Preclinical Considerations For Regulatory Submissions
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0092-8615/2001 Copyright 0 2001 Drug Information Association h e .
PRECLINICAL CONSIDERATIONS FOR REGULATORY SUBMISSIONS PAULBALDRICK, PHD Consultancy and Regulatory Services, Covance Laboratories Ltd, Harrogate, North Yorkshire, England, United Kingdom
‘‘Rules” on how to prepare and present preclinical data in regulatory submissions are well established. Issues/delays in achieving a product license for a new drug can be avoided through a knowledge of these rules and good communication with regulatory agencies. In addition, preclinical evaluation of data needs to be written in a well-balanced, scienti3c manner to highlight the safety projiIe of the new drug in terms of human use and any defciencies in the testing program. Howevec despite available help, preclinical documentation within submissions can be deficient in a number of ways. This paper highlights necessary regulatory requirements within the preclinical summaries of dossiers and comments on areas of neglect along with new challenges for the preclinical expert as well as exploring ways of avoiding adverse regulatory agency comments. Key Words: Preclinical documents; European, United States and Japanese submission; Pharmacodynamic data; Pharmacokinetic data; Toxicology data
INTRODUCTION
cussion to standardize and allow global product license applications. However, the key evaluation process for preclinical data will remain essentially as it is at present. This paper will examine the content of these preclinical sections within dossiers, highlighting regulatory requirements, areas of neglect, and new challenges. The paper will also explore ways of avoiding adverse regulatory agency comments.
FOR NEW DRUG LICENSE applications (Marketing Authorization Applications or MAAs in Europe and New Drug Applications or NDAs in the United States and Japan), key preclinical (safety) data are assessed and evaluated in specific parts of the dossier. Currently, such data occur in the Safety Expert Report (within the summary of the dossier) in Europe, in the Nonclinical Pharmacology and Toxicology section (within the application summary) in the United States, and in the Toxicology, Nonclinical Pharmacology and Absorption, Distribution, Metabolism, and Excretion section (within the Gaiyo summary) in Japan. This format is set for some change as part of the Common Technical Document (CTD) dis-
REGULATORY GUIDANCE International regulatory expectations for the type of preclinical data required for new drug applications are widely available (1-5) and are supported by literature data (eg, 6,7). In addition, preclinical drug testing has benefited from a range of International Conference on Harmonization (ICH) guidelines including expectations of what is required from chronic toxicity, reproduction toxicity, genotoxicity, carcinogenicity, and pharmacokinetic/toxicokinetic evaluation as well as spe-
Reprint address: Paul Baldrick, PhD, Consultancy and Regulatory Services, Covance Laboratories Ltd, Harrogate, North Yorkshire, HG3 IPY, England, United Kingdom.
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