REGULATORY COMPLIANCE GUIDE SERIES (GxP Guides)

Excerpt of Good Clinical Practice Guide

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 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 US 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.

Lack of compliance with GCP may 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, do not lead to marketing approval if GCP compliance is not confirmed.

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 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. The Sponsor applies to the regulatory authorities for permission to perform the clinical study, based upon these pre-clinical 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 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. It is their 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 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.

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 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.

Significant growth has been seen in 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.

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