Scientific Methods to Evaluate Potential Reduced-Risk Tobacco Products
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SCIENTIFIC METHODS TO EVALUATE POTENTIAL REDUCED-RISK TOBACCO PRODUCTS LSRO Life Sciences Research Office 9650 Rockville Pike Bethesda, Maryland 20814 www.LSRO.org Catherine L. St. Hilaire, Ph.D. Editor The distribution or electronic posting of this PDF file is strictly prohibited without the written permission of the Life Sciences Research Office. Copyright © 2007 Life Sciences Research Office No part of this document may be reproduced by any mechanical, photographic, or electronic process, or in form of a phonographic recording, nor may it be stored in a retrieval system, transmitted, or otherwise copied for public or private use, without written permission from the publisher, except for the purposes of official use by the U.S. Government. Copies of the publication may be obtained from the Life Sciences Research Office. Orders and inquiries may be directed to: LSRO, 9650 Rockville Pike, Bethesda, MD 20814-3998. Tel: 301-634-7030; Fax 301-634-7876; web site: www.LSRO.org ISBN: 0-9753167-7-X Library of Congress Catalog Number: 2007921706 The distribution or electronic posting of this PDF file is strictly prohibited without the written permission of the Life Sciences Research Office. FOREWORD The Life Sciences Research Office, Inc. (LSRO) provides scientific assessments of topics in the biomedical sciences. Assessments are based on comprehensive literature reviews and the scientific opinions of knowledgeable investigators who work in relevant areas of science and medicine. This report, which is one of several reports of the LSRO Reduced Risk Review Project (RRRP), was developed under a contract between Philip Morris USA, Inc. (Philip Morris) and LSRO. The findings, conclusions, and recommendations contained in these RRRP reports were developed independently of Philip Morris and are not intended to represent the views of Philip Morris or any of its employees. This report provides the overall conclusions and recommendations of LSRO on scientific methods and approaches to evaluate tobacco products that might pose lower health risks than conventional cigarettes. The other reports provide additional detail on the state-of-the-science related to critical components of the RRRP. Several Expert Advisory Committees provided scientific oversight and direction for all aspects of this project. LSRO independently appointed Expert Advisory Committee members based on their qualifications, experience, judgment, and freedom from conflict of interest; balance and breadth in appropriate professional disciplines were also considered. Committee members were selected with the concurrence of the LSRO Board of Directors. Appendix A provides an overview of the scientific expertise of LSRO staff and Expert Advisory Committee members; additional biographical and professional information for each Committee member is also included. LSRO invited submission of data, information, and views bearing on the topic under study, held a widely advertised Open Meeting on April 27, 2005, and accepted written and electronic submissions. The Expert Advisory Committees convened 18 times between February 2005 and November 2006 to assess the available data. Information about the process, including critical literature and presentations upon which the Expert Advisory Committees based their deliberations, was made publicly available on the LSRO web site at www.lsro.org/rrrvw. LSRO staff drafted this report based on available information, deliberations of the Expert Advisory Committees, and recommendations of the RRRP Core Committee. The draft LSRO RRRP report was submitted to experts in The distribution or electronic posting of this PDF file is strictly prohibited without the written permission of the Life Sciences Research Office. relevant disciplines for independent peer review, and their comments were considered for incorporation by LSRO staff, the RRRP Core Committee, and the LSRO Board of Directors. Philip Morris reviewed the final report for technical accuracy with respect to its products or other possible factual errors. The RRRP Core Committee and LSRO Board of Directors reviewed and approved the final report. Participation in the preparation of this report or membership on an Expert Advisory Committee, or the LSRO Board of Directors does not imply endorsement of all statements in the report. LSRO accepts full responsibility for the study conclusions and accuracy of the report. Michael Falk, Ph.D. Executive Director Life Sciences Research Office, Inc. January 24, 2007 The distribution or electronic posting of this PDF file is strictly prohibited without the written permission of the Life Sciences Research Office. Table of Contents v TABLE OF CONTENTS FOREWORD ............................................................................................. iii EXECUTIVE SUMMARY .......................................................................... 1 I. INTRODUCTION ............................................................................... 8 I.1 PROJECT PURPOSE AND GOALS.......................................... 9 I.2 REDUCED RISK REVIEW PROJECT CONTEXT..................... 9 I.2.1 Public Health Context ................................................... 10 I.2.2 Public Policy Context .................................................... 12 I.2.3 Scientific Context .......................................................... 16 I.3 REDUCED RISK REVIEW PROJECT ANALYTICAL FRAMEWORK................................................... 16 I.3.1 Individual Risk Assessment .......................................... 16 I.3.2 Population Risk Assessment ........................................ 18 I.4 EXPERT ADVISORY COMMITTEES ...................................... 18 I.4.1 Core Committee ........................................................... 18 I.4.2 State-of-the-Science Review Committees .................... 19 I.5 SELECTION OF DISEASE ENDPOINTS ................................ 20 I.6 SELECTION OF CONTROL PRODUCTS ............................... 20 I.7 INITIAL AREAS OF CONSENSUS .......................................... 24 I.8 REPORT ORGANIZATION ...................................................... 24 II. PRECLINICAL STUDIES ................................................................ 25 II.1 INTRODUCTION ..................................................................... 26 II.2 PRODUCT CHARACTERISTICS ............................................ 26 II.3 CHEMISTRY ............................................................................ 28 II.3.1 Mainstream Smoke ....................................................... 28 II.3.2 Environmental Tobacco Smoke .................................... 33 II.4 CYTOTOXICITY AND GENOTOXICITY ASSAYS.................... 34 II.5 ANIMAL STUDIES ................................................................... 37 II.5.1 Study Selection and Design ......................................... 37 II.5.2 Animal Models of Human Disease ............................... 40 II.6 CONCLUSIONS AND RECOMMENDATIONS ........................ 44 III. CLINICAL STUDIES ....................................................................... 45 III.1 INTRODUCTION ..................................................................... 46 III.1.1 Biomarkers..................................................................... 46 III.1.2 Clinical Study Design ..................................................... 48 The distribution or electronic posting of this PDF file is strictly prohibited without the written permission of the Life Sciences Research Office. vi Evaluation of Potential Reduced-Risk Tobacco Products III.2 CLINICAL STUDIES OF EXPOSURE ..................................... 49 III.2.1 Biomarkers of Exposure ............................................... 49 III.2.2 Smoking Topography .................................................... 53 III.2.3 Other Measures of Exposure ........................................ 56 III.2.4 Interpretation of Exposure Study Results ..................... 56 III.3 CLINICAL STUDIES OF EFFECT ........................................... 57 III.3.1 Biomarkers of Effect ..................................................... 57 III.3.2 Selection of Biomarkers of Effect.................................. 63 III.4 CONCLUSIONS AND RECOMMENDATIONS ........................ 65 IV. COMPARATIVE RISK ASSESSMENT ............................................ 66 IV.1 INTRODUCTION ..................................................................... 67 IV.1.1 Context and Purpose of a Risk Assessment ................ 67 IV.1.2 Treatment of Scientific Uncertainty ............................... 67 IV.1.3 Weight of Evidence ....................................................... 68 IV.1.4 PRRTP Risk Assessments ........................................... 69 IV.2 EXPOSURE ASSESSMENT ................................................... 71 IV.2.1 Human Biomarker Studies ............................................ 71 IV.2.2 Smoking Topography .................................................... 71 IV.2.3 Chemistry Studies ........................................................ 71 IV.2.4 Weight of Evidence: Exposure ..................................... 72 IV.3 BIOLOGICAL EFFECTS ASSESSMENT ................................ 72 IV.3.1 Clinical Studies of Biomarkers of Effect ........................ 72 IV.3.2 Preclinical Studies ........................................................ 73 IV.3.3 Weight of Evidence: Biological Effects Assessment ..... 73 IV.4 RISK CHARACTERIZATION ..................................................