Introduction to Clinical Trials

Site: EUPATI Open Classroom
Course: Clinical Trials and Trial Management
Book: Introduction to Clinical Trials
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Date: Monday, 20 March 2023, 4:09 PM

1. How Are Clinical Trials Conducted?

To obtain approval for a clinical trial, the Clinical Trial Application (CTA) must be submitted to regulatory bodies called competent authorities. A Research Ethics Committee (REC) also reviews the protocol and gives a positive or negative opinion. This is to ascertain that the research respects the dignity, rights, safety and well-being of the people who are participating. In order to ensure compliance with ethical standards, the majority of clinical trial protocols are developed in line with the ‘Declaration of Helsinki’, a set of ethical standards for research involving human beings, human material or identifiable data, developed in 1964 by the World Medical Association (WMA) and revised several times.

Clinical trials on medicines are conducted in the European Union (EU) in compliance with regulations, directives and guidelines. The standard to which clinical trials are conducted is called Good Clinical Practice, as defined in a guideline by the International Conference on Harmonisation (ICH-GCP). This is an international quality standard that must be applied in all member states of the EU and describes the responsibilities and expectations of all participants in the conduct of clinical trials, including investigators, monitors, sponsors and ethics committees. GCPs cover aspects of monitoring, reporting and archiving of clinical trial data and incorporating supplements on the Essential Documents and on the Investigator's Brochure which had been agreed earlier through the ICH process.

2. Who Conducts Medicine Clinical Trials and Why?

Clinical trials typically involve a number of different parties. It is helpful to understand who is leading the creation and the conduct of a trial and why they are doing it:
  • A sponsor is the body (usually a company, university or hospital) that takes responsibility for organising the trial and often funds the trial.

  • An investigator (or investigators for multi-centre trials) - the doctor responsible for the performance of the trial.

  • Sometimes the sponsor will engage a contract research organisation (CRO) to help with the logistics (organisation) and the conduct of the trial.
Sponsors can be companies or government funded institutions/agencies. Both may perform trials in order to use the gathered data to support applications that will allow promotion and marketing of products for the approved indication(s).

They may also undertake studies in the best interests of the community to understand diseases. Occasionally they will collaborate with other partners to explore a particular problem, perhaps one that is not of commercial interest but is of interest to patients and the healthcare system.

3. History of Clinical Research Legislation in Europe

Disasters have, in several cases, prompted change in legislation in the US and in Europe. The thalidomide disaster contributed to the publication, in 1965, of the first European Directive, known as 65/65/EEC, enacted by the Council of the European Economic Community. It stated that no medicine could be placed on the market in a member state unless authorisation had been issued by the competent authority in that member state. In essence, pharmaceutical manufacturers had to seek approval for their medicines from each country before marketing could begin in that country.

In 1995, the European System for Marketing Authorisation of Medicinal Products as well as the European Medicines Evaluation Agency (EMEA), was established. Evaluation of applications and elaboration of guidelines was undertaken through the incorporation of the Committee for Proprietary Medicinal Products (CPMP) and the Committee for Veterinary Medicinal Products (CVMP). The centralised procedure eliminated the need for individual member state review - as one approval is given to cover all member states.

The mutual recognition procedure (MRP) and the decentralised procedure (DCP) are used for those medicines not authorised by the centralised procedure. They are similar to the former procedure where an applicant goes directly to a single member state. Once the medicine is approved by that authority, the applicant then seeks to have other member states recognise the approval and grant their own marketing authorisation (MRP) or member states collaborate directly on an application submitted (DCP). In 2004, the full name of the agency was shortened to the European Medicines Agency (EMA). The CPMP was renamed the Committee for Medicinal Products for Human Use (CHMP).

The ICH-GCP guideline, developed in 1996, sets an international harmonised quality standard that protects the rights, safety and welfare of human participants. It minimises human exposure to investigational products, and improves quality of data, with the aim of speeding up development of new medicines and decreasing the cost to sponsors and to the public. Compliance with this guideline provides public assurance that the rights, safety and well-being of trial participants are protected and consistent with the principles of the Declaration of Helsinki. It also assures that the clinical trial data are credible.

There are 13 core principles of ICH-GCP as cited below:
  1. Clinical trials should be conducted in accordance with ethical principles that have their origin in the Declaration of Helsinki, and that are consistent with GCP and the applicable regulatory requirement(s).

  2. Before a trial is initiated, foreseeable risks and inconveniences should be weighed against anticipated benefit for the individual trial subject and society. A trial should be initiated and continued only if the anticipated benefits justify the risks.

  3. The rights, safety and well-being of the trial subject are the most important considerations and should prevail over interests of science and society.

  4. The available non-clinical and clinical information on an investigational product should be adequate to support the proposed clinical trial.

  5. A clinical trial should be scientifically sound, and described in a clear, detailed protocol.

  6. A trial should be conducted in compliance with the protocol that has received prior institutional review board (IRB)/ independent ethics committee (IEC) approval/favourable opinion.

  7. The medical care given to, and medical decisions made on behalf of subject should always be the responsibility of a qualified physician or, when appropriate, of a qualified dentist.

  8. Each individual involved in conducting a trial should be qualified by education, training, and experience to perform his or her respective task(s).

  9. Freely given informed consent should be obtained from every subject prior to clinical trial participation.

  10. All clinical trial information should be recorded, handled, and stored in a way that allows its accurate reporting, interpretation and verification.

  11. The confidentiality of records that could identify subject should be protected, respecting the privacy and confidentiality rules in accordance with the applicable regulatory requirement(s).

  12. Investigational products should be manufactured, handled and stored in accordance with applicable Good Manufacturing Practice (GMP). They should be used in accordance with the approved protocol.

  13. Systems with procedures that assure the quality of every aspect of the trial should be implemented.

4. Current European Legislation Situation

Prior to 2001, each EU member state had its own national clinical trials regulations and approval systems, (e.g. Clinical Trials Act 1987 and 1990 in Ireland). This increased the complexity of multi-national European clinical research, primarily due to differing requirements and approval mechanisms between countries. In an attempt to standardise and harmonise clinical trial approvals amongst member states the European Commission introduced the first European Clinical Trials Directive. In Europe all clinical trials are subject to approval by a regulatory authority and favourable opinion by a Research Ethics Committee (REC). The CT Directive set out the minimum requirements for clinical trials with a specific sub-category of medicines called ‘investigational medicinal products’ (IMPs). This had to be implemented into national law in each European country by May 2004.
These requirements included:
  • Protection of trial participants as stated in the Declaration of Helsinki.
  • Regulatory authority approval per member state, within specific timelines.
  • A single REC opinion (per member state), within specific timelines.
  • Common quality standard of GCP (ICH-GCP).
To find out about the requirements of individual countries please visit the EMA website, where a list of National Competent Authorities (NCAs) in the EU member states can be found here.
One of the major changes introduced is an application procedure that will require sponsors to apply for authorisation to conduct an interventional/low-intervention clinical trial (CT) via a new EU portal.1 The regulation’s effective date is dependent on the availability of the portal and its associated database, which are in development and subject to user acceptance testing by EMA stakeholders. The regulation introduces a single approach for the application and maintenance of a CT authorisation, and applies to both single or multiple member state trials. This procedure not only combines the content of what can be currently referred to as the “regulatory” and “ethics” applications, but also combines the scientific, technical, and ethical review necessary to receive approval to conduct a CT in the EU. In addition, the regulation defines procedural timelines, harmonizes document requirements, and aims to reduce the administrative burden of applications.
The application content and assessment are divided into two parts: Part I contains scientific and medicinal product documentation; Part II contains the national and patient-level documentation (see Table 1, adapted from Juliette L. Kirk, 2017).
Table 1: New CT application summary

Part I

Part II

Application form

Informed consent form and subject
information leaflet

Cover letter (including sponsor’s justification for the classification as a low intervention CT, if necessary

Compensation arrangements

Investigator’s brochure

Suitability of investigators and facilities

Good manufacturing practice

Proof of insurance or indemnification

Investigational medicinal product dossier/
Auxiliary medicinal product dossier

Data protection rules

Scientific advice

Proof of fee payment

EU Paediatric Investigation Plan decision

Note: Precise content will be determined
by each member state

Example of investigational and auxiliary
medicinal product labelling

In Summary
The EU CT regulation introduces a new procedure, new timelines, and revised application content. Although it may increase or decrease the overall timelines in some MSs, it will bring increased predictability for CT start in the EU.
Significant changes for the MS competent authorities, ethics committees, and sponsors.

  • At the MS level, ethics committees and competent authorities will need to agree how to work together to achieve the review outcome within the required timelines.
  • At the EU level, MSs will need to agree how to work together to achieve what is required to complete the application review.
  • Industry CT sponsors will need to prepare themselves to confirm country selections without negatively affecting planned study start (i.e., avoiding multiple applications to add MSs), respond to application review queries within short timelines, and manage changes so they can be submitted when needed rather than waiting for an ongoing application to complete.
1. European Commission. Clinical Trials. Directive No. 2001/20/EC. 4 April 2001.
2. Official Journal of the European Union. Regulations. “Regulation (EU) No 536/2014 of the European Parliament and of the Council of 16 April 2014 on Clinical Trials on Medicinal Products for Human Use, and Repealing Directive 2001/20/EC.” 27 May 2014.