A
Data Sources and Methods

The committee reviewed and considered abroad array of information in its work on issues involving clinical trials of testosterone therapy. Information sources included the primary scientific literature, books and scientific reviews, and presentations from researchers, representatives from federal agencies, and the pharmaceutical industry.

LITERATURE REVIEW

In order to conduct a thorough review of the literature, the committee, Institute of Medicine (IOM) staff, and outside consultants conducted online bibliographic searches, primarily in Medline, in addition to examining reference lists from numerous review articles, textbooks, and reports. Additionally, the literature on research on endogenous testosterone levels was assembled from online and published reference lists from major longitudinal studies of aging, such as the Massachusetts Male Aging Study and the Baltimore Longitudinal Study of Aging. The committee maintained its reference list in a searchable database that was indexed to allow searches by keyword and other criteria.

At the beginning of the study, the IOM staff, in conjunction with staff of the National Research Council Library, conducted a broad literature search of Medline and Embase to determine the scope of the literature on testosterone, and then a more narrowly defined search on Medline to identify clinical trials of testosterone therapy. For the latter Medline search, the search terms were testosterone and androgen replacement therapy or testosterone replacement therapy, and the publication type was limited to ran-



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Testosterone and Aging: Clinical Research Directions A Data Sources and Methods The committee reviewed and considered abroad array of information in its work on issues involving clinical trials of testosterone therapy. Information sources included the primary scientific literature, books and scientific reviews, and presentations from researchers, representatives from federal agencies, and the pharmaceutical industry. LITERATURE REVIEW In order to conduct a thorough review of the literature, the committee, Institute of Medicine (IOM) staff, and outside consultants conducted online bibliographic searches, primarily in Medline, in addition to examining reference lists from numerous review articles, textbooks, and reports. Additionally, the literature on research on endogenous testosterone levels was assembled from online and published reference lists from major longitudinal studies of aging, such as the Massachusetts Male Aging Study and the Baltimore Longitudinal Study of Aging. The committee maintained its reference list in a searchable database that was indexed to allow searches by keyword and other criteria. At the beginning of the study, the IOM staff, in conjunction with staff of the National Research Council Library, conducted a broad literature search of Medline and Embase to determine the scope of the literature on testosterone, and then a more narrowly defined search on Medline to identify clinical trials of testosterone therapy. For the latter Medline search, the search terms were testosterone and androgen replacement therapy or testosterone replacement therapy, and the publication type was limited to ran-

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Testosterone and Aging: Clinical Research Directions FIGURE A-1 Categorization of studies on testosterone therapy. domized controlled trials or clinical trials. In sorting through the results, it was useful to categorize the studies as shown in Figure A-1. The clinical trials of interest are those that are placebo-controlled and in which the participants were middle-aged or older men. As discussed in Chapter 2, the committee focused its review on the randomized placebo-controlled trials conducted in older men. A review of this literature was provided through a contract with Research Triangle Institute (RTI). RTI staff performed a Medline search using the key words testosterone and androgens. The search was limited to English language articles published between 1990 and 2003, and targeted to include placebo-controlled trials in older men. This search, which was last updated on May 1, 2003, yielded 285 abstracts. Additional references were identified by reviewing the reference lists of major review articles and relevant books and by references supplied by IOM staff. The most recently published systematic review by Gruenewald and Matsumoto (2003) was particularly helpful. In total, RTI

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Testosterone and Aging: Clinical Research Directions staff examined 441 abstracts or articles. To meet the criteria for inclusion in RTI’s literature review, the studies had to be placebo-controlled clinical trials of testosterone in middle-aged or older men with at least one clinical outcome of interest. The RTI review was based on 48 articles reporting the results of 39 trials.1 These included the trials of acute effects of testosterone through short-term administration of testosterone intravenously. The results of this work were then presented to the committee to be considered for use, where relevant, in the final drafting of the report. COMMITTEE MEETINGS AND WORKSHOP During the course of the study the committee received input from a number of individuals and organizations involved in areas related to testosterone therapy research. At the committee’s first meeting (January 2003, Washington, DC) the study objectives were outlined and the committee discussed its task with the director of the National Institute on Aging (NIA), Richard Hodes, and NIA staff members Judith Salerno, Evan Hadley, Stanley Slater, and Charles Hollingsworth. Additionally, presentations by Marc Blackman (National Institutes of Health) and Glenn Cunningham (Baylor University) provided information to the committee on the current state of knowledge regarding testosterone therapy and considerations involved in the design of the proposed ESTEEM (Efficacy and Safety of Testosterone in Elderly Men) trial. The committee held a scientific workshop in March 2003, in Phoenix, Arizona. The workshop was held at the same time as the annual meeting of the American Society of Andrology, and the committee benefited from the expertise of many of the society’s members. The workshop provided the committee with the opportunity to hear from many researchers in the field of testosterone therapy and to have discussions with them on issues related to clinical trials (see Box A-1 and Box A-2). During the May 2003 meeting of the committee, the committee had discussions with Andrew von Eschenbach, director of the National Cancer Institute; Donald Coffey (Johns Hopkins University), Alvin Matsumoto (University of Washington), and Glenn Cunningham (Baylor University). At its final meeting in July 2003, the committee finalized its conclusions and recommendations. During these meetings and throughout the course of the study, a number of people and organizations shared written material with the commit- 1   Chapter 2 focuses on 31 placebo-controlled trials in older men and does not include in its count the trials examining acute health effects that generally involved the one-time (usually intravenous) administration of testosterone (these trials are described in the text).

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Testosterone and Aging: Clinical Research Directions BOX A-1 Speakers and Participants Workshop on Clinical Trials of Testosterone Replacement Therapy in Older Men March 31, 2003 Phoenix, Arizona Shalender Bhasin, Charles Drew University Dennis Black, University of California, San Francisco Melanie Blanchard, Solvay Pharmaceuticals, Inc. William Bremner, University of Washington Matthew Casbon, Solvay Pharmaceuticals, Inc. Monique Cherrier, University of Washington Adrian Dobs, Johns Hopkins University Andy Fenchel, Edelman Evan Hadley, National Institute on Aging S. Mitchell Harman, Kronos Longevity Research Institute Dana Hilt, Ascend Therapeutics Jimmy Hinson, Solvay Pharmaceuticals, Inc. Charles Hollingsworth, National Institute on Aging Jeri Janowsky, Oregon Health and Science University Douglas Kamerow, Research Triangle Institute Alanna Keeley, Edelman Joseph Kelaghan, National Cancer Institute Jamie Kelly, Solvay Pharmaceuticals, Inc. tee. These materials were reviewed and considered with respect to the committee’s task and are available in the committee’s public access file maintained by the National Research Council’s Public Access Records Office.

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Testosterone and Aging: Clinical Research Directions Margaret Koster, Kaiser Permanente Hjalmar Lagast, Solvay Pharmaceuticals, Inc. Ricardo Maamari, Organon USA, Inc. Taylor Marcell, Kronos Institute Alvin Matsumoto, University of Washington Norm Mazer, Watson Laboratories, Inc. Wayne Meikle, University of Utah John Morley, St. Louis University Diane Mundt, Applied Epidemiology Ross Prentice, Fred Hutchinson Cancer Research Center Ron Robison, Solvay Pharmaceuticals, Inc. Kevin Rose, Solvay Pharmaceuticals, Inc. Ray Rosen, UMDNJ-Robert Wood Johnson Medical School William Rosner, Columbia University Woun Seo, Solvay Pharmaceuticals, Inc. Stanley Slater, National Institute on Aging Peter Snyder, University of Pennsylvania Ronald Swerdloff, University of California, Los Angeles Lisa Tenover, Emory University Donald Tindall, Mayo Medical School Russell Tracy, University of Vermont Christina Wang, University of California, Los Angeles Medical Center Claire Warga, Neuropsychologist Stephen Winters, University of Louisville REFERENCE Gruenewald DA, Matsumoto AM. 2003. Testosterone supplementation therapy for older men: potential benefits and risks. Journal of the American Geriatrics Society 51(1):101–115.

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Testosterone and Aging: Clinical Research Directions BOX A-2 March 31, 2003 Workshop on Clinical Trials of Testosterone Replacement Therapy in Older Men Phoenix, Arizona AGENDA 7:45–8:00 am Welcome   Dan Blazer, Committee Chair 8:00-9:30 Panel 1: Testosterone Levels and Aging   8:00 Testosterone Levels with Aging in Men   William Bremner, University of Washington   8:15 Correlation of Testosterone Changes and Clinical Outcomes   S. Mitchell Harman, Kronos Longevity Research Institute   8:30 Measuring Testosterone and Free Testosterone   William Rosner, Columbia University   8:45 Testosterone Levels and Aging: Future Research Directions   Stephen Winters, University of Louisville   9:00-9:30 Discussion, Moderated by Daniel Federman 9:35-11:10 Panel 2: Bone-Related Outcomes, Body Composition, and Strength   9:35 Bone-Related Outcomes in Testosterone Replacement Studies   Lisa Tenover, Emory University   9:50 Issues in Measuring Bone-Related Outcomes in Clinical Trials   Dennis Black, University of California, San Francisco   10:05 Body Composition and Strength: Issues in Testosterone Replacement Trials in Older Men   Shalender Bhasin, Charles R. Drew University

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Testosterone and Aging: Clinical Research Directions   10:25 Effects of Testosterone on Muscle and Bone: Future Research   Peter Snyder, University of Pennsylvania   10:40-11:10 Discussion, Moderated by Steve Heymsfield 11:10-11:25 Break   11:25-12:40 pm Panel 3: Prostate Outcomes 11:25 The Role of the Androgen Receptor in the Progression of Prostate Cancer   Donald Tindall, Mayo Medical School   11:40 Issues in Measuring and Monitoring Prostate-Related Outcomes in Clinical Trials   Alvin Matsumoto, University of Washington   11:55 Future Research Directions   John Morley, St. Louis University   12:10-12:40 Discussion, Moderated by Darracott Vaughan 12:40-1:30 Lunch   1:30-3:00 Panel 4: Cognitive, Sexual Function, Mood, and Quality of Life Outcomes   1:30 Biological Plausibility and Brain Targets for Androgens   Jeri Janowsky, Oregon Health and Science University   1:45 Androgen Effects on Cognition   Monique Cherrier, University of Washington   2:00 Sexual Function, Mood, and Quality of Life Outcomes in Testosterone Replacement Studies   Ronald Swerdloff, University of California, Los Angeles   2:15 Measurement of Sexual Function, Mood, and Quality of Life Endpoints in Older Men   Raymond Rosen, Robert Wood Johnson Medical School

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Testosterone and Aging: Clinical Research Directions 2:30-3:00 Discussion, Moderated by Leslie Schover 3:05-4:10 Panel 5: Hematologic and Cardiovascular Outcomes   3:05 Hematologic and Cardiovascular Outcomes in Testosterone Replacement Studies   Adrian Dobs, Johns Hopkins University   3:20 Testosterone, Inflammation, and Clotting   Russell Tracy, University of Vermont   3:35-4:10 Discussion, Moderated by Elizabeth Barrett-Connor 4:10-4:30 Break   4:30-5:15 Perspective from Studies of Postmenopausal Hormone Therapy   4:30 Ross Prentice, Fred Hutchinson Cancer Research Center   4:50-5:15 Discussion, Moderated by Steve Lagakos 5:15-6:15 Perspectives from the Pharmaceutical Industry   5:15 Extent and Nature of Testosterone Use   Kevin Rose, Solvay Pharmaceuticals, Inc.   Clinical Experience with AndroGel   Hjalmar Lagast, Solvay Pharmaceuticals, Inc.   5:45–6:15 Discussion, Moderated by Dan Blazer