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Part I
Exploring Fundamentals
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Chapter 1
Good Clinical Practice Principles: Legal Background and Applicability
Umberto Filibeck, Angela Del Vecchio, and Fabrizio Galliccia
Summary
Since 1991 the European Medicines Agency (EMA, formerly EMEA) adopted the Guidelines of the International Conference on Harmonization (ICH) on Good Clinical Practice (GCP). In this regard, one European Union (EU) Guideline and three EU Directives are in force at present, that is, the E6/CPMP/ICH/135/95 GCP Guideline, Directive 2001/83/EC (Community Codex on Pharmaceuticals), Directive 2001/20/EC (GCP and Clinical Trials, CTs), and Directive 2005/28/EC (Detailed Guidance on GCP).
European Directive 2001/20 on GCP and CTs has been widely criticized by a large portion of the scientific community more directly involved in the promotion and management of noncommercial academic CTs. Since 2003 several scientists from academia highlighted through the international scientific literature the difficulties inherent in the new EU regulation, in particular as regards GCP compliance and quality monitoring problems. Such difficulties have also been acknowledged by Directive 2005/28 where, among others, it is stated that for academic CTs the application of certain GCP aspects may be unnecessary or guaranteed by other means.
None of these documents oblige CTs to be in compliance with the GCP ICH Guideline (GCP-ICH) full text and details. Rather, they prescribe that CTs be in compliance only with GCP principles and with GCP Guidelines laid down in Directive 2005/28 EC, this being less binding when compared to the GCP-ICH Guideline. At the national level, EU Member States (MS) adopted different legislation to implement the GCP obligations. MS GCP Inspectorates generally act as if all GCP aspects were mandatory to verify the reliability of data reported by the CTs audited.
At the international level, in particular in developing countries, where several bioequivalence (BE) studies are conducted and the number of CTs is increasing, often neither specific aspects nor the principles of GCP are complied with. In the case of data submitted to EU MS Regulatory Authorities (RAs) for a Marketing Authorization (MA) of a medicinal product, the CTs of which were performed outside the EU, Directive 2001/83 allows the MA to be granted only if the CTs are in compliance with the ethical principles of GCP, although in practice only a few RAs assess that this actually has been done.
Specific examples are given to illustrate the above issues and a number of key aspects related to laboratory activities are reported and discussed in the frame of different international normative and guidelines on GCP.
1.1. Introduction
Since 1991 the European Medicines Agency (EMA, formerly EMEA)1 adopted the Guidelines of the International Conference on Harmonization (ICH) on Good Clinical Practice (GCP). In this regard, one European Union (EU) Guideline and three EU Directives are in force at present, that is, the E6/CPMP/ICH/135/95 GCP Guideline [1], Directive 2001/83/EC (Community Codex on Pharmaceuticals) [2], Directive 2001/20/EC (GCP and Clinical Trials, CTs) [3], and Directive 2005/28/EC (Detailed Guidance on GCP) [4].
The introduction of GCP in EU is linked with Good Manufacturing Practice (GMP), particularly Annex 1, 13, and 16 (The rules governing medicinal products in the European Union, EudraLex, Vol. 4) [5] regarding directly or indirectly the production of Investigational Medicinal Product (IMP) and Directive 2003/94/EC on GMP for Medicinal Products and IMP [6]. At global level, besides ICH-GCP, WHO has also issued WHO GCP.
The GCP legal background and applicability are discussed hereafter along with the description of related documents and implementation problems. This legal framework is of paramount importance to attach credibility to the experimental information obtained when carrying out clinical investigations, thus substantially contributing to preserving and improving human health.
1.2. Good Clinical Practice
1.2.1. ICH E6: Guidelines for Good Clinical Practice
ICH Guidelines for GCP [1] have been prepared by the ICH of Technical Requirements for Registration of Pharmaceuticals for Human Use, which is composed by the Medicine Regulatory Agencies and members of the pharmaceutical industry of the EU, Japan, and the USA. The WHO, Canada, and European Parliamentary Technology Assessment (EPTA) have observer status. Since its creation in 1990, the ICH has issued 58 Tripartite Guidelines on issues related to its four main areas of work, namely quality, safety, efficacy, and multidisciplinary topics. The process to reach harmonization of technical requirements resulting from scientific progress goes along with the process of keeping up-to-date the current guidelines, in order to ensure that the harmonization process, so far achieved, is not lost. Guidelines are adopted by the Steering Committee and signed by the three regulatory parties to ICH. However, guidelines become binding only when the regulatory bodies in the three regions implement them. The objective of this guidance is to provide “international ethical and scientific quality standards for designing, conducting, recording and reporting trials that involve the participation of human subjects. Compliance with this standard provides public assurance that the rights, safety and well-being of trial subjects are protected, consistent with the principles that have their origin in the Declaration of Helsinki, and that the clinical trial data are credible.”
ICH E6 GCP Guideline is designed to set a unified standard for the ICH countries in order to facilitate the mutual acceptance of clinical data by RAs in these jurisdictions and speed up registration for market authorization of medicines. Topics covered include the composition of Ethics Committees/review boards, the responsibilities of investigators and sponsors, provisions regarding trial protocols and protocol amendments, including treatment of data, informed consent, payment of subjects, insurance in case of harm. This guideline has been adopted by the EU in 1995 (updated version) [1] and largely transposed into their legislation by the United States [7] and Japan in 1997.
ICH Good Clinical Practice Principles
The ICH-GCP Principles can be divided into three different categories:
a. Principles to guarantee the “ethical aspects” of the CT, as follows.
- CTs should be conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and that are consistent with GCP and the applicable regulatory requirements.
- The rights, safety, and well being of trial subjects are the most important considerations and should prevail over interests of science and society. A trial should be initiated and continued only if the anticipated benefits justify the risks.
- Freely given informed consent should be obtained from every subject prior to CT participation.
b. Principles to guarantee the “technical-scientific aspects” of CT, namely.
- The available nonclinical and clinical information on an investigational product should be adequate to support the proposed CT.
- The medical care given to, and medical decisions made on behalf of, subjects should always be the responsibility of a qualified physician or, when appropriate, of a qualified dentist.
- Each individual involved in conducting a trial should be qualified by education, training, and experience to perform his/her respective task(s).
- Investigational products should be manufactured, handled, and stored in accordance with applicable Principles of GMP. They should be used in accordance with the approved protocol.
c. Principles to guarantee the “quality and procedural aspects” of CT.
- All CT information should be recorded, handled, and stored in a way that allows for its accurate reporting, interpretation, and verification.
- The confidentiality of records that could identify subjects should be protected, respecting the privacy and confidentiality rules in accordance with the applicable regulatory requirements.
- CTs should be scientifically sound and described in a clear, detailed protocol.
- A trial should be conducted in compliance with the protocol that has received prior Institutional Review Board (IRB)/Independent Ethics Committee (IEC) approval/favorable opinion.
- Systems with procedures that assure the quality aspects of the trial should be implemented.
GCP Details in the Field of the Quality
ICH-GCP Guidelines describe in detail how the principles can be implemented. Principles related to the quality of the CT are crucial for all clinical investigations. Many paragraphs of GCP are related to quality principles. Among others, the following should be noted.
- The investigator/institution should maintain the trial documents as specified in “Essential Documents for the Conduct of a Clinical Trial” and as required by the applicable regulatory requirement(s). The investigator/institution should take measures to prevent accidental or premature destruction of these documents (par. 4.9.4).
- The sponsor is responsible for implementing and maintaining Quality Assurance (QA) and Quality Control (QC) systems with written Standard Operating Procedures (SOPs) to ensure that trials are conducted and data are generated, documented (recorded), and reported in compliance with the protocol, GCP, and the applicable regulatory requirement(s) (par. 5.1.1).
- QC should be applied to each stage of data handling to ensure that all data are reliable and have been processed correctly (par. 5.1.3).
- If significant formulation changes are made in the investigational or comparator product(s) during the course of clinical development, the results of any additional studies of the formulated product(s) (e.g., stability, dissolution rate, bioavailability) needed to assess whether these changes would significantly alter the pharmacokinetic profile of the product should be available prior to the use of the new formulation in clinical trials (par. 5.13.5).
- The sponsor should
a. take steps to ensure that the investigational product(s) are stable over the period of use;
b. maintain sufficient quantities of the investigational product(s) used in the trials to reconfirm specifications, should this become necessary, and maintain records of batch sample analyses and characteristics. To the extent stability permits, samples should be retained either until the analyse...
