Vous êtes sur la page 1sur 27

Curso GCP -

GCP1: Overview of ICH GCP

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.

LESSON 1: An Evolutionary Regulatory Environment


Regulation of the pharmaceutical industry has evolved over time and usually in response to tragic events. Good Clinical Practice (GCP) and the regulatory requirements intended to

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

The pharmaceutical industrys desire for more reliable and


better quality data from clinical studies and more uniform international standards for submission Although guidelines such as GCP have been established on the international level, it is the responsibility of individual countries to implement regulations that uphold these guidelines. Key regulations in the 20th century began with proper labeling of ingredients and grew to include manufacturing practices, the application process, clinical research, and post-marketing safety reporting. As a result of GCP, the trend in regulations has been toward greater uniformity among countries.
(At the beginning of the 20th century, there were few government regulations controlling the clinical research process. As companies became more global through conducting studies in various countries, they needed more uniform standards for clinical studies. By the end of the century, we were beginning to see international recognition of the principles of GCP and a global regulatory environment. Now, GCP is the international standard and acts as a foundation for clinical research regulations in many countries.)

Key Historical Dates


Todays regulatory environment has evolved on a national level by individual countries implementing laws and regulations relating to clinical research. The following is a timeline of key events that occurred in various countries and regions over the last century.

Pure Food and Drugs Act

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.

Beneficence is an obligation and includes the following rules:

Do not harm.

Maximize possible benefits and minimize possible harms.

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.

The Nuremberg Code

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.

An Overview of the ICH


Good Clinical Practice currently reflected in national regulations is based on harmonized practices developed by the International Conference on Harmonisation (ICH). The ICH is an international organization of experts from both regulatory agencies and pharmaceutical manufacturing associations from three global regionsEurope, United States and Japanthat issues expert guidance documents and standards to rationalize and harmonize regulations. It grew in response to: Rising research and development costs;

Increasing length of time in bringing needed products to


market; and Inconsistencies in technical requirements among countries.

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.

Process The process for establishing a new regulation is as follows:

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

Biotechnological Products Pharmacology Studies

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

European Federation of Pharmaceutical Industries and


Associations (EFPIA) Ministry of Health, Labor, and Welfare (MHLW), Japan

Japan Pharmaceutical Manufacturers Association (JPMA) US Food and Drug Administration (FDA) Pharmaceutical Research and Manufacturers of America
(PhRMA) WHO (observer)

European Free Trade Area (EFTA), represented at ICH by


Swissmedic Switzerland (observer) Canada, represented at ICH by Health Canada (observer)

International Federation of Pharmaceutical Manufacturers


Associations (IFPMA) (non-voting member)

ICH GCP in the World


In 1995, the ICH reached consensus on harmonizing the GCP requirements of the US, EU, and Japan (Step 4 document) and issued its final version of the document known as ICH E6: Good Clinical Practice with an effective date of January 1997. Hereby, GCP is now a globally accepted collection of guidelines and quality research practices that seek to ensure subject rights and safety as well as high-quality study data. These guidelines define the standards and procedures for the acceptable conduct of clinical studies and define the roles of those involved. GCP has been embraced by health authorities, the medical profession, human rights groups, and the pharmaceutical industry for two main reasons: It protects the rights, safety, and well-being of study subjects. It ensures verification of the quality and integrity of the data obtained through clinical studies. Quality Data The GCP guideline addresses the quality of clinical trial data in a number of ways: Defined criteria for trial design and data handling

Defined criteria for investigator and monitor selection Required compliance of investigator with protocol

Guidance on monitoring to ensure accurate and complete


data Criteria for documentation Subject Safety The GCP guideline addresses the safeguarding of trial subject safety and rights: Defined contents for Investigators Brochure

Requirement involvement of Institutional Review


Board/Independent Ethics Committee (IRB/IEC) Defined process for informed consent

Safety reporting criteria and procedures Study drug labeling guidelines


The guidelines of GCP are not law; however, all over the world countries are incorporating them into their regulations, and GCP is rapidly becoming the global standard for clinical research.
The United States Different aspects of the ICH GCP guidelines have been read specifically into the Code of Federal Regulations (CFR) and as such have the power of law. Others have been included in various guidance documents, which are not mandatory but are consistent with FDA requirements. The European Union In 2001, the EU issued Directive 2001/20/EC. This directive regulates the common administrative aspects for the conduct of clinical studies in the EU and directs Member States to implement laws, regulations, and administrative processes needed to support those guidelines. As a direct consequence from the 2001/20/EC directive (which had been foreseen in its text), a subsequent directive was issued (2005/28/EC) which directs that all clinical trials in the EU should be conducted in line with the GCP Principles. The individual Member States of the EU were mandated to implement the EC directives into their national laws. As a consequence this helped to ensure harmonization with ICH GCP throughout Europe, but did not completely prevent specific national and regional regulations from varying. Japan GCP was first issued in Japan in 1989 as a guidance document referred to as Notification No. 874. After study of the clinical trial process in Japan and in accordance with ICH GCP, Japan issued MHW (Ministry of Health and Welfare) Ordinance No. 28, Standards for the Conduct of Clinical Studies and Joint

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.

ICH GCP in the World (continued)


The European Agency for the Evaluation of Medicinal Products (EMEA) was founded in 1995 to coordinate the EU licensing system. Actual review is directed by the Committee for Proprietary Medicinal Products (CHMP). The EU adopted ICH GCP in 1996, with an effective date of January 1997, as a guideline. Hence, GCP was still to be implemented through the laws of each Member State of the EU. Subsequently, the EU Directive 2001/20/EC finally stipulated that GCP must be addressed in national laws in the Member States and set forth the development of a subsequent directive (2005/28/EC) to require that the GCP Principles should be implemented in the national regulations in the Member States. In addition, four guidelines were developed as the outcome of the 2001/20/EC directive, dealing with the notification of trials to the Health Authorities and the Ethics Committees, adverse event reporting, and the set-up of the EU Clinical Trial database. One of the additional outcomes of the directive 2001/20/EC is that the Health Authorities in the Member States will exchange and accept each others Inspection Reports, which will contribute to harmonization across the EU region.

ICH GCP Principles


There are 13 principles that underlie ICH GCP. They are consistent with the principles that have their origin in the Declaration of Helsinki. The GCP principles are listed in Section 2.0 of ICH E6.

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:

The Clinical Research Process


The clinical research process consists of four main phases. Each phase has unique characteristics, priorities, and GCP responsibilities. As testing in humans progresses from Phase I to Phase IV, our knowledge of the new drug grows and GCP considerations change.
(The clinical research process consists of four phases. As we transition from one phase to the next, our knowledge of the new drug grows. Both sponsors and regulatory authorities carefully assess the data gathered at each phase to make decisions regarding the safety and efficacy of the drug. Sometimes a sponsor may terminate a program early because evidence of efficacy is weak or the risk-to- benefit ratio is unacceptable. Regulatory authorities may discontinue the program due to concerns over serious adverse events. And sometimes in the case of life-threatening diseases that have few therapies, results may be so promising that the drug receives early approval. The GCP principles help make the decisions to terminate or proceed a program through each of the phases.) Phase Phase Phase Phase I: Human pharmacology studies II: Therapeutic exploratory studies III: Therapeutic confirmatory studies IV: Post-marketing studies

Phase I:

Human pharmacology studies

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.

Roles in Clinical Research


There are six main roles in clinical research. GCP describes the ways in which each carries out its responsibilities in ensuring the safety of subjects and the generation of high-quality data. While each role has its own individual responsibilities, they all work closely together in the clinical research process. The sponsor should define, establish, and allocate all study-related duties and functions prior to initiating a study.

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.

Approval to Conduct a Clinical Study


ICH states that when planning studies, the sponsor should ensure that sufficient safety and efficacy data from nonclinical studies and/or clinical studies are available to support human exposure by the route, at the dosages, for the duration, and in the study population to be studied. Once the investigational product and study population have been determined, the sponsor must submit any required applications to the appropriate authorities for review, acceptance, and/or permission to begin the study. This application should be dated and contain sufficient information to identify the protocol. Prior to initiating the study, the sponsor should allocate all study-related duties, including designating appropriately qualified medical personnel to advise on any medical questions or problems. These persons must be readily available but, if necessary, may be outside consultants. Throughout the conduct of the study, the sponsor must utilize appropriately qualified individuals to supervise conduct of the study, handle and verify data, conduct statistical analyses, and prepare study reports.

Contract Research Organizations (CROs)


A contract research organization is a person or organization (commercial, academic, or other) contracted by the sponsor to perform one or more study- related duties or functions. Any or all studyrelated duties may be transferred from the sponsor to a CRO. Sponsors may choose to use the services of a CRO to improve efficiency of study conduct. For example, the monitoring services of a CRO may be used for an investigative site that is in a location inconvenient to the sponsors monitors. Prior to study initiation the sponsor must define, establish, and allocate study duties in writing. Any duties that are not defined and clearly allocated to the CRO in writing remain the responsibility of the sponsor. When duties have been allocated to a CRO, all ICH guidelines that refer to the sponsor also refer to the CRO. Although the sponsor may delegate all study-related duties to the CRO, ultimate responsibility for the quality and integrity of the study data always resides with the sponsor.

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

At least one member whose primary area of interest is


in a non- scientific area At least one member who is independent of the institution/study site Nonmembers may be invited to a particular meeting if they have expertise in a specific area. The investigator of the study may provide information at the meeting, but should not participate or vote. Only those members who are independent of the investigator and sponsor may vote. Additionally, only those members who were involved in the review and discussion may vote. Investigators, sponsors, or regulatory authorities may ask the IRB/IEC to provide its written procedures and membership lists. A list of IRB/IEC members and their qualifications as well as all relevant written records (e.g., written procedures, meeting minutes, submitted documents, correspondence) must be maintained for at least 3 years after study completion. Procedures The IRB/IEC should establish, document in writing, and follow its procedures, which should include: Determining its composition (names and qualifications of the members) and the authority under which it is established.

Scheduling, notifying its members of, and conducting


its meetings. Conducting initial and continuing review of studies.

Determining the frequency of continuing review, as


appropriate. Providing, according to the applicable regulatory requirements, expedited review and approval/ favourable opinion of minor change(s) in ongoing studies that have the approval/favourable opinion of the IRB/IEC. Specifying that no subject should be admitted to a study before the IRB/IEC issues its written approval/favourable opinion of the study. Specifying that no deviations from, or changes of, the protocol should be initiated without prior written IRB/IEC approval/favourable opinion of an appropriate amendment, except when necessary to eliminate immediate hazards to the subjects or when the change(s) involves only logistical or administrative aspects of the study (e.g., change of monitor(s), telephone number(s)). Specifying that the investigator should promptly report to the IRB/IEC: - Deviations from, or changes of, the protocol to eliminate immediate hazards to the study subjects. - Changes increasing the risk to subjects and/or affecting significantly the conduct of the study. - All adverse drug reactions (ADRs) that are both serious and unexpected. - New information that may affect adversely the safety of the subjects or the conduct of the study.

Ensuring that the IRB/IEC promptly notify in writing


the investigator/institution concerning: - Its study-related decisions/opinions. - The reasons for its decisions/opinions. - Procedures for appeal of its decisions/opinions.

Overview of the IRB/IEC Responsibilities


The IRBs/IECs first priority is to ensure the safety and well-being of study subjects. To do this, they will carefully review all documentation relating to the proposed clinical study, to confirm that the risk-tobenefit ratio of the study is acceptable and that subjects' rights are protected throughout the study. The IRB/IEC provides its conclusion regarding the study to the investigator. This conclusion may be one of the following: Approval/favorable opinion

Modifications required prior to its approval/favorable


opinion Disapproval/negative opinion The IRB/IEC conducts a continuing review of the ongoing study at intervals appropriate to the degree of risk to the subjects, or at least once per year. If any changes are made to the documentation or conduct of the study, the IRB/IEC must review the revised documents and grant their re-approval for the study to continue. The IRB/IEC also has the responsibility to terminate or suspend a study for which they granted prior approval/favorable opinion if they feel subjects safety or well-being is in danger. Documents for the IRB/IEC

The following documents must be approved by the IRB/IEC: Study protocol/amendments

Written informed consent forms and consent form


updates Subject recruitment procedures (e.g., advertisements)

Written information to be provided to subjects


The following documents do not need to be approved by the IRB/IEC but should be submitted to the IRB/IEC for review purposes: Investigators brochure

Available safety information Information on payment and compensation to


subjects Investigators current CV or other documentation evidencing qualifications Any other documents the IRB/IEC may request (e.g., qualification of support staff, conflict of interest documents). Once the IRB/IEC has reviewed the appropriate documentation on the study, it communicates its approval/favorable opinion to the investigator. The sponsor must then obtain from the investigator: Name and address of the IRB/IEC.

Statement from the IRB/IEC that it is organized and


operates according to GCP and applicable laws and regulations. Documented IRB/IEC approval/favorable opinion.

Date approval/favorable opinion was granted.

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.

Informed consent form. Written information provided to subjects. Procedures.


During the study, the investigator will also provide the sponsor with documentation of any IRB/IEC reapprovals/re-evaluations, and of any withdrawals or suspensions of approval/favorable opinion.

Vous aimerez peut-être aussi