Bioidentical Hormones - U.S. Senate Special Committee on Aging

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included when central adjudication has not yet been completed. Centrally adjudicated results are available for 95.7% ofCHDevents,92.4% ofstrokes, 91.8% of PE cases, 97.2% of breast cancers, 99.2% of colorectal cancers, 89.2% of hip fractures, and 80.3% of deaths. Detailed outcome definitions and methods for ascertaining, documenting, and classifying outcomes have been published." Cardiovascular Disease. Coronary heart disease was defined as acute Ml requiring overnight hospitalization, silent Ml determined from serial electrocardiograms obtained every 3 years, or death due to CHD. Stroke was defined as the rapid onset of a neurologic deficit lasting more than 24 hours, supported by imaging studies in most cases (89.8% had computed tomography/ magnetic resonance imaging IMRII studies available). Venous thromboembolism was defined as PE or DVT and required clinical symptoms supported by relevant diagnostic studies. Total cardiovascular disease events include CHD, stroke, VTE, angina requirinig hospitalization, coronary revascularization procedures, congestive heart failure, carotid anery disease, and peripheral vascular disease. Ct.s-i.. Als cancers other ttan nonmelanoma skin cancers were confinned by pathology reports, available for 98.2% of invasive breast, 95.0% of colorectal, and 80.6% of other cancers. Fractures. All reported clinical fractures other than those of the ribs, chest/ sternum, skull/face. lingers, toes, and cervical vertebrae were verified by review of radiology MRI, or operative reports. WHI investigators did not obtain spine radiographs to ascertain subclinical vertebral fractures. Global Index. A global index of risks and benefits was defined for each woman as the time to the first event among the monitored outcomes (CHD, stroke, PE, breast cancer, colorecial cancer, hip fractures, and death). " Statistical Power and Analyses The trial design assunied 12 375 women would need to be randomized to achieve 171 81% power to detect a 21% reduction in CHD ratesover the projected 9-year average follow-up. This sample size would provide 65% power to detect a 20% reduction in hip fracture rates. An additional 5 years of lollow-up without intervention was planned li achieve 79% power to detect a 22% increase in breast cancer risk.' Calculations based on the observed sample size and age distribution gave power estimates of 72%, 55%, and 71% for CHD, hip fracture, and breast cancer, respectivelyit Lack of adherence to study medication was summarized at each follow-up year as the cumulative proportion of randomized participants who had stopped taking study medications (dropouts) and similarly the proportion of women who began taking prescription menopausal hormones through their own health care practitioner (drop-ins), after excluding preceding deaths. Participants were classified by their most recent status with regard to study medications (stopped or not). Thus, women who temporarily stopped taking study medication were considered adherent its this analysis. Event rate comparisons were based on the intent-to-treat principle using faiiure time methods. F-or a given outcome, the time of event was defined to be the number of days from randomizattot to the first postrandomization diagnosis of the designated eveni For silent MIs, the date of the follow-up electrocardiogram was used as lie event date. Follow-up time was censored at the time of the last documented follow-up contact or death. Comparisons of primary outcomes are presented as hazard ratios (HRs) and 95% confidence intervals (Cls) from Cox proportional hazard analysesi stratified by age, prior disease, and randomization status in the low-lat diet trial. Cumulative hazard rates were esLimated by the Kaplan-Meier method for each designated outcome. Two forms of Cis were calculated, nominal and adjusted. This report primarily presents the nominal 95% CIs because they provide traditional esti- EFFECTS OF POSTMENOPAUSAL ESTROGEN mates of variability and, as such, are comparable to most other reports of hormone therapy studies. To acknowledge multiple testing issues, adjusted CIs were calculated using group sequential methods, and for secondary outcomes a Bonferrom correction based on the data and safety monitoring plan (see below). Because the trial was nearing the planned termination, the impact of the group sequential adjustmenit on the width of the Cis is small. The Bonferroni correction reflects the study design and trial monitoring piorites and hence may be somewhat less relevant for interpreting the trial results. Unless othervise indicated, all CIs and P values are nominal. Statistical analyses were performed using SAS version 9.0 (SAS Institute, Cary, NC) and significance was set at the .05 level. The possibility of important subgroup effects was explored by testing for interactions in expanded Cox models. Because 23 interactions are reported, chance alone could produce a significant interaction at the .05 lesel for approximately 1 factor in the series. Sensitivity analyses were conducted to explore the possible impact of lack of adherence to study medications. In these complier" analyses, the randomization assignment was preserved but follow-up for a woman was censored 6 months after she first became nonadherent (defined as taking
EFFECTS OF POSTMENOPAUSAL ESTROGEN considered if a disease-specific boundary was crossed and the global index 02as stupportive of the overall direction of CEE effects. Fortmal monitoring of disease rate comparisons began in the tall of 1997 with trial termination planned for March 2005. Additional aspects of the monitoring plan have been published." 172 RESULTS Trial Monitoring and Early Stopping In early 2000 and again in 2001. after reviewitg the data from the estrogenalone and the estrogen plus progestin trials, the DSMB recommended that participants in both trials be informed of early itcreases in rates of heart dis- Table 1. 6aseline Demographic and Clinicai Characterstis of the Womenis Health initative Estrogen-Alone Trial Paltidcpanls With Pripr Hysterectoiy (N = 10 739) by Randomization Assignnen(t CEE Plaetbo Chanacteistics In = 5310) (n . 5429) Ago at sonenN.l moan (SD) y 63 6 (7.3) 63,6 (7.3) Age group at sceen1ng. y, No .%) 50-69 1637(30.8) 1673(30.8) 60-69 2387 (45.0) 2435 (45.') 70-79 1286(24.2) 1291 (23.8) Rrcootshnslc No. (%) Whlto 4007 15.5) 4075(75.1) Black 782(14.7) 835(15.4) Hisp4nic 322(6.1) 333(6.1) A-,enan Indian 41 (0.8) 34 (0.6 As-loPaific Islander 86 ( .6) 78 (1.4) Unknow.t 72 (1.4) 74 (1.4) Homioo 0se, No. (16) Neove, 2769 (52.2) 2770 (51.1) Pas. 1871 (35.2) 1948 (35.9) Corbett 689(12.6) 708(130) Du0ati0n of pmor hpmonoe u, y, No. (%l)t
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S. HRG. 110-129 Bioidentica
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CONTENTS Page Opening Statement of
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2 The sale of bioidentical hormone
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4 ever, as Dr. Wartofsky points out
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6 with every stage of the disease:
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8 I am pleased to appear before thi
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10 When the trials began, many rese
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Women who began treatment more than
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14 One small trial using oral estra
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16 FDA is aware that a growing numb
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18 DEPARTMENT OF HEALTH & HUMAN SER
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20 safety and efficacy. However, as
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22 adulteration and misbranding pro
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24 The 2002 CPG reflects FDA's curr
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26 Equally concerning are claims by
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28 concerned about the use and mark
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30 Part I: Materials and Partnershi
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32 drugs, when the compounding of t
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34 Our staff identified 34 Web site
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1. Introduction 36 Chairman Kohl, R
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diet and fitness products. 5 For ex
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include "natural" progesterone crea
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42 unique to the computer age, such
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computer users to spam(ftuce.0ov -
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46 accuracy of advertising for heal
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48 Now, you have identified in your
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50 claim." Therefore, since the ter
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52 Such quality control problems ha
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54 Statement Before the U.S. <stron
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in the U.S., whereas WHI participan
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58 between science and hearsay and
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60 How can we determine whether bio
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62 doctors-are not getting the obje
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64 27. Writing Group for the PEPI T
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66 Dr. MANSON. Well, I think that m
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68 Statement of Leonard Wartofsky,
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70 in the WHI. In fact, no study as
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In summary, the Endocrine Society i
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74 The FDA also regulates aspects o
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Statement of Loyd V. Allen, Jr., Ph
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82 Senator SMITH. Dr. Allen, as I h
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84 Now, when you are talking about
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86 The only thing the WHI proved wa
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88 Testimony Of T.S. Wiley before t
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Confusion and Media Hype 90 Instead
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92 see a doctor tell a diabetic nea
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94 the only compelling reason to ta
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96 identical hormones synthesized f
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98 The world as we know it, from ba
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100 thereby experienced long period
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102 Bio-identical progesterone repl
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104 had reached optimum theoretical
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106 and the patient can be can reas
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108 Estradiol and Analytical Resear
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110 A controlled systematic pilot c
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112 of set doses. The Wiley Protoco
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114 I'd advocate for either Accredi
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116 D.C., and established a goal to
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118 If this legislation passes, fed
Page 123 and 124: first and second finger on the barr
Page 125 and 126: 122 These products that have been s
Page 127 and 128: 124 Bcl-2, survivin and variant CD4
Page 129 and 130: 126 These are experiments by other
Page 131 and 132: 128 cerebro-cellular inflammation c
Page 133 and 134: 130 Years # women *1>0.5 8 *1+ 9 *2
Page 135 and 136: *Breast cancer 132 -57 y.o. recurre
Page 137 and 138: 134 *Labor intense for patient and
Page 139 and 140: 136 Senator SMITH. Thank you very m
Page 141 and 142: 138 makes these hormones uniquely s
Page 143 and 144: 140 tomize the Wiley Protocol by ra
Page 145 and 146: 142 "natural," because all lead to
Page 147 and 148: 144 maceutical commerce, often with
Page 149 and 150: 146 WHITE PAPER #1 DID YOU KNOW THA
Page 151 and 152: 148 WHITE PAPER #2 Pharmacy Compoun
Page 153 and 154: 150 bleeding of the bowel, locate t
Page 155 and 156: 152 compounding standards can be en
Page 157 and 158: 154 I. The FDA's definition of a "N
Page 159 and 160: 156 ORIIGINAL CONTrMIBTION JANMA-EX
Page 161 and 162: Initially, the design allowed women
Page 163 and 164: ards analyses," stratified by clini
Page 165 and 166: year). These 'drop-in" rates were a
Page 167 and 168: years of prior use, 11 vs 2; HR, 4.
Page 169 and 170: trogen plus progestin exposure. Clo
Page 171 and 172: 168 RISKS AND BENEFITS OF ESTROGEN
Page 173: EFFECTS OF POSTMENOPAUSAL ESTIROGEN
Page 177 and 178: EFFECTS OF POSTMENOPAUSAL ESTROGEN
Page 179 and 180: pEyECTS OF POSTMENOPAUSAL ESTROGEN
Page 185 and 186: 10000 isoor i I ea '° a wan 20-24
Page 187 and 188: ~SDt~rpa g~2~Q ~ !~fm~. b~e ~ ng jh
Page 189 and 190: Is associated with an Increased ris
Page 191 and 192: 188 Postmenopausal hormone therapy
Page 193 and 194: group (P= 04001), and In this subgr
Page 195 and 196: Treatmnent recommendations Based on
Page 197 and 198: 21.Grodsteln F. Manson JE, Colditz
Page 199 and 200: _ ORWIGNAL CONTIuBUTION 196 Postmen
Page 201 and 202: showed no striking differences in H
Page 203 and 204: (214 cases; P for trend=.72): howev
Page 205 and 206: 202 HORMONE THERAPY USE AND RISK OF
Page 207 and 208: mal studies, and laboratory studies
Page 213 and 214: 210 ,lmcCII na: CLI I tr: tarty ver
Page 215 and 216: 212 ,mucmai rimi &ronos farty bstro
Page 217 and 218: 214 LntIucwu miau: rronos nary estr
Page 219 and 220: XVI. PNharmacy Licensure Requiremen
Page 221 and 222: XVI. Pharmacy Licensure Requirement
Page 223 and 224: 220 Roster of Board of Pharmacy Ece
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050. 0l7404405400 Al-h. PeVbU 03283
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Conclusions * Age is a powerful ris
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Women's Health Initiative Trials of
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Hormone Therapy after WHI * Change
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Statement of the American Pharmacis
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232 APhA Statement to the S
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240 Written Testimony of Steven F.
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242 STATEMENT OF DAVID G. ADAMS On
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244 Report on State Laws and Regula
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246 Only one state, Utah, requires
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248 5. Compounding Copies of FDA-Ap
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Bioidentical Hormones - U.S. Senate Special Committee on Aging

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