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Guidance for Industry: M3(R2) Nonclinical Safety Studies for the Conduct of Human Clinical Trials

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Guidance for Industry: M3(R2) Nonclinical Safety Studies for the Conduct of Human Clinical Trials Guidance for Industry M3(R2) Nonclinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER) January 2010 ICH Revision 1 Guidance for Industry M3(R2) Nonclinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals Additional copies are available from: Office of Communications Division of Drug Information Center for Drug Evaluation and Research Food and Drug Administration 10903 New Hampshire Ave. Bldg. 51, Room 2201 Silver Spring, MD 20993-0002 (Tel) 301-796-3400 http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm and/or Office of Communication, Outreach and Development, HFM-40 Center for Biologics Evaluation and Research Food and Drug Administration 1401 Rockville Pike, Rockville, MD 20852-1448 (Tel) 800-835-4709 or 301-827-1800 http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/default.htm. U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) Center for Drug Evaluation and Research (CBER) January 2010 ICH Revision 1 Contains Nonbinding Recommendations TABLE OF CONTENTS List of Abbreviations I. INTRODUCTION (1)....................................................................................................... 1 A. Objectives of the Guidance (1.1)...................................................................................................1 B. Background (1.2)............................................................................................................................2 C. Scope of the Guidance (1.3)...........................................................................................................2 D. General Principles (1.4).................................................................................................................3 E. High Dose Selection for General Toxicity Studies (1.5)..............................................................3 II. PHARMACOLOGY STUDIES (2)................................................................................. 6 III. TOXICOKINETIC AND PHARMACOKINETIC STUDIES (3) ............................... 6 IV. ACUTE TOXICITY STUDIES (4) ................................................................................. 6 V. REPEATED-DOSE TOXICITY STUDIES (5) ............................................................. 7 A. Clinical Development Trials (5.1).................................................................................................7 B. Marketing Authorization (5.2)......................................................................................................9 VI. ESTIMATION OF THE FIRST DOSE IN HUMANS (6)............................................ 9 VII. EXPLORATORY CLINICAL TRIALS (7)................................................................. 10 A. Microdose Trials (7.1)..................................................................................................................10 B. Single-Dose Trials at Subtherapeutic Doses or Into the Anticipated Therapeutic Range (7.2) 11 C. Multiple Dose Trials (7.3)............................................................................................................11 VIII. LOCAL TOLERANCE STUDIES (8) .......................................................................... 16 IX. GENOTOXICITY STUDIES (9)................................................................................... 16 X. CARCINOGENICITY STUDIES (10) ......................................................................... 16 IX. REPRODUCTION TOXICITY STUDIES (11)........................................................... 17 A. Men (11.1).....................................................................................................................................17 B. Women Not of Childbearing Potential (11.2) ............................................................................17 C. Women of Childbearing Potential (11.3) ...................................................................................17 D. Pregnant Women (11.4)...............................................................................................................18 XII. CLINICAL TRIALS IN PEDIATRIC POPULATIONS (12) .................................... 19 XIII. IMMUNOTOXICITY (13)............................................................................................. 20 XIV. PHOTOSAFETY TESTING (14).................................................................................. 20 XV. NONCLINICAL ABUSE LIABILITY (15).................................................................. 20 XVI. OTHER TOXICITY STUDIES (16) ............................................................................. 21 i Contains Nonbinding Recommendations XVII. COMBINATION DRUG TOXICITY TESTING (17) ............................................. 21 XVIII. CONTINUING EFFORTS TO IMPROVE HARMONIZATION (18)................ 23 XIX. ENDNOTES (19)............................................................................................................. 24 XX. REFERENCES (20)........................................................................................................ 25 ii Contains Nonbinding Recommendations LIST OF ABBREVIATIONS AUC Area Under the Curve Cmax Maximum Plasma Concentration EU European Union GLP Good Laboratory Practices HCG Human Chorionic Gonadotropin HIV Human Immunodeficiency Virus ICH International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use i.v. Intravenous MFD Maximum Feasible Dose MTD Maximum Tolerated Dose NOAEL No Observed Adverse Effect Level PET Positron Emission Tomography PD Pharmacodynamics PK Pharmacokinetics SAR Structure-Activity Relationship siRNA Small Interfering RNA WOCBP Women of Childbearing Potential i Contains Nonbinding Recommendations Guidance for Industry1 M3(R2) Nonclinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals This guidance represents the Food and Drug Administration's (FDA’s) current thinking on this topic. It does not create or confer any rights for or on any person and does not operate to bind FDA or the public. You can use an alternative approach if the approach satisfies the requirements of the applicable statutes and regulations. If you want to discuss an alternative approach, contact the FDA staff responsible for implementing this guidance. If you cannot identify the appropriate FDA staff, call the appropriate number listed on the title page of this guidance. I. INTRODUCTION (1)2 A. Objectives of the Guidance (1.1) The purpose of this document is to recommend international standards for, and promote harmonization of, the nonclinical safety studies recommended to support human clinical trials of a given scope and duration as well as marketing authorization for pharmaceuticals. Harmonization of the guidance for nonclinical safety studies will help to define the current recommendations and reduce the likelihood that substantial differences will exist among regions. This is a revision of the ICH guidance “M3 Nonclinical Safety Studies for the Conduct of Human Clinical Trials for Pharmaceuticals” that published in 1997. The revisions further harmonize recommendations in a number of areas and include a new section on exploratory clinical studies. This revised guidance discusses other nonclinical studies that should be conducted on a case-by-case basis as appropriate, including phototoxicity studies, immunotoxicity studies, juvenile animal toxicity studies, and abuse potential studies. This guidance should facilitate the timely conduct of clinical trials, reduce the use of animals in accordance with the 3R (reduce/refine/replace) principles, and reduce the use of other drug 1 This guidance was developed within the Expert Working Group (Multidisciplenary) of the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) and has been subject to consultation by the regulatory parties, in accordance with the ICH process. This document has been endorsed by the ICH Steering Committee at Step 4 of the ICH process, June 2009. At Step 4 of the process, the final draft is recommended for adoption to the regulatory bodies of the European Union, Japan, and the United States. 2 Arabic numbers reflect the organizational breakdown in the document endorsed by the ICH Steering Committee at Step 4 of the ICH process, [date]. 1 Contains Nonbinding Recommendations development resources. Although not discussed in this guidance, consideration should be given to use of new in vitro alternative methods for safety evaluation. These methods, if validated and accepted by all ICH regulatory authorities, can be used to replace current standard methods. This guidance promotes safe, ethical development and availability of new pharmaceuticals. B. Background (1.2) The recommendations of this revised guidance further harmonize the nonclinical safety studies to support the various stages of clinical development among the regions of the European Union (EU), Japan, and the United States. The present guidance represents the consensus that exists regarding the type and duration of nonclinical safety studies
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