate participation in clinical trials by offering maximum flexibility and convenience.

For instance, they can enable participants to:

• have health visits at home;
• receive study medicine shipments at home;
• provide their consent electronically

The Clinical Trials Coordination Group (CTCG)is overseeing a project on decentralised clinical trials called the EU Decentralised Clinical Trials project (EU DCT project).

The project aims to identify:

• innovative designs and methodologies for clinical trials;
• opportunities provided by decentralised clinical trials in Europe;
• the challenges that decentralised clinical trials provide.

The project began in March 2022.

The project delivered a recommendation paper on the use of decentralised elements in clinical trialsin December 2022.

• Recommendation paper on decentralised elements in clinical trials

The development of this paper took account of the perspectives of all areas of the research community on decentralised clinical trials, including at a multi-stakeholder workshop hosted by ACT EU in October 2022.

Guidance is available for clinical trial sponsors, clinicians engaged in clinical trialsand marketing authorisation applicants on planningand conducting complex clinical trials:

• Complex clinical trials – questions and answers

The guidance covers the following topics:

• Planning and conducting complex clinical trials
• Designing and conducting master protocols
• Methods for clinical trial analysis (e.g. Bayesian approaches)
• Biomarkers and their assays
• Reporting trial information to regulatory authorities
• Transparency

EMA, the European Commission and the Heads of Medicines Agencies (HMA) published this guidance under the ACT EU initiative.

Itaims tostrengthenthe link between scientific advice offered by regulators and innovative clinical research.

They published the guidance in May 2022.

For more information, see:

• Accelerating Clinical Trials in the EU (ACT EU)
• EudraLex - clinical trial guidelines

The Clinical Trials Regulation (Regulation (EU) No 536/2014)entered into application on 31 January 2022, repealing theClinical Trials Directive (EC) No. 2001/20/EC.

The Regulation is part of a broad initiative to transform the EU / EEA clinical trials environment in support of large clinical trials in multiple European countries, to the benefit of medical innovation and patients.

For more information, see Clinical Trials Regulation.

By 31 January 2025, any ongoing trials approved under the Clinical Trials Directive will fall under the Clinical Trials Regulation.

For more information, see:

• Transition period for clinical trial sponsors

Clinical Trials Information System

The Clinical Trials Information System (CTIS)supports interactions between clinical trial sponsors (researchers or companies that run clinical trials and collect and analyse the data) and regulatory authorities in the EU Member States and EEA countries, throughout the lifecycle of a clinical trial.

CTIS went live with a searchable public website on 31 January 2022.

It serves to implement EU pharmaceutical law in the Clinical Trials Regulation - Regulation (EU) No 536/2014.

For more information, see:

• Clinical Trials Information System

EMA is responsible for the development, maintenance and coordination of theEuropean Union Drug Regulating Authorities Clinical Trials (EudraCT) database.

The EudraCT databaseincludes data on the following clinical trials:

• Interventional clinical trials run in the EU/ EEA under the Directive 2001/20/EC
• Interventional clinical trials run outside the EU / EEA that are part of a paediatric investigation plan (PIP),as required by Article 41 of the Paediatric Regulation (Regulation (EC) No 1901/2006)
• Interventional clinical trials run outside the EU / EEA that are in scope of Articles 45 and 46 of the Paediatric Regulation (Regulation (EC) No 1901/2006)

Update: As of 31 January 2023, all initial clinical trial applications in the EU / EEA must be submitted through the Clinical Trials Information System.

The EudraCT database remains available for uploading the following:

• Amendments, trial statuses and results of trials that are already in EudraCT
• Third country files of trialsconducted exclusively outside of the EU / EEA that are part of a paediatric investigation plan (PIP) or are in scope of Article 46 of the Paediatric Regulation (EC) No 1901/2006.

From 31 January 2025, any ongoing trial in the EU / EEA will need to comply with the Clinical Trials Regulation. For more information, see Clinical Trials Regulation: Transition period for clinical trial sponsors.

A subset of this data isavailable through the European Union Clinical Trials Register, which EMA manages on behalf of EU and EEA Member States. Users are able to view protocol and result information regarding:

• phase-II to phase-IV adult clinical trials where the investigator sites are in the EEA;
• any clinical trials in children with investigator sites in the EU and any trials that form part of a PIP including those where the investigator sites are outside the EU.

Information about the results of public clinical trials is shownin the European Union Clinical Trials Register - if publishedby the relevant sponsor on the EudraCT database.

Requirements for sponsors

In line with European Commission guideline 2012/C 302/03, sponsors are required to post results of allclinicaltrials in EudraCT that arecompleted globally.

They need to post results within 12 months of completing the trial for clinical trials in adults, and within six months for clinical trails in children.

In July 2019, EMA published a letter co-signed by the European Commission and the Heads of Medicines Agencies (HMA) reminding all sponsors of their obligation to poston EudraCTthe results of completed trials:

• Joint letter by the European Commission, EMA and HMA to stakeholders regarding the requirements to provide results for authorised clinical trials in EudraCT

As of June 2022, 81% of clinical trials are compliant with this requirement in EudraCT.

Between April 2019 and June 2022, the compliance rate rose:

• from 24% to 64% for non-commercial sponsors;
• from 77% to 86% for commercial sponsors.

EMAand national competent authorities enabled these compliance rates throughreminders sentto clinical trials sponsors.A full list of clinical trials for which sponsorsdid not follow up on these reminders is available on the European Clinical Trials Register.

From October 2020, sponsors can also post results ofclinical trials that ended prematurely, whether theywere approved but never started or started but terminated early. Sponsors should provide the reasonsfor the premature end andany partial results, ifavailable.

For more information, see the EudraCT databasewebsite.

The Agency has a separate policy on the publication of clinical reports submitted by pharmaceutical companies to support their regulatory applications for human medicines.

For more information, see Clinical data publication.

Clinical trials conducted outside the EU but submitted in an application for marketing authorisation in the EU have to follow the principles which are equivalent to the provisions of the relevant EU legislation.

For more information, see Clinical Trials Regulation.

In addition, sponsorsshould continue to submit information onclinical trials in EudraCT if they are:

• conductedexclusively outside of the EU / EEA and part of an agreed paediatric investigation plan (PIP);
• in scope of Article 46 of the Paediatric Regulation (Regulation (EC) No 1901/2006).

For more information, see:

• EudraCT database
• EU Clinical Trial Register.

In 2012, the Agency published the final version of this paper:

• Reflection paper on ethical and good-clinical-practice aspects of clinical trials of medicinal products for human use conducted outside of the European Union (EU) / European Economic Area and submitted in marketing-autho....

This paper aims to strengthen existing processes to provide assurance that clinical trials meet the required ethical and GCP standards, no matter where in the world they have been conducted.

The number of clinical trials and clinical trial subjects outside Western Europe and North America has been increasing for a number of years. More information is available in this document:

• Clinical trials submitted in marketing-authorisation applications to the European Medicines Agency: Overview of patient recruitment and the geographical location of investigator sites

The Clinical Trials Coordination Group(CTCG) is a working group of the Heads of Medicines Agencies.

The CTCGaims to help make the EU / EEA more attractive for clinical trials activities.

It is responsible forharmonising and optimisingthe regulatory environment while assuring the protection of rights, safety and wellbeing of clinical trial participants andensuringthe generation of robust data.

The group is composed of experts in the classification, assessment and oversight of clinical trials from national agencies.

The Clinical Trials Coordination Group replaced theClinical Trials Facilitation and Coordination Group.

The Clinical Trials Highlightsnewsletter covers topics such as Accelerating Clinical Trials in the EU (ACT EU)and the development of CTIS.

Issues from July2023 (Issue 15) onwards are available at the link below:

• Clinical Trials Highlights: Issue 15onwards

Previous issuesare available on EMA's website in PDF format:

• Clinical Trials Highlights: Issues 1 - 14

Use the link below to receive Clinical Trials Highlights by email:

• Subscribe to Clinical Trials Highlights