Performing Phase I Clinical Trials of Anticancer Agents: Perspectives from within the European Union and Japan Martin D. Forster 1 , Nagahiro Saijo 2 , Lesley Seymour 3 , and Hilary Calvert 1 Abstract Drug discovery and early clinical development is an international endeavor, conducted in partnership between commercial entities such as biotechnology and pharmaceutical companies and academic inves- tigators. Although once considered quite disparate, early clinical trials requirements and conduct are largely harmonized between the European Union, Japan, and the United States, increasing the opportu- nities for productive commercial-academic collaborations. Clin Cancer Res; 16(6); 1737–44. ©2010 AACR. Cancer drug discovery and development is an interna- tional activity. Many of first-in-human studies of antican- cer drugs are conducted in two sites in different countries, usually in North America (United States or Canada) and the other in Europe. Additional phase I studies including Japanese patients are often required for later marketing approvals in Japan. Phase I capabilities exist worldwide, including Australia, Asia, and South America. Although there are differences in attitudes between different countries in general, the concerns and approaches of phase I investigators are similar across the world. In particular there is emphasis on trial designs that minimize the num- ber of patients treated with ineffective doses and maximize the possibility of eliciting therapeutic signals. We summa- rize here early clinical trial activities in Europe and Japan, highlighting key opportunities and challenges as part of this issue of CCR Focus, which examines the phase I clini- cal trial process (1). European Union In terms of organization, there is no overarching organi- zation for European countries or even for one individual country. Rather, the tendency has been for potential spon- sors to negotiate individually with individual centers. This has led to the focusing of many studies in relatively few centers where the expertise and the reputation for the con- duct of these studies have been established. Of note, pri- vately owned and commercially operated phase I clinical trials centers are emerging in Europe. Marketing approval for new drugs within the European Union is the responsibility of the European Medicines Agen- cy, which is a decentralized body of the European Union with headquarters in London. The agency is responsible for the scientific evaluation of applications for European market- ing authorization for medicinal products using a centralized procedure. Companies submit a single marketing authoriza- tion application to the agency. Once granted by the European Commission, this authorization is valid in all European Union (EU) and EEA-EFTA states (Iceland, Liechtenstein, and Norway). In contrast, approval for clinical trials of new agents is the responsibility of each member state, with each country providing its own regulatory authority. First in human trials are clinical experiments and are therefore governed by a number of regulations and guide- lines. Patients who participate are given an intervention that they would not normally receive, with an unknown efficacy and toxicity profile, and often undergo additional clinical assessments and tests. It is therefore essential to protect their safety and well being, which is the primary role of the regulatory guidelines. Adherence to these guide- lines is particularly relevant in phase I studies, in which the investigational medicinal product may have been ad- ministered to few, if any, humans previously. The regu- lations also aim to ensure that the clinical trial data produced are robust and accurately represent the activities of the Investigational Medicinal Product (IMP). The first internationally recognized guidelines were the Nuremberg Code, developed in 1948, following the inhu- mane experimentation on subjects without appropriate consent during the Second World War (2). The Nuremberg Code formed the basis for the Declaration of Helsinki, first declared by the World Health Authority in 1964, which has undergone a number of subsequent revisions (latest in 2008: ref. 3). All clinical studies need to follow its guidelines, although it is not legally binding in interna- tional law, and it has formed the backbone to the Code of Federal Regulations (title 45, volume 46) in the United States (4) and the International Conference on Harmoni- zation of Technical Requirements for the Registration of Pharmaceuticals for Human Use (ICH) guidelines. Authors' Affiliations: 1 The Cancer Institute, University College London, London, United Kingdom; 2 Kinki University School of Medicine, Osaka- Sayama, Japan; and 3 NCIC Clinical Trials Group, Queens University, Kingston, Ontario, Canada Corresponding Author: Hilary Calvert, UCL Cancer Institute, Paul O'Gorman Building, 72 Huntley Street, London, WC1E 6BT, United King- dom. Phone: 44-20-7679-0744; E-mail: hilary.calvert@cancer.ucl.ac.uk. doi: 10.1158/1078-0432.CCR-09-2228 ©2010 American Association for Cancer Research. www.aacrjournals.org 1737 CCR FOCUS Downloaded from http://aacrjournals.org/clincancerres/article-pdf/16/6/1737/1994997/1737.pdf by guest on 06 December 2022