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Welcome
The International Conference on Harmonisation (ICH) Good Clinical Practice Guideline (E6) contains the essential building blocks for conducting clinical trials. GCP is an international ethical and scientific quality standard 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.
Lessons and Objectives
Lesson 1: Evolution of the Regulatory Environment When you have completed this lesson, you will be able to: 1 Explain the need for harmonized clinical practices and standards. 2 List the key events in the evolution of the regulatory environment. 3 Describe the structure and purpose of the ICH. 4 List the principles of ICH GCP. Lesson 2: The Clinical Research Process and Roles When you have completed this lesson, you will be able to: 1 Describe the phases of clinical research. 2 Describe the main roles in clinical research and how they work together. 3 Describe the process of transferring responsibilities from the sponsor to a CRO. 4 Describe the purpose and make-up of IRBs/IECs.
support it have continually advanced over time. There have been three primary drivers for change: The desire to protect patients against products whose safety has not been thoroughly proven The response to human rights abuses during World War II
In 1906, the United States passed the Pure Food and Drugs Act. The primary goal of this act was to enforce requirements for accurate labeling of food and drug products. Drugs had to abide by standards of purity and quality (e.g., US Pharmacopeia, National Formulary) as determined by committees of physicians and pharmacists. However, manufacturers could also set their own standards as long as the ingredients were stated on the label. Making false or misleading label statements constituted misbranding.
Federal Food, Drug, and Cosmetic Act This act was passed in response to the sulfanilamide elixir tragedy, which resulted in 107 deaths. This law built on the Pure Food and Drugs Act of 1906 and included new provisions that:
Extended control to cosmetics and therapeutic devices. Required manufacturers to test drugs for safety and present the results to the US FDA prior to marketing. Instituted the New Drug Application (NDA) process. Authorized factory inspections. Authorized standards of identity, quality, and fill-of-containers for food. Provided that safety tolerances be set for unavoidable poisonous substances.
Kefauver-Harris Amendments The thalidomide tragedy demonstrated the need for even greater regulation over the testing of investigational drugs. With the passing of the KefauverHarris Drug Amendments, manufacturers were required to prove drug efficacy. The 1962 amendments required:
Informed consent from subjects used in drug studies The sponsor to report any adverse reactions to the FDA
It also included the Investigational New Drug (IND) procedure, which required the submission of documents to the FDA prior to testing in humans.
Japan saw its own version of the thalidomide tragedy in 1994. Fifteen deaths from the interaction of sorivudine, an anti-viral, with an anti-cancer drug caused the restructuring of the Japanese drug review and approval process. The Pharmaceutical Affairs Law, MHLW Ordinance No. 28 and several Notification documents have incorporated the principles of GCP.
National Research Act This act was passed due to the publicity of the unethical Tuskegee Syphilis Study. The act created the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. It also required the establishment of Institutional Review Boards (IRBs) for all research that received funding from the US government. It was later modified to require IRB approval for all drugs or products regulated by the FDA, independent of the funding source.
EC Directives Directive 75/318/EEC discussed the need for protocols and analytical pharmacological, toxicological, and clinical standards for clinical and preclinical studies in the European Economic Community (EEC). These tests should be carried out before a marketing authorization is granted. Directive 75/319/EEC addressed the need for a body to regulate drug development. The Committee for Proprietary Medicinal Products (CHMP) was established to advise the European Commission on issues of safety, efficacy, and quality in medicinal products.
Belmont Report The US Belmont Report identified ethical principles, including the respect for persons, beneficence, and justice, that should underlie the conduct of biomedical/behavioral research involving human subjects. The respect for persons includes two ethical convictions:
Individuals should be treated as autonomous agents. Persons with diminished autonomy are entitled to protection.
Do not harm.
The ethical principle of justice states that the burdens and benefits of research should be justly distributed.
EC GCP On 1, July 1990, the European Guideline for Good Clinical Practice for the Clinical Research with Medicinal Products in the European Community, (EG doc lll/3976/88 FINAL) was issued. Following this recommendation, the directive 91/507/EEC required all phases of clinical investigations to be conducted in accordance with principles of GCP. However, this directive did not overcome differences in national laws. To support the harmonization of regulation the European Medicines Evaluation Agency (EMEA) was established in 1995, Following the course of the ICH process, the Committee for Proprietary Medicinal Products (CHMP) issued its guidelines on GCP in the document Good Clinical Practices for Trials on Medicinal Products in the European Community, here referred to as ECGCP.
EC Directive Directive 2001/20/EC required the implementation of Good Clinical Practice by all member states. This directive harmonized clinical research guidelines and processes across the EU. It states that all clinical studies, including bioavailability and bioequivalence studies, shall be designed, conducted, and reported in accordance with the principles of Good Clinical Practice. Commission Directive 2005/28/EC, which is foreseen in the 2001/20/EC directive, covers the principles of GCP and details provisions relating to manufacture/ import authorizations with respect to investigational medicinal products. EU Member States had to comply with the provisions of this Directive by 29 January 2006. Note that older directives are labeled EEC while newer directives are labeled EC.
One of the first international standards established in response to the ethical and medical misconduct of the Nazis in World War II. The Nuremberg Code laid down 10 standards that include voluntary informed consent, risk to subject must be weighed against benefits, actions that injure human subjects must be avoided, and the subject has the right to end the experiment at any time.
Declaration of Helsinki Developed and adopted by the World Medical Assembly, the Declaration of Helsinki became a key international document describing the ethical principles that underlie GCP. These principles provide guidance in medical research involving human subjects. The document has been amended since 1964, with its most recent update done in 2008, in Seoul, South Korea.
CIOMS The Council for International Organizations of Medical Sciences (CIOMS) is an international, non- governmental, nonprofit organization established jointly by the World Health Organization (WHO) and the United Nations Educational, Scientific and Cultural Organization (UNESCO) in 1949. CIOMS, in conjunction with WHO, issued a document in 1982 titled Proposed International Guidelines for Biomedical Research Involving Human Subjects to help developing countries apply the principles of the Declaration of Helsinki and the Nuremberg Code. These guidelines were revised in 1992, which resulted in the International Ethical Guidelines for Biomedical Research
ICH Due to the growing globalization of clinical research, the International Conference on Harmonisation (ICH) was established and met for the first
time in 1990. As stated by ICH, The purpose is to make recommendations on ways to achieve greater harmonisation in the interpretation and application of technical guidelines and requirements for product registration in order to reduce or obviate the need to duplicate the testing carried out during the research and development of new medicines. The objective of such harmonisation is a more economical use of human, animal and material resources, and the elimination of unnecessary delay in the global development and availability of new medicines whilst maintaining safeguards on quality, safety and efficacy, and regulatory obligations to protect public health."
WHO GCP The World Health Organization (WHO) developed GCP guidelines as globally applicable standards for the conduct of research on human subjects. These guidelines present principles that provide a basis for the ethical and scientific integrity of clinical studies. The objective was to provide a standard that could be applied worldwide. The guidelines are addressed to investigators, ethics review committees, sponsors of research, and drug regulatory authorities.
ICH has defined a set of unified standards that have been established for the European Union, Japan, and the United States to facilitate mutual acceptance of clinical data.
(The International Conference on Harmonisation is a group composed of US, EU, and Japanese representatives from regulatory authorities and pharmaceutical manufacturing associations in each country. In addition, the ICH includes observers from other countries and key organizations. The goal of the ICH is to ensure the development of safe and effective medicines through harmonizing the processes and technical requirements across political and economic boundaries.) Goals Goal statement from the 1990 conference in Tokyo:
Increase international harmonization to ensure quality, safe, and effective medicines are developed and registered in the most efficient and cost- effective manner. Allow regulators and industry to reach consensus and set realistic, practical targets for harmonization. Ensure worldwide benefits of harmonization effort. Minimize future divergence among nations registration requirements.
Consensus-building (development of rapporteurs initial draft guideline) Referral of draft guideline to regulatory agencies Regulatory review and creation of final document Adoption of tripartite harmonized text Implementation by member nations regulatory agencies TOPIC AREAS:
Quality Guidelines on chemical and pharmaceutical quality assurance. They address manufacturing issues (e.g., stability testing), data analysis, and uniformity among pharmacopeias. Quality guidelines include the following categories:
Stability
Analytic Validation Impurities Pharmacopeias Quality of Biotechnological Products Specifications Good Manufacturing Practice
Efficacy Guidelines on conducting clinical studies in human subjects, including study design (e.g., sample size, duration of exposure, choice of control group, dose-response data), special populations, and the content of the clinical study report. Efficacy guidelines include the following categories:
Clinical Safety Clinical Study Reports Dose-Response Studies Ethnic Factors Good Clinical Practice Clinical studies Guidelines for Clinical Evaluation by Therapeutic Category Clinical Evaluations
Note: The ICH GCP document was developed as part of the Efficacy working group's activities. Safety Guidelines on in vitro and in vivo preclinical testing, including carcinogenicity, genotoxicity, toxicokinetics and pharmacokinetics, reproductive toxicity, and pharmacology. Safety guidelines include the following categories:
Carcinogenicity Studies Genotoxicity Studies Toxicokinetics and Pharmacokinetics Toxicity Testing Reproductive Toxicology
Multidisciplinary Guidelines on topics that do not fit uniquely into any of the other categories. These include:
Medical Terminology Electronic Standards for Transmission of Regulatory Information Timing of Pre-Clinical Studies in Relation to Clinical studies The Common Technical Document
ICH Structure
The ICH is composed of steering committee members and observers from all over the world, but formally from the three regions, (EU, US, and Japan). Members work in expert working groups to address specific topics. ICH has focused its purpose into four topic areas: Quality, Efficacy, Safety, and Multidisciplinary. In each working group, multiple guidelines have been and continue to be developed and updated. In the EU, most of the technical guidelines are adopted by the CHMP and are expected to be followed in the development, and (at a later stage) in the marketing and pharmacovigilance activities of medicinal products at a global level.
(ICH includes steering committee members and observers from all over the world. These regulatory authorities and pharmaceutical experts meet to discuss scientific and technical aspects of product development and registration. These meetings as well as more specific task groups ensure that ICH guidelines are continuously evolving as science continues to advance.)
MORE INFORMATION Steering Committee Members and Observers: European Commission of the European Union
Japan Pharmaceutical Manufacturers Association (JPMA) US Food and Drug Administration (FDA) Pharmaceutical Research and Manufacturers of America
(PhRMA) WHO (observer)
Defined criteria for investigator and monitor selection Required compliance of investigator with protocol
Notification on application of Guidelines for Good Clinical Practice PAB/PCD Notification No. 445/PAB/SD Notification No. 68 in 1997. The ICH GCP guidelines are addressed in the current Notification: ELD Notification No. 0921001 in 2006.
Principle 1 Clinical studies 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.
Principle 2 Before a study is initiated, foreseeable risks and inconveniences should be weighed against the anticipated benefit for the individual study subject and society. A study should be initiated and continued only if the anticipated benefits justify the risks.
Principle 3 The rights, safety, and well-being of the study subjects are the most important considerations and should prevail over interests of science and society.
Principle 4 The available nonclinical and clinical information on an investigational product should be adequate to support the proposed clinical study.
Principle 5 Clinical studies should be scientifically sound, and described in a clear, detailed protocol.
Principle 6 A study should be conducted in compliance with the protocol that has received prior Institutional Review Board (IRB) [in the US] /Independent Ethics Committee (IEC) [in the EU] approval/favourable opinion.
Principle 7 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.
Principle 8 Each individual involved in conducting a study should be qualified by education, training, and experience to perform his or her respective tasks.
Principle 9 Freely given informed consent should be obtained from every subject prior to clinical study participation.
Principle 10 All clinical study information should be recorded, handled, and stored in a way that allows its accurate reporting, interpretation and verification.
Principle 11 The confidentiality of records that could identify subjects should be protected, respecting the privacy and confidentiality rules in accordance with the applicable regulatory requirements.
Principle 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.
Principle 13 Systems with procedures that assure the quality of every aspect of the study should be implemented.
A Global Community
The intentional acceptance of ICH GCP as the prevailing scientific and ethical standard for the conduct of clinical trials has been a boon toward an increasing amount of harmonization of global practices and the reflection of GCP in each nations laws. This harmonization safeguards the safety, rights, and well-being of clinical research subjects as well as ensuring that the research has provided accurate data and sound evidence that the drug is safe and effective. As our standards become global, so does our marketplace. Study data submitted to one regulatory authority may have been gathered in many countries. A pharmaceutical company may seek simultaneous marketing approval in different countries. Successful product life cycles depend on licensing in new markets so a pharmaceutical company may expand product use into new areas of the globe. Information provided to the Health Authorities (such as Clinical Study Reports, Adverse Event Reports) may be shared by them with others, similarly to their own Inspection Reports. This obviously contributes the global availability of safety and quality knowledge available on a larger scale. The field of clinical research is continually evolving and so are the guidelines and laws that guide and regulate it. Therefore, it is important to always keep informed of local and international guidelines and regulations.
(The field of clinical research is continually evolving. As our marketplace has become global, the need for cooperation among countries has become necessary for businesses to thrive. As an increasing number of studies are being conducted in different countries throughout the world, harmonization of global clinical research practices has become even more critical.)
LESSON 2:
Phase I:
Phase I typically consists of human pharmacology studies. This phase uses healthy subjects or certain types of subjects (e.g., subjects with mild hypertension). In some cases, ethical conduct requires subjects who are the targeted patient group (e.g., cancer or HIV drugs). The purpose of this phase is to determine the tolerability of the dose range, the nature of adverse reactions, and the characterization of the drugs absorption, distribution, metabolism, and excretion. Phase II: Therapeutic exploratory studies
Phase II typically consists of therapeutic exploratory studies. The objective of Phase II studies is to explore therapeutic effect in subjects. These studies include subjects that fit a relatively narrow criteria, leading to a fairly homogeneous population. The objective of this phase is to determine the dose and regimen of the drug and to provide an evaluation of potential study endpoints and target populations (e.g., mild versus severe disease). Phase III: Therapeutic confirmatory studies
Therapeutic confirmatory studies are typical of Phase III. The objective is to demonstate and confirm therapeutic benefit to provide adequate basis for marketing approval. The focus is to explore the drugs use in wider populations to confirm that the drug is safe and effective in the intended indication and recipient population. Phase IV: Post- marketing studies
Phase IV begins after drug approval and consists of studies that were not considered necessary for approval but optimize
the drugs use. Examples of Phase IV research include studies of new or modified indications and additional patient population.
Sponsor ICH defines the sponsor as "an individual, company, institution, or organization which takes responsibility for the
initiation, management, and/or financing of a clinical trial." Monitor The monitor acts as the main line of communication between the sponsor and investigator. ICH states that "Monitoring is the act of overseeing the progress of a clinical trial, and of ensuring that it is conducted, recorded, and reported in accordance with the protocol, standard operating procedures (SOPs), Good Clinical Practice (GCP), and the applicable regulatory requirements." Investigator ICH defines the investigator as "a person responsible for the conduct of the clinical trial at a trial site. If a trial is conducted by a team of individuals at a trial site, the investigator is the responsible leader of the team and may be called the principal investigator. The subinvestigator is any individual member of the clinical trial team designated and supervised by the investigator at a trial site to perform critical trial-related procedures and/or to make important trial- related decisions." Subject ICH defines a subject as "an individual who participates in a clinical trial, either as a recipient of the investigational product(s) or as a control." IRB/IEC An Institutional Review Board or Independent Ethics Committee is "an independent body constituted of medical, scientific, and non- scientific members, whose responsibility is to ensure the protection of the rights, safety, and well- being of human subjects involved in a trial by, among other things, reviewing, approving, and providing continuing review of trial protocol and amendments and of the methods and material to
be used in obtaining and documenting informed consent of the trial subjects." Regulatory Authorities Regulatory authorities are defined as bodies having the power to regulate. In the ICH GCP Guideline, the expression "regulatory authorities" includes the authorities that review submitted clinical data and those that conduct inspections. These bodies are sometimes referred to as competent authorities.
IRB/IEC Structure
An Institutional Review Board (IRB) or Independent Ethics Committee (IEC) is an independent body made up of a group of people who are knowledgeable in the regulations governing clinical research, a particular area of study, and those who are not involved in the scientific area. The IRB/IEC performs its function according to written practices that include holding announced meetings with at least a quorum to review documentation that outlines the proposed research.
Composition According to ICH, the IRB/IEC should have a composition of the following: At least five members
If the IRB/IEC granted its approval/favorable opinion of the study based upon changes to the study, the sponsor should obtain a copy of these changes if they are modifications to the: Protocol.