GOOD CLINICAL PRACTICE (GCP): A REVIEW

 

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ABOUT AUTHOR:
Bushra Shamim
Department of Pharmaceutics, Faculty of Pharmacy,
Hamdard University, New Delhi.
bushrashamim21@gmail.com

ABSTRACT
Good Clinical Practice (GCP) is an international ethical and scientific quality standard designed to conduct, performance, monitor, audit, record, analyse and report clinical trials. It protects the rights, integrity and confidentiality of trial subjects. Clinical research trails are increasingly playing a role in various medical disciplines.  GCP guidelines are used in clinical trials through out the globe with the main aim of protecting and preserving human rights. In this review article the historical background and the events that led up to the formation of these guidelines, key trial activities and principles of GCP are discussed.

REFERENCE ID: PHARMATUTOR-ART-2239

PharmaTutor (ISSN: 2347 - 7881)

Volume 2, Issue 9

Received On: 02/07/2014; Accepted On: 04/07/2014; Published On: 01/09/2014

How to cite this article: B Shamim; Good Clinical Practice (GCP): A review; PharmaTutor; 2014; 2(9); 20-29

INTRODUCTION:[1]
Good Clinical Research Practice (GCP) is a process that incorporates established ethical and specific quality standards for the design, conduct, recording and reporting of clinical research involving the participation of human subjects. Compliance with GCP provides public assurance that the rights, safety, and well-being of research subjects are protected and respected, consistent with the principles enunciated in the Declaration of Helsinki and other internationally recognized ethical guidelines, and ensures the integrity of clinical research data. The conduct of clinical research is complex and this complexity is compounded by the need to involve a number of different individuals with a variety of expertise, all of who must perform their tasks skill fully and efficiently. The responsibility for GCP is shared by all of the parties involved, including sponsors, investigators and site staff, contract research organizations (CROs), ethics committees, regulatory authorities and research subjects. “Any proposal relating to human subjects including healthy volunteers that cannot be considered as an element of accepted clinical management or public health practice and that involves either (i) physical or psychological intervention or observation, or (ii) collection, storage and dissemination of information relating to individuals. This definition relates not only to planned trials involving human subjects but to research in which environmental factors are manipulated in a way that could incidentally expose individuals to undue risks.” (World Health Organization, Governance, rules and procedures, WHO Manual XVII). Before medical products can be introduced onto the market or into public health programmes, they must undergo a series of investigations designed to evaluate safety and efficacy within the parameters of toxicity, potency, dose finding, and field conditions. Full information must be documented on therapeutic indications, method of administration and dosage, contraindications, warnings, safety measures, precautions, interactions, effects in target populations and safety information. During the clinical research and development process, most medical products will only have been tested for short-term safety and efficacy on a limited number of carefully selected individuals. In some cases, as few as 100 and rarely more than 5000 subjects will have received the product prior to its approval for marketing. Given these circumstances and because the decision to allow a new product on the market has such broad public health significance, the clinical trial process and data must conform to rigorous standards to ensure that decisions are based on data of the highest quality and integrity. In the early 1960s, widespread concern about the safety and control of investigational drugs and the clinical research process developed among members of the medical profession, the scientific community, regulatory authorities, and the general public. In 1968, WHO convened a Specific Group on Principles for Clinical Evaluation of Drugs. The Specific Group was charged with reviewing and formulating principles for clinical evaluation of drug products, whether new or already marketed, including considerations for new indications or dosage forms for marketed products and new combination products. In 1975, another WHO Scientific Group was convened to specifically consider all aspects of the evaluation and testing of drugs and to formulate proposals and guidelines for research in the field of drug development. These reports formed the basis for WHO’s “Guidelines for good clinical practice (GCP) for trials on pharmaceutical products”, published in 1995, as well as many national and international guidelines that have subsequently been developed, including:
· International Conference on Harmonization (ICH) E6, “Good Clinical Practice: Consolidated Guideline” (1996)
· International Standards Organization (ISO), “Clinical investigation of medical devices for human subjects, Part I (General requirements) and Part 2 (Clinical investigation plans) (2001)
· Pan American Health Organization (PAHO). Pan American Network on Drug Regulatory Harmonization (PANDRH). “Good Clinical Practices: Document of the Americas” (2005)

The conduct of clinical research in accordance with the principles of GCP helps to ensure that clinical research participants are not exposed to undue risk, and that data generated from the research are valid and accurate. By providing a basis both for the specific and ethical integrity of research involving human subjects and for generating valid observations and sound documentation of the findings, GCP not only serves the interests of the parties actively involved in the research process, but also protects the rights, safety and well being of subjects and ensures that investigations are scientifically sound and advance public health goals. The objectives of this are following:
· To support and promote the achievement of a globally applicable unified standard for the conduct of all clinical research studies on human subjects;
· To provide an overview and practical advice on the application and implementation of internationally accepted principles for GCP and clinical research in human subjects;
· To provide an educational and reference tool for anyone interested in, or intending to become or already actively engaged in, clinical research by providing the necessary background and insight into the reasons for the requirements of GCP and their efficient application;
· To assist editors in evaluating the acceptability of reported research for publication, and regulators in evaluating the acceptability of any study that could affect the use or the terms of registration of a medical product.

Where national regulations or requirements do not exist or require supplementation, relevant regulatory authorities may designate or adopt these GCP principles and standards. Where national or adopted international standards are more demanding than WHO GCP, the former should take precedence. Guidance on various aspects of clinical research is also available from several other national and international bodies such as, the International Conference on Harmonization (ICH), the International Standards Organization (ISO), and the Council for International Organizations of Medical Sciences (CIOMS), the European Agency for the Evaluation of Medicinal Products (EMEA), and the United States Food and Drug Administration (FDA).

SCOPE[1]
To the extent possible, the principles of GCP should generally apply to all clinical research involving human subjects, and not just research involving pharmaceutical or other medical products. Included here are:
· studies of a physiological, biochemical, or pathological process, or of the response to a specific intervention – whether physical, chemical, or psychological – in healthy subjects or in patients;
· controlled studies of diagnostic, preventive or therapeutic measures, designed to demonstrate a specific generalizable response to these measures against a background of individual biological variation;
· studies designed to determine the consequences for individuals and communities of specific preventive or therapeutic measures;
· studies concerning human health-related behaviour in a variety of circumstances and environments;
· studies that employ either observation or physical, chemical, or psychological intervention. Such studies may generate records or make use of existing records containing biomedical or other information about individuals who may or may not be identifiable from the records or information. The use of such records and the protection of the confidentiality of data obtained from those records are discussed in the “International Guidelines for Ethical Review of Epidemiological Studies” (CIOMS, 1991, currently being updated).

Although some principles of GCP may not apply to all types of research on human subjects, consideration of these principles is strongly encouraged wherever applicable as a means of ensuring the ethical, methodologically sound and accurate conduct of human subject’s research.

HISTORICAL BACKGROUND:[2]
In 1938, the Federal Food, Drug and Cosmetic Act was enacted by the Food and Drug Administration (FDA) and for the first time, manufacturers were required to test drugs for safety and present the evidence of safety testing to the FDA prior to marketing [3]. In 1947, the Nuremberg Code was created as a result of the unethical and horrific experiments carried out during World War II at Nazi war camps by German physicians, who were subsequently tried and charged at the Nuremberg Military Tribunal. This code states the need for a scientific basis in research on human subjects and voluntary consent and protection of participants [4,5]. The Universal Declaration of Human Rights (December 10th 1948) was also adopted and proclaimed by the United Nations after the atrocities of World War II and it further reiterated the human factor involved in medical experiments. In 1964, the Declaration of Helsinki was developed by the World Medical Association, forming the basis for the ethical principles that underlie the ICH-GCP guidelines we have today. The focus of this declaration is the protection of the rights of human subjects and this is clear in its introduction [6]: “The World Medical Association has developed the Declaration of Helsinki as a statement of ethical principles to provide guidance to physicians and other participants in medical research involving human subjects. It is the duty of the physician to promote and safeguard the health of the people. The physician’s knowledge and conscience are dedicated to the fulfillment of this duty” In 1962 the world was once again shocked by the severe foetal limb deformities linked to the use of maternal thalidomide. In fact this drug reaction was only discovered after 10,000 infants were born in over 20 countries worldwide. In response to this, the Kefauver- Harris Amendments were passed which required the FDA to evaluate all new drugs for safety and efficacy [3]. Another important milestone in the formation of the ICH-GCP guidelines was The Belmont Report which was issued in April 1979 by the National Commission for Protection of Human Subjects of Biomedical and Behavioural Research [7]. The principles of this report are as follows:
1. Respect for Persons: This principle acknowledges the dignity and freedom of every person. It requires obtaining informed consent from research subjects (or their legally authorised representatives)
2. Beneficence: This principle requires that researchers maximize benefits and minimize harms associated with research. Research related risks must be reasonable in light of the expected benefits.
3. Justice: This principle requires equitable selection and recruitment and fair treatment of research subjects.

In 1982, the World Health Organization (WHO) and the Council for International Organizations of Medical Sciences (CIOMS) issued a document entitled ‘International Guidelines for Biomedical Research Involving Human Subjects‘. This document was released to help developing countries apply the principles of the Declaration of Helsinki and the Nuremberg Code [3]. Worldwide, many organisations and committees issued various documents and guidelines on the same issue, and a decision was taken to consolidate all these guidelines into one universal guideline to be used globally. In an effort to overcome international GCP inconsistencies throughout the countries, the International Conference for Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) issued the ICH Guidelines: Topic E6 Guideline for GCP. This guideline was approved on 17 July 1996 and implemented for clinical trials from 17 January 1997. The participants of these guidelines were representatives of authorities and pharmaceutical  companies from the EU, Japan and the United States as well as those of Australia, Canada, the Nordic countries and WHO [8].

KEY TRIAL ACTIVITIES INCLUDE: [1]

Development of the trial protocol
Within GCP, clinical trials should be described in a clear, detailed protocol. The sponsor, often in consultation with one or more clinical investigators, generally designs the study protocol; clinical investigators may also design and initiate clinical studies, as sponsor-investigators. Integral to protocol development are the concepts of risk Identification, study design and control groups, and statistical methodology. The sponsor and clinical investigator(s) should be aware of any national/ local laws or regulations pertaining to designing, initiating, and conducting the study.

Development of standard operating procedures (SOPs)
All parties who oversee, conduct or support clinical research (i.e., sponsors, clinical investigators, Independent Ethics Committees/ Institutional Review Boards [IECs/IRBs] monitors, contract research organizations [CROs]) should develop and follow written standard operating procedures (SOPs) that define responsibilities, records, and methods to be used for study-related activities. Sponsors should consider preparing SOPs for:
• developing and updating the protocol, investigator’s brochure, case report forms (CRFs), and other study-related documents;
• shipping, handling, and accounting for all supplies of the investigational product;
• standardizing the activities of sponsors and study personnel (e.g., review of adverse event reports by medical experts; data analysis by statisticians);
• standardizing the activities of clinical investigators to ensure that trial data is accurately captured;
• monitoring, to ensure that processes are consistently followed and activities are consistently documented;
• auditing, to determine whether monitoring is being appropriately carried out and the systems for quality control are operational and effective.

Similarly, clinical investigators should consider developing SOPs for common trial-related procedures not addressed in the protocol. These may include but are not limited to: communicating with the IEC/IRB; obtaining and updating informed consent; reporting adverse events; preparing and maintaining adequate records; administering the investigational product; and accounting for and disposing of the investigational product. IECs/IRBs should develop and follow written procedures for their operations, including but not limited to: membership requirements; initial and continuing review; communicating with the investigator(s) and institution; and minimizing or eliminating conflicts of interest. Regulators should consider developing written procedures for activities pertaining to the regulation of clinical research. These may include but are not limited to: reviewing applications and safety reports; conducting GCP inspections (where applicable) and communicating findings to the inspected parties; and establishing an infrastructure for due process and imposing sanctions on parties who violate national/local law or regulations.

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