Dr Carson trained as an organic chemist (PhD) and safety and health expert (MSc). He was formally employed by Unilever as research scientist and Head of Science Support Services at their Research and Development Laboratory, Port Sunlight. Responsibilities included, occupational health, safety and environment; consumer safety; ethics of animal and human testing; Quality Assurance (GCP,GLP, GMP, ISO 14001/17025/OHSAS 18001); Project Risk Management and member of the Management Committee. Current posts include Quality Director (4-Front Research Ltd), a H&S consultant, Chairman of CIREC (a research ethics committee recognised for reviewing Phase 1 studies on healthy human volunteers) and member of a local hospital clinical ethics committees. Since 1983 he has been a member of the Institution of Chemical Engineers ‘Loss Prevetion Panel’ and is a member of the Association of Reserach Ethics Committee. He is past member of the Chemical Industries Association Health Advisory Group and past Chairman of their Hygiene Working Group. Bewteen 1990-2000 he was visiting lecturer in chemistry at UMIST and was PhD examiner for Aston University Chemical Engineering Department. He has over 60 technical publications including The Safe Handling of Chemicals in Industry (3 volumes), Longman The Hazardous Chemicals Handbook (2 editions), Butterworth Heinemann Good Clinical, Laboratory and Manufacturing Practices (2 editions), Royal Society of Chemistry He is also coauthor of ‘Silver Screens of Wirral’ (2 volumes), Countyvise Ltd

Good Clinical, Laboratory and Manufacturing Practices

Techniques for the QA Professional

By PA Carson, N Dent

The Royal Society of Chemistry

Copyright © 2007 The Royal Society of Chemistry
All rights reserved.
ISBN: 978-0-85404-834-2

Contents

Part 1: Good Clinical Practice, 1,
Chapter 1 Introduction: Good Clinical Practice D. Talbot and N. Downes, 3,
Chapter 2 The Protocol, Case Report Form and Initial Documentation: Quality Assurance Involvement and Common Problems N.J. Dent, 13,
Chapter 3 Standard Operating Procedures in the Good Clinical Practice Environment P. Charnley Nickols and J. Nickols, 39,
Chapter 4 Preparing for Regulatory Inspection of Company Pharmacovigilance Systems and Practices in the European Union and United States E.G. Brown and S.A. Goldman, 57,
Chapter 5 Investigator, Sponsor and Contract Research Organisation Audits P. Fitzgerald, 73,
Chapter 6 Data Audits J.V. Birnie, 89,
Chapter 7 Research Ethics Committees S. Eckstein, 99,
Chapter 8 Good Clinical Practice/Good Manufacturing Practice (GCP/GMP) Interface, Investigational Product Accountability D. Bailes, 109,
Chapter 9 Monitoring and Quality Control A. Bevan and S. Ollier, 121,
Chapter 10 Phase I Healthy Volunteers Studies R. Cope and P. Rolan, 137,
Chapter 11 Clinical Laboratories P.J. Ford, 147,
Part 1: Good Clinical Practice 1,
Chapter 12 Introduction: Good Laboratory Practice Th. Helder, 171,
Chapter 13 Quality Assurance in GLP P.A. Carson, 183,
Chapter 14 The Master Schedule Index J. Goeke, 199,
Chapter 15 Study Plans and Their Audits J.R. Pateman, 209,
Chapter 16 Standard Operating Procedures for Good Laboratory Practice Work P. Hallin and A. Wichman, 223,
Chapter 17 Inspections: Procedural, Process and Facility A. Waddell, 235,
Chapter 18 Report and Data Audits J. Janssens, 249,
Chapter 19 Quality Assurance and Contract Research Organisation: GLP Studies R. Chapman, 263,
Chapter 20 Good Laboratory Practice and Pharmacology M.J. Benton, 271,
Chapter 21 Application of GLP in Analytical Chemistry with Cross Reference to GMP and GCP A. Anderson, J.G. Maxwell and H.M. Hill, 279,
Chapter 22 GLP in Drug Metabolism and Pharmacokinetics N.J. Dent, 305,
Chapter 23 Issues of Quality in Pathology K. Isaacs, 317,
Chapter 24 Good Laboratory Practices in Ecotoxicology and Field Studies D.L. Colinese, 335,
Chapter 25 Animal Health K. De Keulenaer, 353,
Part 3: Good Manufacturing Practice,
Chapter 26 Introduction: Good Manufacturing Practice J.R. Dolman, 371,
Chapter 27 Standard Operating Procedures V. Edy and M. Gamlen, 387,
Chapter 28 Release of Bulk and Filled Finished Product J. Sharp, 399,
Chapter 29 Good Manufacturing Practice for Investigational Medicinal Products V. Edy and M. Gamlen, 407,
Chapter 30 Chemical Analysis P. Newton, 419,
Chapter 31 Good Manufacturing Practice for Sterile Products J. Sharp, 435,
Chapter 32 Statistics for QA Auditors of GLP and GCP Studies I. Townshend, 463,
Chapter 33 Metrics and Trend Analysis P. Carson, 473,
Chapter 34 Supplier Auditing A. McCraight, 479,
Chapter 35 Centralised Supplier Audits for Animal Studies P. Withers, 489,
Chapter 36 Document Control: From Concept to Archiving J. Gumley, 497,
Chapter 37 Computing and GXPs A. Nelms, 511,
Chapter 38 QA Developing a Regulatory Compliance Training Strategy: An Opportunity for QA to Improve Quality and Provide Greater Value to the Business L. Brown, 529,
Chapter 39 Training and Staff Records for GXP H. Neal, 541,
Chapter 40 Integrating Quality Systems P. Baxter, 551,
Glossary of Some Commonly-used Abbreviations P. Carson and N. Dent, 563,
Appendix GLP Comparison, OECD, USA and Japan J. Somorai, 575,
Subject Index, 599,

CHAPTER 1

Introduction: Good Clinical Practice

D. TALBOT AND N. DOWNES

1.1 INTRODUCTION

Good Clinical Practice (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. Although born as a guideline, in many parts of the world it is now a legal requirement to work to GCP standards when conducting clinical research. The large body of literature on the subject of GCP confirms its importance and the seriousness with which those working in clinical research regard the subject. At its most basic level, GCP is a set of rules establishing the standards for performing and documenting clinical trials so that participating subjects are protected and that cross-national acceptance of study data by clinicians and regulators is achieved.

1.2 BACKGROUND

Following the well publicised medical research horrors that were described at the Nuremburg trials, during which it was revealed that Nazi physicians had undertaken experiments on prisoners without their consent and without regard for the individual’s well-being, the Nuremburg Code was published in 1949 (US Government Printing Office). The Nuremburg Code described for the first time the principles of Informed Consent. This became the basis for the Declaration of Helsinki made by the World Medical Association (WMA) at their annual meeting in Helsinki in 1964 (see Chapter 7, Research Ethics Committees). Just before this, in 1962, the Drug Amendment Act had been approved in the United States. This became the Food and Drug Administration (FDA) Regulations governing clinical research which obligated investigators to inform the FDA of any proposed clinical trials, required the submission of pre-clinical data to support the proposed trials, and required informed consent of the trial subjects to be obtained and that the trial results would be reported. The FDA Regulations of 1962 were subsequently expanded to include Good Manufacturing Practice (GMP) in 1963, Institutional Review Boards in 1971 and GCP in 1977. This was the start of a framework of legislation and guidelines that are now in place covering the majority of clinical research in almost every country in the world.

During the 1970s and 1980s other countries developed their own guidelines for GCP. In Europe, guidelines were developed in a number of countries including Austria, Finland, France, Germany, Greece, Ireland and the United Kingdom. The Nordic GCP guidelines were also developed. Eventually, in 1990, there was some harmonisation of GCP standards to be followed across Europe when the European Committee for Proprietary Medicinal Products (CPMP) GCP guidelines were issued. In other regions of the world, Canada, Israel and Japan also developed GCP guidelines and the World Health Organisation (WHO) issued their set of GCP guidelines in 1993, by which time it was becoming increasingly obvious that a global standard for GCP was required. The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) recognised this need in 1991 and set up an Expert Working Group to draft a guideline on GCP. This was issued as a finalised guideline, ICH E6 GCP Consolidated Guideline,in May 1996, and was adopted by the three main ICH regions – CPMP in Europe, published in the Federal Register in the United States and adopted by the Ministry of Health and Welfare (MHW) in Japan, in the following year. This GCP guideline also attracted considerable interest from those countries and organisations outside the three main ICH regions such as Canada, South Africa, Australia and the WHO. Thus the ICH GCP guideline quickly became the most widely accepted and followed GCP guideline globally. The benefits of a global standard for drug development can be huge, both as a cost saving by not having to repeat similar studies in different countries, and by allowing the introduction of new treatments more quickly.

1.3 SCOPE OF GOOD CLINICAL PRACTICE

Much of the drive for one standard of GCP is the multi-national nature of clinical research and the consequent need to have common standards of ethics, behaviour and process so that the data are equally acceptable to regulatory authorities worldwide. The ICH GCP guideline should be followed when gathering clinical trial data that are intended to be submitted to regulatory authorities, and the principles can be applied to all clinical investigations that may impact on the safety and well-being of human subjects. There has been some resistance from the academic community to fully comply with GCP when performing medical research not intended for a licence submission. However, it does not seem justifiable that research participants should have any lower standards of protection when involved in academic research.

1.4 LEGISLATION

The finalised ICH E6 guideline on GCP, which was published in May 1996 was adopted by the three main ICH regions – Europe, the United States and Japan – in the following year.

The legislation that underpins the standards of GCP that must be followed in clinical investigations in the three ICH regions are: the US FDA Code of Federal Regulations Title 21(21 CFR), the European Union (EU) Directives and the Japanese Pharmaceutical Affairs Law. The EU Directives cover all phases of clinical research, including post-marketing (Phase IV therapeutic use) studies, but the FDA and Japanese regulations only cover those investigations that are intended to be submitted for regulatory approval.

In the United States, the regulations in 21 CFR support applications for research or marketing permits for products regulated by the FDA. 21 CFR is kept up-to-date by the individual issues of the Federal Register; so these two publications must be read together to ascertain the latest version of any given rule. The ICH E6 GCP guideline was published in the Federal Register on 9th May 1997 (62 FR 25692) and is applicable to drug and biological products, but it remains a guidance and has not been incorporated into 21 CFR. The Guidance for Industry published by FDA, however, notes that ‘this guidance (ICH E6) represents the Agency’s current thinking on good clinical practices’ which gives a strong recommendation that ICH E6 should be followed when performing clinical studies that are destined for submission to the FDA. The parts of 21 CFR that cover different aspects of GCP are: part 50 – Protection of Human Subjects, part 54 – Financial Disclosure by Clinical Investigators, part 56 – Institutional Review Boards, part 312 – Investiga-tional New Drug (IND) Application and part 314 – Application for FDA approval to market a new drug.

Within the EU, legislation to implement GCP is driven by two directives. Directive 2001/20/ECtook effect on 1st May 2001 and required member states to implement GCP in the conduct of clinical trials on medicinal products for human use as from 1st May 2004. This was accompanied by five legally binding guidance documents giving more details on applications to competent authorities, ethics committees, obtaining a EudraCT number and two guidances that describe the reporting of adverse reactions. By the end of 2005 most of the 25 member states had legislation in place to achieve this. To support this, another EU Directive 2005/28/EC has been introduced which lays down the principles and detailed guidelines for GCP as regard to investigational medicinal products (IMPs) for human use as well as the requirements for authorisation of the manufacturing or importation of such products (see Chapters 8 by Bailes and 27 by Edy). Directive 2005/28/EC took effect on 20th April 2005 and member states were directed to incorporate it into local law by 29th January 2006. This directive lays down the principles of GCP, the requirements for authorisation of the manufacture or importation of IMPs and the documentation relating to clinical trials, archiving, qualifications of inspectors and inspection procedures. It is interesting to note that the directive requires the 1996 version of the Declaration of Helsinki and the ICH GCP guidelines that reached a consensus in 1995 to be followed. The trial master file will provide the basis for audit and inspection and will consist of essential documents the contents of which will be published in an additional guidance.

In Japan, ICH GCP was published as ‘Japanese Technical Requirements for New Drug Registration 1997 by the MHW and has been enforced as Ministerial Ordinance Number 28 since April 1997. The Pharmaceutical Affairs Law and subordinate regulations were amended using ICH GCP as a guideline and implemented in April 1998.

1.5 RESPONSIBILITIES

The ICH GCP guideline is divided into eight chapters beginning with a glossary in Chapter 1, which aims to ensure a common understanding of terms. Chapter 2 states the underpinning Principles of ICH GCP which have their origin in the Declaration of Helsinki. The responsibilities of the Institutional Review Board/Independent Ethics Committee (IRB/IEC), Investigator and Sponsor are clearly set out in Chapters 3, 4 and 5, respectively. The guidance to ensure the documentation that complies with GCP is given for the Clinical Trial Protocol, the Investigator’s Brochure and the Essential Documents for the Conduct of a Clinical Trial are present in Chapters 6, 7 and 8, respectively.

1.5.1 Responsibilities of the Institutional Review Boards/Independent Ethics Committees

Under GCP the ethics committee is responsible for safeguarding the rights, safety and well-being of all trial subjects. This usually involves the ethics committee reviewing the research proposal and the sites at which it is proposed to conduct the research. To review the study it is suggested that a comprehensive list of documents are reviewed; the protocol and investigator’s brochure are obvious candidates, but the list also includes subject recruitment procedures, including any advertisements, written patient information and the informed consent signature form. Any compensation payable to the subjects has to be declared, and the committee can review any additional document it feels necessary to fulfil its responsibilities. The committee should give its decision within a reasonable time, and review any amendments to the approved protocol before they are implemented. To review the research site it is suggested the curriculum vitae (CV) of the investigator is considered together with any other relevant documentation.

It is required that the IRB/IEC conducts ongoing review of the research, for example at yearly intervals, and it may request additional written information for the trial subjects if appropriate to protect their rights, safety or well-being. If a trial is proposed, which may include adults unable to consent for themselves, consent should be sought from a legally acceptable representative. The implementation of the EU Directive on clinical trials since May 2004 has helped to harmonise this requirement within the EU and an acceptable way forward has been found to conduct research in those unable to consent for themselves in most EU member states. GCP allows for research in the emergency situation where consent may not be possible, and if such research is to continue, the role of the ethics committee is pivotal in ensuring that an acceptable form of ‘consent’ is included. Under GCP subjects may receive payment, particularly when they are not expected to derive any benefit from the treatment under investigation, such as in phase I (human pharmacology) studies (see Chapter 10 by Cope), however, payments must be prorated and approved by the IRB/IEC beforehand.

1.5.2 Responsibilities of the Investigator

Investigators are obviously crucial members of the team responsible for the satisfactory completion of a clinical trial and their responsibilities under GCP are therefore described in some detail in the guideline.

1.5.2.1 Investigator Qualifications and Agreements. The investigator should be qualified by education, training and experience to assume responsibility for the proper conduct of the clinical trial, and provide documentary evidence of this to ethics and regulatory bodies. He/she should be thoroughly familiar with information on the investigational product (IP) provided by the sponsor; permit monitoring, audit and inspection of his/her conduct of the trial and, of course, comply with GCP. If any duties or responsibilities are delegated, a list of delegated duties and responsible persons should be kept.

1.5.2.2 Adequate Resources. The investigator should be able to demonstrate adequate potential subjects for the study as well as time, equipment, qualified staff and adequate facilities to conduct the trial properly and safely.

1.5.2.3 Medical Care of Trial Subjects. Under GCP a qualified physician (or dentist when appropriate) should be responsible for trial-related medical decisions. It is recommended that a subject’s primary physician be informed of a subject’s participation in a clinical trial, if the subject agrees. If a subject withdraws prematurely, an investigator should make reasonable attempts to determine ‘why’, in case it is due to an adverse event, although it must be remembered that a subject can withdraw at any time without giving a reason.

1.5.2.4 Communication with IRB/IEC. Before initiating the trial an investigator should either have written and dated approval/favourable opinion for the trial protocol and associated documents submitted for review. Any updated documents should be submitted by the investigator for review and approval before implementation, except to remove a potential hazard to the subject (see Chapter 7 by Eckstein).

1.5.2.5 Compliance with the Protocol. GCP requires that the investigator complies with the approved current version of the protocol, and that any deviations are documented.

1.5.2.6 Investigational Products. Responsibility for IPs accountability rests with the investigator. In practice it is often delegated to a pharmacist to store IPs and maintain records of delivery to the site, dispensing and return of products used by subjects in a clinical trial and disposal or return of the IP to a sponsor.

(Continues…)Excerpted from Good Clinical, Laboratory and Manufacturing Practices by PA Carson, N Dent. Copyright © 2007 The Royal Society of Chemistry. Excerpted by permission of The Royal Society of Chemistry.
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