Risk assessment harmonization

The first edition1 of this book was published approximately 13 years ago. Its primary objective was to present an overview and a "roadmap" of the process of new drug discovery and development, particularly oriented to individuals or companies entering the pharmaceutical field. It was written by one of the authors (Smith), with no contributors, and drawn on Smith s experiences in the industry and field over the course of nearly 40 years. In the second edition, the scope of the first book has been expanded and technical details in the form of hard data have been included. In addition to the editors own commentary and contributions, the major part of the book is the result of contributions of experts in the industry. New chapters on risk assessment, international harmonization of drug development and regulation, dietary supplements, patent law, and entrepreneurial startup of a new pharmaceutical company have been added. Some of the important, basic operational aspects of drug discovery and development (e.g., organizational matters, staff requirements, pilot plant operations, etc.) are not repeated in this book but can be found in the first edition. 

Fortunately, well-developed methods exist for assessing the risks posed by chemicals to humans and the environment. The focus of this book is on the description of the existing risk assessment methodologies for human health. New developments in these methodologies will also be described. Throughout the book, the emphasis will be on international harmonization, and the application of test methods and guidance documents developed by international expert groups. The book only... 

As a tool to make mutual acceptance of risk assessments possible, OECD has developed the concept of Good Laboratory Practice (GLP). The OECD Principles of GLP are an integral part of the 1981 OECD council decision on the Mutual Assessment of Data (MAD) in the Assessment of Chemicals (revised 1997, Section 2.2.2). MAD also harmonizes procedures of GLP compliance monitoring, ensuring that preclinical safety studies are carried out according to the principles of GLP and that countries can have conftdence in the quahty and rigor of safety tests. 

Other terms often used indiscriminately for the dose-response relationship include concentration-effect relationship and dose-effect relationship. According to the joint OECD/IPCS project (OECD 2003 a), which has developed internationally harmonized generic and technical terms used in chemical hazard and risk assessment, the following definitions have been provided although consensus was not achieved ... 

WHO/IPCS. 2007. IPCS Project on the Harmonization of Approaches to the Assessment of Risk from Exposure to Chemicals. General Conclusions and Recommendations of an IPCS International Workshop on Skin Sensitization in Chemical Risk Assessment. http /www.who.int/ipcs/methods/ harmonization/areas/sensitization summaiy.pdf... 

Vermeire et al. (1999) have published a discussion paper with focus on assessment factors for human health risk assessment. The status quo with regard to assessment factors is reviewed and the paper discusses the development of a formal, harmonized set of assessment factors. Options are presented for a set of default values and probabilistic distributions for assessment factors based on the state of the art. Methods of combining default values or probabUistic distributions of assessment factors (Section 5.11) are also described. In relation to assessment factors, the authors recommended ... 

A WHO/IPCS (2005) Harmonization Project Document has proposed using chemical-specific toxicological data instead of default assessment factors, when possible. The concept of Chemical-Specific Adjustment Factors (CS AFs) has been introduced to provide a method for the incorporation of quantitative data on interspecies differences or human variability in either toxicokinetics or toxicodynamics into the risk assessment procedure, by modifying the relevant default UF of 10. Incorporation of toxicokinetic or toxicodynamic data becomes possible if each factor of 10 is divided into appropriately weighted sub-factors as suggested by Renwick (1991, 1993) and adopted by WHO/IPCS (1994), see Section 5.2.1.3. 

EFSA. 2005. Draft opinion on a harmonized approach for risk assessment of compounds which are both genotoxic and carcinogenic. Request No EFSA-Q-2004-020, EFSA Scientific Committee, The European Food Safety Authority, 7 April 2005. Brussels EFSA. http /www.efsa.eu.int/en/... 

The approach to exposure assessment is not as internationally harmonized as hazard assessment. A synopsis of current activities regarding exposure assessment for industrial chemicals in a number of OECD Member countries has been published (OECD 2006). The executive summary of this document states that while there is a significant level of sharing of approaches used for hazard characterization for risk assessment, this is not the case for exposure characterization. Although broad consistency in the overall approaches used by different countries in conducting exposure assessment exists, there is variation in policy-related factors, including the regulatory context for assessment and the way that information is applied, as well as in the types of approaches and tools used. 

The International Programme on Chemical Safety (IPCS) has undertaken a project to harmonize approaches to the assessment of risk from exposure to chemicals through increased understanding. The project focuses on specific issues and attempts to achieve agreement on basic principles. Among the project s focus areas are exposure assessment and terminology for exposure assessment and risk assessment. The status for the activities of the harmonization project is published in a newsletter (WHO/IPCS 2007). 

WHO/IPCS. 2004. IPCS glossary of key exposure assessment terminology. In IPCS Risk Assessment Terminology. Harmonization Project Document No. 1. Geneva WHO. http //www.inchem.org/documents/sids/ sids/risk assess.pdf... 

Harmonization activities focus on reducing and simplifying the types of studies that the pharmaceutical industries need to carry out in order to register a medical product in another country, protocols to be followed when performing these studies, techniques used to validate supporting data, and techniques used to perform risk assessment. 

IPCS (1995) International Programme on Chemical Safety/Organisation for Economic Cooperation and Development Workshop on the Harmonization of Risk Assessment for Reproductive and Development Toxicity, 17-21 October 1994. Carshalton, Surrey, United Kingdom, BIBRA International (IPCS/95.25). 

OECD/IPCS (2001) Project on the harmonization of chemical hazard/risk assessment terminology Critical analysis of survey results. Organisation for Economic Co-operation and Development and World Health Organization, International Programme on Chemical Safety (in press). 

Other particularly controversial issues of hazard and risk assessment that urgently need harmonization refer to the potential impact of residues of antimicrobial drugs on the human gut flora, the impact of bound residues, and the impact of residues at injection site on the calculation of ADIs. 

Directive in the EU will be applied more explicitly to pharmaceuticals in order to control discharges to the aquatic environment. The environmental risk assessment of active ingredients is likely to become more sophisticated and uniform among Europe, Japan, and North America. However, a referral to the International Conference on Harmonization (ICH) of Technical Requirements for Registration of Pharmaceuticals for Human Use is probably premature in view of the rapid scientific developments in this area. Nevertheless, harmonization by ICH is possible within the next 10 years. 

Borton, H. A., M. E. Anderson, and H. J. Clewell. Harmonization Developing consistent guidelines for applying mode of action and dosimetry information for applying mode of action and dosimetry information to cancer and noncancer risk assessment. Hum. Ecol. Risk Assess. 4 75-115, 1998. 

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