Guide to Good Clinical Practice, 3rd Edition

by Alex D. Kanarek, Ph.D.

The most time-consuming and expensive task in achieving approval to market a new drug biological or medical device is to confirm the safety and efficacy of the product by testing it on human subjects. In order to ensure that the clinical studies or "trials" are performed in a scientific, humane and ethical manner, codes of Good Clinical Practice (GCP) have been drawn up by many countries and are now the subject of international agreement.

Lack of compliance with GCP in sponsoring or performing clinical studies will result in sanctions and refusal of approvals which will adversely affect the company's plans to launch a new drug product, device or diagnostic. The regulations state that it is the responsibility of the company, as sponsor, to ensure that investigators follow the protocols and comply with GCP in all aspects of trial conduct. The commercial implications are therefore for the expenditure of significant sums of money on studies which, even if they appear to demonstrate the safety and efficacy of the new product, will not lead to marketing approval if GCP compliance is not confirmed.

D&MD's Guide to Good Clinical Practice, 3rd Edition updates the regulations and their respective amendments since the 2nd edition was published in 2005. The guide details the duties of the sponsors, institutional review boards (IRB), investigators, and trial monitors. Practical advice is given on the various mandates for achieving GCP compliance. The templates of forms for study audits, data integrity checks and IRB operations are included for the reader's access.

Computerized processes for trial data accrual and reporting are given special attention. The guide will provide assistance to corporate clinical development personnel involved in active or planned trials, trial monitors and those performing auditing functions, members of IRBs, as well as clinical investigators and their supporting staff. This guide notates the latest amendments for the U.S. Food and Drug Administration, the Canadian Food and Drug Regulations, the European Union's Directives and the Japanese Pharmaceutical Affairs Law (PAL).

About the Author:

Dr. Alex Kanarek received his B.S. with honors from Imperial College, University of London and his Ph.D. from Cambridge University. He has operated his own consultancy (originally Bio-Development Consulting Services, now AK Consulting) for the past 14 years. Based upon more than 30 years' experience in the biopharmaceutical industry with the Wellcome Foundation (now GlaxoSmithKline) in the UK and Connaught Laboratories (now Sanofi Pasteur) in North America, his consultancy has specialized in technology transfer, biopharmaceutical development and regulatory compliance in development and manufacturing laboratories. Apart from this third edition of his successful Guide to GCP, Dr. Kanarek has written Drug and Market Development's Guides to GMP, GLP, Good Validation Practice and Good Facility Design, as well the first and second editions of its market analysis report, The Bioprocessing Industry. He was Contributing Editor of the monthly Bioprocess News for the first 18 months of its existence and continued to contribute the Regulatory Notes column until it ceased publication. Dr. Kanarek is now on the Editorial Advisory Board of the BioProcess International journal.

September 2007 468 Pages Format PDF

CHAPTER 1: EXECUTIVE SUMMARY

The most time-consuming and expensive task in achieving approval to market a new drug, biological or medical device is to confirm the safety and efficacy of the product by testing it on human subjects. The average cost of developing a new drug reached $802m in 2000, according to the Tufts Center—10 years previously, a similar study estimated the average cost at $231 million. CMSInfo, Chesam, UK, reported recently that national spending on clinical trials in the United States was nearly $24 billion in 2005. This number is expected to grow at an average rate of 4.6% per year, rising to over $32 billion in 2011. The expansion of clinical testing in other developed regions is comparable, while many pharmaceutical companies are seeking to perform clinical trials in developing regions such as India and China, in order to access new populations and control costs.

However, none of this vast expenditure will be effective unless the results of the trials are acceptable to the drug regulating authorities of the countries concerned. This means that they must have been conducted in compliance with specific regulatory requirements. In order to ensure that the clinical trials or “studies” are performed in a scientific, humane and ethical manner, codes of Good Clinical Practice (GCP) have been drawn up by most countries and are now the subject of international agreement. Good Clinical Practice has been defined by the International Conference on Harmonization as “A standard for the design, conduct, performance, monitoring, auditing, recording, analyses, and reporting of clinical trials that provides assurance that the data and reported results are credible and accurate, and that the rights, integrity, and confidentiality of trial subjects are protected.”

The regulations governing GCP originated in the laws of countries like the USA and the United Kingdom, but are now international in nature. Originally, unlike those for Good Manufacturing Practice, they were not particularly detailed or specific in nature, and generally formed part of the regulations which described the means of obtaining approval to perform a clinical study and then to market a new drug. More recently, however, the regulations have been made more specific, especially in Europe. Much more detailed instructions on the design and conduct of a study are contained in Guidelines which were issued by the International Conference on Harmonization (ICH) in 1996.

For the individual investigator and the institution in which he or she is working, the implications of GCP non-compliance may be loss of recognition by the regulatory authorities as being acceptable as an investigator for future studies. The US Food and Drug Administration (FDA) publishes on its Web site a list of clinicians who it will not accept as investigators in any new clinical study.

A clinical study is initiated and monitored by the Sponsor, planned and performed by the Investigator and reviewed and approved by the Institutional Review Board (IRB). This Guide examines in detail the responsibilities and activities of these three main parties and gives practical advice to assist each to fulfill their obligations. The sponsor of a study is usually the company which performed the development of the investigational product and either did the preclinical testing of safety and efficacy in its own laboratories, or had some or all of the work done under contract by a CRO. The sponsor applies to the regulatory authorities for permission to perform the clinical study, based upon these preclinical findings. The sponsor selects the investigator and writes the Investigator’s Brochure. The study protocol is prepared jointly by the sponsor and the investigator. The sponsor then supplies the investigational product. The sponsor is responsible for the monitoring of the clinical study, as well as submitting the final report from the investigator to

the regulatory agency.

The clinical investigator obviously occupies the prime position in the study environment. His or her education, training and experience must be sufficient to permit him or her to assume full responsibility for the conduct of the study and for the well-being of the subjects of the trial. It is his or her responsibility to ensure that all aspects of the study at the individual subject level are in full compliance with GCP. In fact, once the design of the study is established and the institutional review board has approved the trial protocol, “Good Clinical Practice” refers to the way in which the supervising clinician and all of his or her staff go about their study duties on a day-to-day basis. The quality and integrity of the data generated by the study depend entirely on these operations. This is confirmed by monitoring and auditing procedures initiated by the sponsor.

The responsibilities for the ethical aspects of clinical studies, including the means of safeguarding the safety and welfare of the subjects, have been invested by regulation in review bodies that are independent of the study, but qualified to determine its acceptability. In most cases, the review body is a Board set up by the institution in which the study will be performed; hence the title Institutional Review Board or IRB. The Board will be invested with powers to approve or disapprove a study and will also monitor and review its progress and may require that a study be suspended or stopped, if there is a potential for damage to the rights, safety or well-being of the subjects. An alternative approach, usually adopted in Europe, is to arrange that the study is examined by an Independent Ethics Committee (IEC), which will provide advice to the institution.

In this case, the IEC will hand down opinions and the institution will take the executive action. The interrelationship and interaction between the sponsor, clinical investigator and IRB may be very complex. The regulations do not prohibit direct sponsor-IRB contacts, but the clinical investigator generally provides the communication link between the IRB and the sponsor. Such linkage is agreed to by the sponsors and investigators when they sign the agreement covering the conduct of the trial.

The composition of the IRB is a critical GCP factor. The members should be from varying backgrounds; at least one should be primarily a scientist and one other should have primary concerns in a non-scientific area. The IRB cannot consist only of members of one profession, (e.g. physicians). The regulation specifically requires that every non-discriminatory effort should be made to ensure that both men and women should be members, but selection must not be made on a gender basis. At least one member should not be affiliated with the institution and not of the immediate family of a person who is affiliated with the institution. The members should be sufficiently qualified through experience, expertise and diversity that the advice and counsel of the IRB in safeguarding the rights and welfare of human subjects will be respected. The members should demonstrate understanding of, and sensitivity to such issues as community attitudes. A significant growth has been seen in the fortunes of contract research organizations (CROs) which have specialized in the design, conduct and analysis of clinical trials. Companies have preferred to pay CROs to perform the critical studies in the hope that their compliance expertise will be greater than that of the sponsor. CROs may also offer specialized clinical and statistical knowledge and easier access to prime clinical research sites. Employing a CRO to perform the clinical trials does not, however, relieve the sponsor of the ultimate responsibility for GCP compliance. This means adequate monitoring of the studies, whoever is performing them. To support the work of these three main participants in the clinical study process, numerous forms and check-lists have been prepared and some of them are incorporated into official Guidelines. The most relevant of these have been reproduced in this Guide and may be copied by readers for their own use. Finally, the text of all major regulations and guidelines have been included.

This 3rd edition Guide to Good Clinical Practice does not seek to lay down the clinical and statistical methods to be applied to a specific study—this remains the responsibility of the participating physicians and other professionals. The Guide will assist these people to structure and monitor the study so as to ensure its acceptance by the regulatory agencies as being unbiased, accurate and humane.

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