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

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RISKS AND BENEFITS OF ESTROGEN PLUS PROGESTIN FIgure 2. Cumulative Dropout and Doop-in Rates by Randomization Assignment and Follow-up Duration Ioos . 0.1.)p10 0 25 620- 161 Prevalence of prior cardiovascular disease was low and levels of cardiovascular risk factors were consistent with a generally healthy population of postmenopausal women. An assessment of commonly studied breast cancer risk factors, both individually and combined using the Gail model," indicate that the cohort in general was not at increased risk of breast cancer. 05 Follow-up, Adherence, and Unblinding Vital status is known for 16025 ran- 0 2 3 4 01000 5 E 7 domized participants (96.5%), including 449 (2.7%) known to be deceased. Dropout Wef to 000e0 0h6 diron0liu.d study A total of 583 (3.5%) participants were -ediatiOn; d00p in, w10000 who disonti-ued study 0 t0r6010 and reslWved poto-n"p-al ho6000000 lost to follow-up or stopped providing through th1i0 00 00ni00. outcomes information for more than 18 Table 2. Clincal Outcomes by Randonizaton Assignment- No. of P0600t4 (Amnooaiwcd %) months. The remaining 15 576 (93.8%) provided recent outcome information (Figure 1). At the time of this report, all women had beent enrolled for at least 3.5 years, with an average follow-up of 5.2 years and a maximum of 8.5 years. A substantial number of women had stopped taking study drugs at some Lime (42% of estrogen plus progestin and 38% of placebo). Dropout rates over time (FIGURE 2) exceeded design projections, particularly early on, but compare favorably with community-based adherence to postmenopausal hormones." Some women in both groups initiated hormone use through their own clinician (6.2% in the estrogen plus progestin group and 10.7% in the placebo group cumulatively by the sixth Enfrogen. P00gesti. Plcebo Outicomes in . 8506) in =- 1021 Haaod Ratbo Noninal 95% CI Adjs-ted 95% CI Fo.o5-pptbte, o n(SD), nlo 62.2(16.1) 61.2(15.0) NA NA NA CarrsascuIo dteaoet CHD 164(0.37) 122(0.30) 1.29 1.021.6 085-197 CHD dradth 33 (0.07) 26 (0 06) 1.18 0.70-1.97 0.47-2.9d NonftalMI 133(030) 9685.23) 1.32 1031.72 0.82-2.13 CASG/FTCA 183(042) 1711041) 104 0.84 1.28 0.71-1.51 St0ok, 127(0.29) 89(0.21) 1.41 1.07-1.85 0.8-2.31 Falal 16 P04) 1310.031 I2 0.5S-2.50 0.-4.:S Nonfatal 94(0.21) 59(0.14) 1.50 1.082.08 03-2.70 Vreshroonb0oemicdoseoso 151 (0.34) 67)0.16) 2.11 1.58-2.82 1.26-3.55 D05poonih bonstOs 115(0026) 52)0.13) 207 1.492.87 1.14.374 PoFynonasoolbobrn 70(0.16) 31 (0.08) 2.13 1.39-3.25 0.99-4.56 Totalcaodblsascladasuso 54)(1.57) 546(1.32) 1.22 1.08 1.36 1.001.49 Cancer lnvosxa'beadst 1660).38) 124(0.30) 1.26 1.00 1.59 0.83-1.92 Endon rlnn) 22 (0.05) 25 (0.06) 0.83 0.47.1.47 0.29-2.32 Cobneslal 45)O10) 67)0.16) 0.63 0.43.0.92 0.32-1.24 Total Fractures 502(1.14) 458(1.11) 1.03 0.90.117 0e8-1.22 Ssi-p 44(010) 62(0.15) 066 0.450.98 0.33-1.33 Verlebll 41_ )009) 80p15) 0.66 0.44-098 0.32-134 Ollo~~r 0010011010501 579)1 31) ~ 701)(1.7)0 0.77 0.69-0.66 0.63-0.94 Tol01 650(1.47) 789(1.91) 0.76 069-0.85 0.3-0.892 Dooth Due tootho causos 165(0.37) 166(0.40) 0.92 0.74-1.14 0.62-1.35 T1tal 2310.52) 218)053) 098 082-1.18 0.70137 Global ind-§ 751(1.70) 023(1.51) 1.15 1.03-1.28 0.8951.39 'GI rdicolns 5r0d1 01 t0r04; NA. rr 0..t 0110. F C moro htwt 00. m- Ml. rryoardt 6040100. CA0G0 corwary en 00y o-00s pa PICAad PICA D.e= t10010 000 0 MI r0a0t1,14011 MIo') 0000098-100 101 sa.8 . 0nd00101400h. y cri Tr0tro 00 06 8 Mt .TO76 5 11000 t01106 tOhro .ococto3 k bd a3 trcWtrt oth.r Dan t0c-3M-. WV%. "-.est 1r-. end -W a~b-. attI ttipar hD itdvtntra rtts rt3; rr Pr.ts 10h00,bbaW 0 016 6055001 rI" eW lo fc2 0100 pauqhw.o Oooooono tm t.2-ing ft IyM! GHD. 99 s . n. b-h.0 19 40001 Id. ta 00"W c 50000 r0 Dtur=.00 and d000h don 100 -0600000 326 AiAJuly 17,2002-V1288. No. 3 (Rsponted) 02002 Amitencan Molttal As.,aclaoa All righNs r-ec-d. Downloadtd f-000 wwjfmaf.co0 at National I00titt0 orHlih on Aprl 16.2007
year). These 'drop-in" rates were also greater than expected. At the time of this report, clinic gynecologtsts had been unblinded to treatment assignment for 3444 women in the estrogen plus progestin group and 548 women in the placebo group, primarily to manage persistent vaginal bleeding. During the trial, 248 women in the estrogen plus progestin group and 183 in the placebo group had a hysterectomy. Intermediate Cardiovascular Disease End Points Blood lipid levels, assessed in an 8.6% subsample of fasting blood specimens collected from women at baseline and year 1, showed greater reductions in low-density lipoprotein cholesterol (-12.7%) and increases in highdensity lipoprotein cholesterol (7.3%) and triglycerides (6.9%) with estrogen plus progestin relative to placebo (data not shown), consistent with HERS and PEPl.iOa Systolic blood pressure was, on average, 1.0 mm Hg higher in women taking estrogen plus progestsi at I year, rising to 1.5 mm Hg at 2 years and beyond (data not shown). Diastolic blood pressures did not differ. Cbnal Outcomes Cardiovascular Disease. Overall CHD rates were low (TABLE 2). The rate of women experiencing CHD events was increased by 29% for women taking estrogen plus progestin relative to placebo (37 vs 30 per 10000 personyears), reaching nominal statistical significance (at the .05 level). Most of the excess wvas in nonfatal Ml. No significant differences were observed in CHD deaths or revascularization procedures (coronary artery bypass grafting or percutaneous transluminal coronary angioplasty). Stroke rates were also higher in women receiving estrogen plus progestin (41% increase; 29vs 21 per 10000 person-years), wvith most of the elevation occurring in nonfatal events. Women in the estrogen plus progestin group had 2-fold greater rates of venous thromboembotism (VTE), as well as DVT and PE individually, with almost all associated Cis excluding 1. P2002 Anicrim. itedical Associatio. Alt rights reserved. 162 RISKS AND BENEFITS OF ESTROGEN PLUS PROGESTIN Table 3. Cause of Death by Randoniation Assignment No lAasaaiiaed %) TOtSl deaths Estrogen raestUn (n . 8506) 231 (0.52) Placebo In = 81 02 218 (0.53) Adjuatcated deaths Cm2oeascutar Breastvaer 215 (045) 61 (0,15) as 3 (0.01) 201 (0,49) (0. 1 3) 2 (x0.01) otheivancer Othe, kincs se Unknown causo 104 (0.24) 34(0.08) (.002) 83 (0.21) 41 (0.10) 17 (0.04) Rates of VTE were 34 and 16 per 10000 person-years in the estrogen plus progestin and placebo groups, respectively. Total cardiovascular disease, including other events requiring hospitalization, was increased by 22% in the estrogen plus progestin group. Cancer. The invasive breast cancer rates in the placebo group were consistent with design expectations. The 26% increase (38 vs 30 per 10000 person-years) observed in the estrogen plus progestin group almost reached nominal statistical significance and, as noted herein, the weighted test statistic used for monitoring was highly significant. No significant difference was observed for in situ breast cancers. Follow-up rates for mammography were comparable in the estrogen plus progestin and placebo groups. Colorectal cancer rates were reduced by 37% (10 vs 16 per 10000 person-years), also reaching nominal statistical significance. Endometrial cancer incidence was not affected, nor was lung cancer incidence (54 vs 50; HR, 1.04; 95% Cl, 0.71-1.53) or total cancer incidence. Fractures. This cohort experienced low hip fracture rates (10 per 10000 person-years in the estrogen plus progesun group vs 15 per 10000 personyears in the placebo group). Estrogen plus progesin reduced the observed hip and clinical vertebral fracture rates by one third compared with placebo, both nominally significantly. The reductions in other osteoporotic fractures (23%) and total fractures (24%) were statistically significant (all associated Cis exclude 1). The global index showed a nominallysignificant 15% increase in the es- Dos-sloodet fine swr jasiarei at National Itoiitite of Hlhh on Apil 16, 2007 trogen plus progesuin group (170 vs 151 per 10000 person-years). There were no differences in mortality or cause of death between groups (TABLE 3). lime Trends The Kaplan Meier estimates of cumulative hazards (FIGURE 3) for CHD indicate that the difference between treatment groups began to develop soon after randomizatiuon. These curves provide little evidence of convergence through 6 years of follow-up. The cumulative hazards for stroke begin to diverge between I and 2 years after randomization, and this difference persists beyond the fifth year. For PE, the curves separate soon after randomization and show continuing adverse effects throughout the observation period. For breast cancer, the cumulative hazard functions are comparable through the first 4 years, at which point the curve for estrogen plus progestin begins to rise more rapidly than that for placebo, Curves for colorectal cancer show benefit beginning at 3 years, and curves for hip fracture show increasing cumulative benefit over time. The difference in hazard rates for the global index (FIGURE 4) suggests a gradual increase in adverse effects compared with benefits for estrogen plus progestin through year 5, with a possible narrowing of the difference by year 6; however, HR estimates tend to be unstable beyond 6 years after randomization. Total mortality rates are indistinguishable between estrogen plus progestin and placebo. Tests fortinear trends with time since randomization, based on a Cox proportional hazards model with a time- sntued) JAIA. .,ty 17. 20o2-V.1 280. N.. 3 327
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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
Page 113 and 114: 110 A controlled systematic pilot c
Page 115 and 116: 112 of set doses. The Wiley Protoco
Page 117 and 118: 114 I'd advocate for either Accredi
Page 119 and 120: 116 D.C., and established a goal to
Page 121 and 122: 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: ards analyses," stratified by clini
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 and 174: EFFECTS OF POSTMENOPAUSAL ESTIROGEN
Page 175 and 176: 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
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Page 213 and 214: 210 ,lmcCII na: CLI I tr: tarty ver
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212 ,mucmai rimi &ronos farty bstro
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214 LntIucwu miau: rronos nary estr
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XVI. PNharmacy Licensure Requiremen
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XVI. Pharmacy Licensure Requirement
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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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