In a special lecture given at the Applied Clinical Trials European Summit, held in Lyon, France, from 22 to 24 April, Marijke Korteweg, PhD, quality manager, European Agency for Evaluation of Medicinal Products, London, outlined the vital role of quality management in medicinal drug development. She traced the field’s development since June 1991, when the European Organisation for Quality (EOQ) organized the first workshop dedicated to Good Clinical Practice and ISO (International Standards Organization).

Steady progress was made during the mid-1990s, culminating in the optional guidelines for GCP auditing devised by the European Network of GCP Auditors and other GCP Experts (ENGAGE) and based on ISO10011. According to Korteweg, who has been an active member of ACT’s Editorial Advisory Board since 1992, confirmation of the continued progress will become evident at the 46th EOQ Congress (30 September–2 October 2002, Harrogate, UK), where details will be presented about benchmarking of quality management systems of regulatory authorities.

“Good regulatory practices and quality management systems deserve to be a priority action area, and several competent authorities have experience with the implementation of a quality system, whereas others would like to benefit from the experience already gathered,” she said. “Benchmarking is therefore appropriate to assure the quality of the tasks of the competent authorities in a cost-effective way. Selected innovative and best practices (cost-effective, efficient, and feasible) are furthered in the framework of the Pan-European Regulatory Forum.”

Auditing is recognized as an integral part of the quality system, added Korteweg. Assurance of quality (an aspect of regulatory compliance) is achieved by well-functioning systems of recruitment, training, monitoring, and follow-up, and by well-written standard operating procedures, well-planned quality control steps, reliable documentation, and well-organized archives.

She explained that about 12 years ago, auditing of pivotal clinical trials occurred quite close to the submission of a New Drug Application. The audit group was considered to be the group giving “bad messages,” delaying submissions or complicating them. In fact, quality control occurred much too late in the process, and it remains valid that “one cannot inspect or audit quality into clinical studies,” she noted.

“The evolution from single clinical trial auditing to the audit of systems and processes led to the conclusion that the quality awareness of all parties had to increase, that there had to be quality management beyond compliance. Quality has to be built in at the moment of developing a strategic product development plan, a trial protocol, shaping the CRFs, distributing monitoring tasks, writing SOPs, establishing audit units,” said Korteweg. Compliance with harmonized standards facilitates mutual acceptance of data by authorities and allows faster registration and marketing, amounting to business excellence, she concluded.

Clinical safety data
How best to guarantee quality was also a central theme in the focus session about reporting adverse events (AEs), organized by Francis de Halleux, MD, medical director of Benelux countries, Schering Plough, Brussels, and Dr. Iain Cockburn, PhD, director, European Drug Safety, Eisai, London. An effective, coherent, and workable system for AE reporting is required to ensure full compliance, and such systems should be ethical, legal, and medically correct.

“The most relevant constraints are the varying regulations, the involvement of CROs and/or the co-development (of drugs) with partners, and licensees,” said de Halleux. “There are issues with marketing studies, data privacy issues, trial process and organization, investigator notification (IND studies), the need of annual reports (United States), and updates of the investigator brochure.”

Problems can occur when two or more companies or CROs are running trials in the same countries at the same time, often with the same investigators. It is essential to decide who is responsible for collecting and reporting AEs and to ensure a rapid exchange of information with the partners, he noted.

Careful planning and efficient organization is necessary because the FDA does unscheduled audits of AE reporting systems, either at random or for a specific reason. The visits can last from a few days to seven months, and they tend to concentrate on international AEs and their timely transmission to the United States for reporting to FDA, according to de Halleux. For U.S. IND studies, investigators must be trained to report serious AEs within 24 hours, monitors must be ready to accept and act on AEs within two days, AE data must be entered into the computer system, and a medical review should be completed within a few days. It should be determined if the situation warrants a seven or 15-day IND report, and relevant details must be reported to FDA.

“Computer systems need to be reliable and capable of producing required validated reports (MedWatch, CIOMS 1),” he said. “Do you buy or build such systems? In any case, it is very expensive.”

Ethics revisited
The pressure on clinical researchers to keep themselves well-informed about ethical issues, and to make sure their companies have internal training strategies, has never been greater.

“Ethical issues are as important as scientific issues in protocol design,” said Henri Debois, MD, senior medical affairs specialist, Aventis Pasteur, Lyon. “When we discuss protocol design in a review committee, ethical issues should be identified, discussed thoroughly, and revisited periodically. Maybe those responsible for quality assurance should be involved in those discussions.”

He expressed deep concern that the October 2001 clarification to the revised Declaration of Helsinki has reopened the door to controversies between science, ethics, and economic interests. And it risks dividing the scientific community. Under this clarification, a placebo-controlled trial is ethical “where for compelling and scientifically sound methodological reasons, its use is necessary to determine the efficacy or safety of a prophylactic, diagnostic, or therapeutic method; or whether a prophylactic, diagnostic, or therapeutic method is being investigated for a minor condition and the patients who receive placebo will not be subject to any additional risk or irreversible harm.” The first condition may be problematic because no criteria are provided for “compelling reasons” for departing from the principle, and “scientifically sound” methodology is always required in every study, argued Debois. Similarly, it is always a top priority to prevent serious or additional harm to trial subjects.

“With the present guidelines (Helsinki, CIOMS), no sponsor can avoid a debate on the ethical aspects of placebo-controlled trials in developing countries,” Debois noted. “The other potential matters of disagreement (conflict of interest, informed consent, drug accessibility) must be carefully monitored.”

Phase 4 studies
Another topic to attract the interest of delegates was the role and organization of Phase 4 studies. Registration of pharmaceuticals offers little more than a skeleton and is the beginning of a process rather than the end, according to Uwe Gudat, PhD, manager of Artaeus in Geneva, Switzerland, who organized a focus session on this topic with Kenneth Getz, MBA, publisher, CenterWatch, Boston. Phase 4 trials should focus on efficacy (new indications, claim expansion), safety (interactions, special populations, concomitant illness, co-medication), physicians’ use of the drug, and understanding what the drug does best and in whom, and when it outperforms the competition.

“Phase 4 activities often have to be better designed than Phase 3 because they have smaller budgets, less time, multiple objectives, more public scrutiny, less regulatory protection, and less experienced investigators,” he said. “You must have a strategy. What activities are planned and how do they link? Why is it being conducted and what is the expected benefit? Is the strategy achievable with allocated resources?”

Common problems are that Phase 4 studies are poorly designed (underpowered, unclear objectives, and too many variables); poorly conducted (poor compliance, high variability, and loss of power); have poor recruitment (uninterested investigators, over-restrictive criteria); and are GCP noncompliant. Most problems can be avoided by being scientifically rigorous, focusing on what is important, not overburdening investigators, and not compromising GCP.

“Also, you should work with—not against—your marketing colleagues. Their information is less scientifically rigorous, but often closer to reality,” said Gudat. “Plan with ingenuity, consider example patients, use pharmacovigilance data and soft market research data to plan trials, and look for new, meaningful patient outcomes.”

Acknowledgements
The editors and conference staff at Applied Clinical Trials wish to thank all the speakers, moderators, and program advisory panel members for their contributions to the Lyon meeting. Next year’s ACT European summit will be held on 13–15 May 2003 at the Management Centre Europe, Brussels. For more details, contact Siân Winston, + 44 1244 393 159, fax + 44 1244 370 560, email: swinston@advanstar.com.