[Senate Hearing 110-129]
[From the U.S. Government Printing Office]

                                                        S. Hrg. 110-129
          Bioidentical Hormones: Sound Science or Bad Medicine 

                               before the

                       SPECIAL COMMITTEE ON AGING
                          UNITED STATES SENATE

                       ONE HUNDRED TENTH CONGRESS

                             FIRST SESSION


                             WASHINGTON, DC


                             April 19, 2007


                            Serial No. 110-5

         Printed for the use of the Special Committee on Aging

  Available via the World Wide Web: http://www.gpoaccess.gov/congress/

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                       SPECIAL COMMITTEE ON AGING

                     HERB KOHL, Wisconsin, Chairman
RON WYDEN, Oregon                    GORDON H. SMITH, Oregon
BLANCHE L. LINCOLN, Arkansas         RICHARD SHELBY, Alabama
EVAN BAYH, Indiana                   SUSAN COLLINS, Maine
THOMAS R. CARPER, Delaware           MEL MARTINEZ, Florida
BILL NELSON, Florida                 LARRY E. CRAIG, Idaho
KEN SALAZAR, Colorado                NORM COLEMAN, Minnesota
ROBERT P. CASEY, Jr., Pennsylvania   DAVID VITTER, Louisiana
CLAIRE McCASKILL, Missouri           BOB CORKER, Tennessee
SHELDON WHITEHOUSE, Rhode Island     ARLEN SPECTER, Pennsylvania
                      Julie Cohen, Staff Director
            Catherine Finley, Ranking Member Staff Director



                            C O N T E N T S

Opening Statement of Senator Gordon H. Smith.....................     1
Opening Statement of Senator Larry Craig.........................     3

                                Panel I

Jacques Rossouw, chief of the Women's Health Initiative Branch, 
  National Heart, Lung and Blood Institute, National Institutes 
  of Health, Bethesda, MD........................................     4
Steve Galson, director, Center for Drug Evaluation and Research, 
  Food and Drug Administration, Rockville, MD....................    15
Eileen Harrington, deputy director, Bureau of Consumer 
  Protection, Federal Trade Commission, Washington, DC...........    33

                                Panel II

JoAnn Manson, chief of Preventive Medicine, Brigham and Women's 
  Hospital, professor of Medicine, Harvard Medical School, 
  Boston, MA.....................................................    51
Leonard Wartofsky, president, The Endocrine Society, Chevy Chase, 
  MD.............................................................    66
Loyd Allen, editor-in-chief, International Journal of 
  Pharmaceutical Compounding, on behalf of The International 
  Academy of Compounding Pharmacists, Sugarland, TX..............    73
T.S. Wiley, writer/researcher, Creator of the Wiley Protocol, 
  Santa Barbara, CA..............................................    85


Responses to Senator Smith Questions from JoAnn Manson...........   141
Responses to Senator Smith Questions from Leonard Wartofsky......   142
Response to Senator McCaskill Question from Leonard Wartofsky....   143
Responses to Senator Smith Questions from Loyd Allen.............   144
White Paper submitted by Loyd Allen..............................   146
Additional Information submitted by National Institutes of Health   156
Statement of the American Pharmacists Association................   230
Written Testimony of Jane L. Murray, board chair, Women in 
  Balance........................................................   239
Written Testimony of Steven F. Hotze, MD.........................   240
Statement of David Adams, Venable LLP............................   242




                              ----------                              --

                        THURSDAY, APRIL 19, 2007

                                       U.S. Senate,
                                Special Committee on Aging,
                                                    Washington, DC.
    The Committee met, pursuant to notice, at 10:05 a.m., in 
room 526, Dirksen Senate Office Building, Hon. Gordon H. Smith 
    Present: Senators Smith and Craig.


    Senator Smith. Good morning, ladies and gentlemen. With the 
permission of the Chairman, Senator Kohl--he has asked us to 
    We thank you for attending today's hearing, ``Bioidentical 
Hormones: Sound Science or Bad Medicine?''
    As the title suggests, we are here today to closely examine 
the controversy surrounding the production and use of 
bioidentical hormones as an alternative to conventional hormone 
    The intent of this hearing is not to endorse one therapy 
over another. Rather, it is to ensure that the Federal 
Government is providing the information and oversight necessary 
so that consumers, women specifically, are able to make safe 
and well-informed decisions about their individual health-care 
    From my review, it seems that the Federal Government and 
medical practitioners are playing a guessing game with women's 
health in the prescribing of hormone therapies. Today's hearing 
reflects my belief that women deserve better. I hope to get 
some answers today regarding the state of the science and the 
Federal Government's oversight role in this arena.
    Over a decade ago, the National Institutes of Health set 
out to shed some light on the effect of hormone therapy on 
preventing heart disease in women through the largest research 
initiative ever undertaken of this kind: the Women's Health 
    When evidence indicated that the health risks of the 
therapies studied in the WHI exceeded the benefits, the study 
was prematurely ended, scaring thousands of women away from 
traditional hormone therapy.
    As an alternative, bioidentical hormones have become a 
popular and controversial option, not only for aging women, but 
for men and women of all ages seeking a route to the fountain 
of youth.
    The sale of bioidentical hormone products are on the rise 
and have been promoted by such distinguished actresses as 
Suzanne Somers and major marketing campaigns in doctors' 
offices, pharmacies and the Internet touting bioidenticals as 
natural and, thus, safer alternatives to traditional hormone 
    There has been much debate in the scientific community, 
however, as to whether the science exists to support these 
claims. By the end of this hearing, I hope to have a clear 
understanding of whether additional federally funded studies 
are needed to address concerns regarding the safety and 
efficacy of these products.
    Today, we will also address the regulatory issues relating 
to the manufacturing of these products, especially those that 
are custom-made or compounded in pharmacies.
    I am particularly troubled that compounded medications are 
not routinely tested and are not accompanied by warning labels 
and risk indicators that are required for traditionally 
manufactured medications.
    Further, there is a lack of information available to assist 
Congress in determining the proper roles of the Federal 
Government, the State Governments and the industry in 
regulating pharmacy compounding. That is why I have asked the 
Congressional Research Service to conduct a 50-State survey 
that will help me and my colleagues determine the best course 
of action going forward.
    Ultimately, the Federal Government must do a better job of 
empowering consumers to make informed decisions regarding 
hormone therapies and compounded medications. But the current 
regulatory framework is hazy and creating confusion between the 
Federal Trade Commission, the Food and Drug Administration, and 
State boards of pharmacy, regarding who has ultimate regulatory 
    I fear that lack of consistent and certain oversight has 
created an atmosphere ripe with opportunities for fraud and 
abuse. By the end of this hearing, I would like to have some 
confidence that the regulatory agencies are taking these issues 
seriously and have a concrete plan of action to address the 
committee's concerns.
    On our first panel this morning, I am pleased that NIH will 
be testifying for the first time before Congress regarding the 
latest findings in the Women's Health Initiative study. Also on 
the first panel will be the FDA and the FTC, who will speak 
about the agencies' enforcement efforts.
    Our second panel promises a lively discussion regarding the 
science of bioidentical hormones and the regulatory issues 
relating to pharmacy compounding. I look forward to that 
    With that, I will turn to my colleague, Senator Craig, from 


    Senator Craig. Well, to the Chairman and to you, the 
Ranking Member, let me thank you for bringing this hearing 
    I will ask unanimous consent that my full statement be a 
part of the record, Gordon. Let me say----
    Senator Smith. Without objection.
    Senator Craig [continuing]. Just one thing.
    One of the expectations, I believe, that Americans have of 
their Government is, in part, to keep them safe. This is 
especially true in a protection from pharmaceuticals whose 
potential negative side effects outweigh their potential 
benefits. Americans want to know they can take a drug that is 
prescribed by their physician with the knowledge that this drug 
will treat or cure what ails them.
    However, like all other governmental responsibilities, we 
must balance our obligation to protect with our responsibility 
to allow individual freedoms. That is a rather precarious 
balance at times that we especially try to achieve in the area 
of medicine, certainly in the area of pharmaceuticals.
    So--I keep wanting to say, Mr. Chairman. Senator Smith--
    Senator Smith. ``Senator'' works fine.
    Senator Craig. OK.
    That is why I think this hearing is important; that you 
come back to this issue, as you should, in an area where we may 
not be as aggressive or as responsible as we should be.
    Thank you.
    [The prepared statement of Senator Craig follows:]

               Prepared Statement of Senator Larry Craig

    Mr. Chairman, I know that we have a lot of witnesses that 
we want to hear from today, so I will be brief in my comments. 
First of all, I want to thank you for holding this hearing 
today. Bioidentical hormones are a part of the lives of many 
Americans and I think the questions surrounding them bear 
further examination. This hearing brings together a cross-
section of issues: individual freedom to choose alternative 
therapies vs. ensuring drug safety.
    One of the expectations that Americans have of their 
government is that we keep them safe. This includes protection 
from pharmaceuticals whose potential negative side effects 
outweigh their potential benefits. Americans want to know they 
can take a drug that is prescribed by their physician with the 
knowledge that this drug will treat or cure what ails them. 
However, like all other governmental responsibilities, we must 
balance our obligation to protect with our responsibility to 
allow individual freedom.
    Many Americans utilize various alternative drug therapies 
or dietary supplements as a significant part of their health 
care regimen. They want the freedom to have more control of 
their health and to utilize what they believe are more natural 
drug treatments. It is important that we do not eliminate that 
    As Congress, our challenge is to strike the proper balance 
between these responsibilities. We must ensure drug safety 
without infringing upon personal freedom and choice.
    When I first became aware of the concerns surrounding 
bioidentical hormones, my first inclination was to keep the 
government out of the issue. Women should have the freedom to 
choose natural treatments that may work better for them. 
However, as I have learned more about this issue a few items 
raised some red flags in my mind.
    Many Americans, and I suspect many American women, are 
aware of the results of the National Institutes of Health (NIH) 
Women's Health Initiative relating to hormone replacement 
therapy. Unfortunately, the general public does not fully 
understand the nuances of the findings. The story people heard 
was that hormone replacement therapy was bad for you. And as 
the witnesses will testify, there was a significant drop in the 
number of women using hormone replacement therapy. However, as 
Dr. Wartofsky points out, many women went straight to what they 
thought were natural alternative treatments. Many women are not 
fully aware of the differences, and more importantly, the 
similarities between bioidentical hormones, compounded 
hormones, and those hormones used in the Women's Health 
Initiative. It concerns me that women who think they are 
choosing a natural alternative may not have all of the facts.
    That is why this hearing is so important. Hopefully it will 
shed more light on compounded bioidentical hormones so that not 
just Congress, but consumers, are more educated about the 
products that are out there. With that said, I want to welcome 
our witnesses and I look forward to hearing from them.

    Senator Smith. Thank you, Senator Craig.
    Our first panel consists of Dr. Jacques Rossouw, who is the 
chief of the Women's Health Initiative branch of the National 
Heart, Lung and Blood Institute at NIH. Dr. Rossouw will 
discuss findings from the Women's Health Initiative and its 
implications for the current approach to hormone therapy.
    He will be followed by Dr. Steve Galson. He is the deputy 
director for the Center for Drug Evaluation and Research at 
FDA. We look forward to hearing about FDA's suggestions for 
legislative and regulatory initiatives.
    Eileen Harrington is the deputy director of the Bureau of 
Consumer Protection at the FTC. Ms. Harrington will discuss the 
FTC's enforcement efforts regarding online sales of hormone 
products. We look forward to hearing FDA's future plans for 
oversight in the area.
    So with that, Dr. Rossouw, take it away.


    Dr. Rossouw. I am pleased to appear before this----
    Senator Smith. Hit your button there on the microphone.
    Dr. Rossouw. Yes.
    I am pleased to appear before this committee. I am here to 
tell you about the Women's Health Initiative, which used 
conjugated equine estrogens. I will also briefly comment on 
other forms of estrogen therapy.
    Recall that, prior to 1990, the main use of hormone therapy 
in post-menopausal women was to treat the symptoms of menopause 
and prevent osteoporosis. During the 1990's, there was 
increasing use for prevention of coronary heart disease. In 
fact, that was the standard recommendation at that time.
    This recommendation was based on preceding observational 
studies indicating benefit for cardiovascular disease in 
particular in hormone users compared to nonusers.
    NIH felt that this recommendation was an example where the 
policy was exceeding the science basis and mounted the Women's 
Health Initiative to test the very hormones--conjugated equine 
estrogens and medroxyprogesterone--which were suggested to be 
associated with benefit in preceding observational studies.
    The expectation was that we would show benefit for hormone 
therapy--either estrogen alone or in combination with a 
progestin. What we found was that the estrogen alone and the 
estrogen with progestin did not protect against coronary heart 
    In fact, for the combination therapy, the trial was stopped 
early because of an excess risk of breast cancer and heart 
disease and stroke and blood clots. These harms exceeded any 
potential benefits.
    The estrogen-only trial was also stopped prematurely 
because of an increased risk of stroke and no benefit for the 
primary outcome of coronary heart disease.
    As a result of these findings, the prescriptions for 
hormone therapy dropped by about 60 percent after 2002.
    Now, because the primary findings were what they were--in a 
negative direction--certain questions then arose which would 
not have arisen if the findings had been as expected: that is, 
of benefit for coronary heart disease. But because there was no 
benefit, these secondary questions gained importance.
    First of all, would the result have been different if the 
hormone therapy had been started at an earlier age, closer to 
the menopause? In the Women's Health Initiative, the age range 
was 50 to 79 because those are the women to whom hormone 
therapy was being prescribed for prevention of coronary heart 
disease. So that is what we tested. Would it have been 
different if most of the women had been closer to the 
menopause? First question.
    Second question, would the result have been different and 
more beneficial if we had used a different kind of estrogen, 
such as estradiol, the estrogen produced by the human body?
    So I want to get straight to the heart of the matter, if I 
may--pun intended--and direct your attention within your packet 
to these posters here, because to understand these questions 
one has to know a little bit about the science.
    Atherosclerosis, which is the precursor of heart attacks 
and stroke, is an age-related disease. You can divide it into 
stages. Of course, that is artificial. I mean, it is a 
continuum. But for the purposes of understanding this, I have 
divided it into some stages.
    There is the initiation phase, which occurs in the young 
adult. This is a process that involves the lining of the 
artery, the endothelium, and it then leads to fatty streaks.
    At middle age, there is the increasing prevalence of raised 
lesions--progression to raised lesions.
    From then onwards into old age, there is an increasing 
prevalence of complicated lesions, some of which will 
eventually rupture or erode, and a blood clot will form. This 
leads to the heart attack or stroke.
    Now, these are age-related changes. Some of it is due 
directly to the aging of the arteries. Some of it is due to the 
increasing prevalence of risk factors, such as high blood 
pressure and high blood cholesterol as people age.
    Now, we cannot stop aging. We haven't figured out how to do 
that. But we can treat the risk factors.
    That is what we mean by ``prevention.'' You are not 
preventing age, but you are treating the risk factors 
associated with age, and thereby you are preventing the 
complications of age. Or, you are not preventing them totally, 
but you are decreasing them.
    So one example of such a prevention is lowering of the high 
blood cholesterol--lipid lowering. I will use the example of 
statins because there is an awful lot of data on statins. 
Statins will interfere with every stage of the disease: from 
the initiation, to the progression, to the treatment of the 
complications--that is, people who have already had heart 
    Statins are effective at every stage, OK? So, therefore, 
one can assume that if you start statins at a young age and 
continue them lifelong, they will continue to have benefit. 
That is an assumption because that trial is not feasible, as it 
is also not feasible to do a really long-term lifelong trial of 
hormone therapy.
    So statins represent a favorable or an acceptable 
prevention strategy. There are no known long-term 
    The situation is different with estrogens, be they 
Premarin, conjugated estrogens or estradiol.
    There is increasing evidence that estrogens, generally, may 
retard the earliest stages, the initiation, of atherosclerosis. 
There will be more evidence in the next coming years that may 
or may not be consistent with that idea. But at the moment 
there is reasonably good evidence that that is the case, 
including from the Women's Health Initiative, the recent 
    However, once there are established raised lesions, 
established atherosclerosis, there is good evidence that 
estrogen in any form, be it conjugated estrogens or estradiol, 
does not prevent further progression. There is also good 
evidence that once there are complicated lesions, estrogens 
actually trigger events and make matters worse.
    So estrogens do not represent a good prevention strategy. 
We cannot assume that if you start it early, and there is 
potential benefit, that that benefit will persist into older 
    Again, that is an assumption. We cannot do that trial. But 
knowing what we know, that would be a very far stretch of the 
imagination to imagine that if you start it early and use the 
right estrogen, you will get a different outcome than we found 
in the Women's Health Initiative.
    So, again, we don't think that there is any essential 
difference between estradiol and conjugated equine estrogen as 
far as heart disease is concerned. We don't believe that this 
window of opportunity is anything but a window into the 
present. There is a reasonably safe period to use hormone 
therapy close to the menopause, but it is not necessarily a 
window into the future if you start then and persist that that 
benefit will persist.
    With that, I will close and thank the committee for 
addressing them on this very important issue to women's health. 
I am happy to entertain questions.
    [The prepared statement of Dr. Rossouw follows:]

    Senator Smith. Thank you, Doctor.
    Steve Galson.


    Dr. Galson. Thank you. Mr. Chairman and members of the 
committee, I am Dr. Steven Galson----
    Senator Smith. You need to hit your microphone.
    Dr. Galson. OK. I am Dr. Steven Galson. I am the director 
of the Center for Drug Evaluation and Research at FDA, and a 
Rear Admiral and Assistant Surgeon General in the United States 
Public Health Service.
    I am really very pleased to be here to discuss FDA's role 
regarding the compounding of so-called bioidentical hormone 
    FDA has increasingly seen these products prepared and 
marketed by pharmacists as part of a practice called drug 
compounding. FDA regards traditional drug compounding as 
combining or altering of ingredients by a pharmacist in 
response to a licensed practitioner's prescription, which 
produces a medication tailored to an individual patient's 
    Traditional pharmacy compounding enhances patient treatment 
with individually tailored drugs when a health-care provider 
decides that an FDA-approved drug is not appropriate for that 
particular patient's care.
    Traditional compounding may involve reformulating a drug, 
for example, by removing a dye or preservative in response to a 
patient allergy. Or it may involve making a suspension or a 
suppository form for a child or an elderly patient who has 
difficulty swallowing a tablet.
    Sometimes, however, the risks associated with compounded 
drugs outweigh their benefits. Improper compounding has caused 
patient harm and death.
    Although many pharmacists are well-trained and well-
equipped to compound certain medications safely, not all 
pharmacists have the same level of skill and equipment, and 
some products may not be appropriate in the first place for 
pharmacy compounding.
    In addition, compounding large volumes of standardized 
drugs and copying FDA-approved drugs circumvents important 
public health requirements. These practices undermine the drug 
approval process, which is the evidence-based system of drug 
review that consumers and health professionals rely on for safe 
and effective drugs.
    My written statement that you have describes FDA's 
statutory and regulatory authority over compounded drugs. FDA 
has regulated compounded drugs consistent with its Compliance 
Policy Guide on pharmacy compounding, or CPG.
    This CPG explains that FDA generally exercises enforcement 
discretion toward traditional compounding. But when a 
pharmacy's activities raise concerns normally associated with 
the drug's manufacture and result in significant violations of 
the Food, Drug and Cosmetic Act, FDA considers enforcement 
action. The CPG identifies some of the factors that FDA 
evaluates in deciding when and how to act.
    FDA is aware that a growing number of pharmacists compound 
hormone products for treatment of symptoms of menopause. These 
pharmacists often promote their products as so-called 
bioidentical to the hormones produced by a woman's body. The 
phrase ``bioidentical hormone replacement therapy,'' or BHRT, 
has been used to describe these products.
    Compounded BHRT products typically contain various forms of 
estrogen and progesterone and, in some cases, testosterone and 
    Some compounding pharmacists claim that their BHRT products 
are a ``natural alternative'' to FDA-approved drugs because the 
compounded hormones are identical to the hormones produced in 
the body. These pharmacists may also claim that their natural 
compounded products are safer and more effective than FDA-
approved hormone replacement drugs.
    FDA is not aware of any credible scientific evidence 
supporting these claims. Nor is FDA aware of sound evidence 
showing that the side effects or risks of compounded BHRT 
products are different than those of FDA-approved hormone 
replacement drugs.
    Because many claims regarding the safety, efficacy and 
superiority of compounded BHRT products have not been 
substantiated, FDA is concerned that they mislead patients and 
    In 2003, FDA began a focused public awareness campaign 
about the risks and benefits of hormone therapy for indications 
including the symptoms of menopause. This outreach campaign has 
two parts.
    Part one included the development of partnerships and 
educational materials. In implementing this, FDA's Office of 
Women's Health formed a working group that included members 
from NIH, the Agency for Healthcare Research and Quality, and 
25 women's health and professional organizations.
    The working groups identified a target audience, women aged 
40 through 59, and developed core messages, such as ``Get 
informed'' and ``What can you believe?'' The working groups 
supplemented these messages with campaign materials and 
strategies for disseminating key information.
    Part two was a national media outreach effort. Campaign 
materials developed in part one were publicized through the 
media and community outreach, Internet, and print advertising 
and direct e-mail. The materials developed as part of this 
campaign continue to be requested and distributed, and are 
available on our Web site.
    FDA has not focused only on compounded BHRT drugs. Hormone 
replacement therapy products are also marketed as over-the-
counter drugs and dietary supplements, often on television and 
on the Internet.
    In the fall of 2005, the FDA worked with FTC to address the 
marketing of unapproved hormone replacement products. FDA sent 
warning letters to 16 dietary supplement and hormone cream 
marketers who were making unproven claims that their 
``alternative hormone replacement therapy'' products were 
useful in treating or preventing cancer, heart disease, 
osteoporosis and other serious diseases.
    In closing, I assure you that FDA is aware of and attentive 
to the many concerned voices about hormone replacement therapy 
products, including compounded so-called bioidentical drugs. As 
these products have become increasingly prevalent, so has our 
attention to them.
    I am happy to answer your questions.
    [The prepared statement of Dr. Galson follows:]


    Senator Smith. Thank you very much.
    Dr. Galson. Thank you.
    Senator Smith. Eileen Harrington.


    Ms. Harrington. Good morning, Ranking Member Smith. I am 
Eileen Harrington, the deputy director of the FTC's Bureau of 
Consumer Protection.
    The commission's written testimony has been submitted for 
the record. My oral statement and answers to any questions you 
may have represent my views.
    You have asked us to discuss the FTC's efforts to address 
the misleading online advertising of alternatives to hormone 
replacement therapy, as well as our work to combat all types of 
Internet fraud.
    Among its many benefits, the Internet provides consumers 
with access to a vast array of information and products, 
including health-related items. Unfortunately, it also provides 
an opportunity for irresponsible marketers to prey on 
consumers, making false or misleading claims, causing economic 
injury, and posing potentially serious consequences for 
consumers' health.
    For over a decade, the FTC has been on the forefront of 
efforts to protect consumers from online fraud. In doing this, 
we use a three-pronged strategy.
    First, we take law enforcement action to stop deceptive 
practices and obtain redress for victims of fraudulent schemes.
    Second, we conduct consumer education campaigns, often in 
partnership with colleagues like the FDA, to help consumers 
spot and avoid online scams in the first instance.
    Third, we educate businesses to help them comply with the 
law and avoid engaging in deceptive practices.
    The FTC's work to address deceptive online health and 
safety claims exemplifies our use of this strategy. We have 
aggressively enforced the law, bringing 229 enforcement actions 
challenging online false and misleading health and safety 
claims for products ranging from weight-loss pills to cancer 
    For example, last November, following a fierce trial, the 
FTC won a Federal court order requiring the sellers of the Q-
Ray Bracelet to refund up to $87 million to consumers who had 
purchased the product based on false claims that the bracelets 
would significantly reduce their pain.
    On the consumer education front, the FTC provides consumers 
with useful, creative and timely information to help them avoid 
falling victim to false claims for everything from cure-alls to 
diet and fitness products. We provide all of these materials on 
our Web site. We spread the word offline, as well, often 
partnering with private- and public-sector organizations to 
distribute publications and our messages.
    Our efforts involving alternative HRT products are a good 
example of our use of the third prong of our strategy: 
educating business about their legal responsibilities.
    Our staff identified 34 Web sites with claims that 
alternative natural progesterone creams and sprays were safe or 
would prevent, treat or cure serious cancer, heart disease or 
osteoporosis. We sent a warning e-mail to each of those site 
operators; the e-mails putting them on notice that they must 
have substantiation for any health claims that they make about 
their products and urging them to review their product claims 
to make sure they complied with the law.
    Our staff recently conducted a follow-up review of those 
Web sites and has continued working with companies to clean up 
their claims. Fifteen of the 34 Web sites have either removed 
the claims or no longer sell the products.
    As I said, we are continuing to follow up directly with the 
remaining sites, and our staff will be making appropriate 
enforcement recommendations about those that do not comply with 
the law.
    The FTC's efforts to halt deceptive health-related claims 
online are part of its larger program to combat Internet fraud. 
Since 1994, the FTC has launched 538 law enforcement actions, 
garnering nearly $1 billion in judgments against those who have 
used the Internet to prey upon American consumers.
    Online deception generally falls into two categories: old-
fashioned schemes that have simply migrated online and new 
high-tech schemes that are unique to the computer age.
    Spam presents a hybrid of the two. Spammers use low-cost 
new technology e-mails to carpet consumers with old-fashioned 
deceptive claims about everything from miracle cures to bogus 
investment opportunities.
    The FTC has pounded the pavement on the spam beat for over 
a decade. Since 1994, we have litigated 89 actions against 241 
defendants in which spam was an integral element of the scheme, 
and 26 of those cases use the relatively new Can Spam Act.
    As technology and scams change over time, the FTC continues 
to shift its resources and adjust its priorities, targeting 
those frauds that cause the most harm to consumers.
    False and misleading claims that affect consumers' health 
and safety are prime targets, and they will remain prime 
targets, of the FTC's enforcement efforts. We will continue our 
efforts to ensure the truthfulness and accuracy of advertising 
for health-related products, regardless of the medium in which 
those ads appear.
    Thank you, again, for inviting us. I am happy to answer 
your questions.
    [The prepared statement of Ms. Harrington follows:]

    Senator Smith. Thank you very much, Eileen.
    Ladies and gentlemen, I am holding in my hand a jar called 
Products of Nature Natural Woman Progesterone Cream.
    Dr. Rossouw, my staff purchased this on the Internet just a 
few days ago. It comes with certain claims, specifically that, 
if applied topically, it will greatly decrease a woman's risk 
of breast cancer; that women who have previously had breast 
cancer will have little or no reoccurrence if using natural 
progesterone cream.
    In your scientific opinion, are there any studies that 
would support such claims?
    Dr. Rossouw. No. There are no studies that support such a 
claim. I would make two further points.
    First, that, you know, the dichotomy between natural and 
synthetic--which this kind of product plays on--appeals to an 
idea amongst the public that natural is somehow better than 
    From the scientific standpoint, there are either drugs that 
work and are safe or drugs that don't work or are not safe. 
Their origin is quite irrelevant, firstly.
    Second, if you look at the risk factors for breast cancer 
epidemiologically, they are all related to the levels and 
duration of exposure to the natural human hormones estradiol 
and progesterone, such as the earlier the onset of the menarche 
or the later the delay in the menopause; with longer exposure 
the greater the risk of breast cancer.
    So I think the evidence would be, though inferential, to 
the contrary. There is no evidence that progesterone prevents 
breast cancer. I suspect that, in combination with estrogen, it 
probably increases the risk.
    Senator Smith. It increases the risk.
    Dr. Rossouw. From what we know, the likelihood is that it 
increases the risk.
    Senator Smith. Topically applied, I mean, does that--there 
is no value----
    Dr. Rossouw. Well, there is a question of how much is 
absorbed. My colleague from the FDA can address that. But if it 
is absorbed, and a woman has circulating estradiol, then I 
would not regard this as a favorable scenario.
    Senator Smith. You know, on the Western frontier, they had 
a lot of snake oil salesmen. Do we have that in the 21st 
century, if those claims are being made?
    Dr. Rossouw. Well, I would just go so far as to say that 
these claims are unsubstantiated.
    Senator Smith. Ms. Harrington, I am wondering why my staff 
was able to purchase this on the Internet off a Web site that 
was one of 34 companies that you sent warnings to in November 
of 2005.
    Two weeks ago, this company was still in business. As far 
as I know, they still are. As far as I know, this is still--I 
could get it today, or a woman could get it today if she sought 
    Of the 34 companies that received warnings from the FTC in 
2005, 32 of them still had Web sites up and running as of 2 
weeks ago.
    Now, you have identified in your testimony that 19 of these 
sites are still selling hormone products that make 
unsubstantiated health-related claims.
    I guess what I am asking is, what revisions is the FTC 
going to be making to enforce its policies to ensure that this 
type of egregious enforcement lapse does not reoccur?
    Ms. Harrington. Senator, we, as I said, will be receiving 
enforcement recommendations on companies that are not in 
compliance. I can't say, in a public setting, precisely when 
and what the nature of those will be.
    I think we could have moved faster here, and we should 
    Senator Smith. Well, I don't mean any personal 
embarrassment to you. But, I mean, I am just saying that, in 
this senator's opinion, the American people are owed better by 
the FTC than what the evidence shows by my staff's being able 
to buy this with these kind of claims on the Internet; 
something that may be harmless, it may be dangerous, but it is 
unproven and ought not to be out there as modern-day snake oil.
    Ms. Harrington. Point well-taken, Senator.
    Senator Smith. After the early termination of the Women's 
Health Initiative study, the FDA issued a black box warning 
indicating that estrogens with or without progestin should be 
prescribed at the lowest effective doses for the shortest 
    However, it is my understanding that when the FDA issued 
the guidance, there were no studies indicating at what dose 
women faced the lowest risk of serious side effects. It seems 
to me that the Federal Government is playing a guessing game 
with women's health, and I think they deserve better.
    So, Dr. Rossouw and Dr. Galson, without studies indicating 
at precisely what dose women will see less risk of serious side 
effects, why did the FDA take such an extreme position?
    Dr. Galson. Well, let me make a few points.
    The first is that, with any area where there is a lot of 
scientific information, the data available to physicians and 
patients changes month by month with more publications by Dr. 
Rossouw's group and others around the country. The challenge we 
have at FDA is interpreting this information, deciding which of 
that information warrants changing the instructions to patients 
and physicians.
    At any one moment, when we are convening, when we get 
together at advisory committees, and we meet internally and we 
make a decision about how to change a label and change the 
instructions, we base it on the best information that we have 
available at that moment.
    We are aware, as we were when we most recently changed the 
labeling, that there are many ongoing studies on hormone 
products. So we anticipate continuing to make changes in these 
instructions. But at the point which we put on those warnings, 
that was the best information we had.
    We do know that the news is not all bad. There are some 
women, at some times in their life, depending on their 
symptoms, who may benefit from short courses of these hormones. 
It wouldn't be right for us to completely shut the door and say 
they are never indicated, never appropriate.
    Senator Smith. So that brings me to the obvious question: 
Should the FDA then require black box warnings for compounded 
products containing hormones?
    Dr. Galson. The issue there and, you know----
    Senator Smith. There are none now.
    Dr. Galson. We really share your concern about this. One of 
our major problems with compounded products, be they 
prescription compounded products or over-the-counter hormone 
products, is that they don't contain the same sort of 
comprehensive labeling that FDA-approved products have.
    For example, the information available on the Web site for 
the product you mentioned--although I haven't looked at it 
personally, I can see it up there--and other products just 
doesn't match what we think the state of the science indicates 
patients and physicians should have.
    So we share your concern about that.
    Senator Smith. Well, it needs to match.
    It is my understanding that when asked by my staff for a 
full written accounting and summary of enforcement actions 
taken against compounding pharmacies in general, and 
bioidentical products in particular, the FDA proffered a mere 
three examples of enforcement activity.
    Specifically, (1) was a 2001 limited survey of compounded 
drugs; (2) 16 warning letters issued in 2005; and (3) an 
assertion that the FDA may inspect a pharmacy on a for-cause 
    Given that, by your own policy, compounded pharmaceutical 
products are unapproved new drugs subject to enforcement under 
the Food Drug and Cosmetic Act, why has the agency done so 
little to regulate this industry and to protect consumers from 
bad actors?
    Dr. Galson. As you know, there are tens of thousands of 
these pharmacies, and we have a lot of other compliance 
activities that are going on throughout the agency not related 
to compounded drugs. So, at any one moment, we have to balance 
the resources that we have available with the largest risks to 
public health.
    We have taken regular action against compounded pharmacies. 
Sure, you can argue that we should do more. We have to, at any 
moment, balance what we can do with the information out there.
    We do think it is important to continue to take these 
compliance actions, and we are going to do that.
    Senator Smith. Well, I know you are under a lot of pressure 
from a lot of different angles. I am just simply aware in the 
press and best-selling books out there now, a lot of things are 
being pushed right now that really do demand, I believe, a more 
vigorous response from the FDA.
    I am very troubled by the thousands of Web sites touting 
bioidentical products as natural and safe, in light of the fact 
that there is no regulation regarding the term 
``bioidentical.'' What precisely that term means, I don't know. 
I don't know that there is a definition out there. I think 
there needs to be one. Medical doctors have one definition, yet 
marketers use the term in a myriad of ways.
    The FDA has indicated to my staff that, ``The term 
'bioidentical' has no defined meaning in any medical or 
conventional dictionary and is not accepted by the agency as a 
substantiated labeling claim.'' Therefore, since the term 
``bioidentical'' has become commonplace in the industry, 
shouldn't the FDA develop guidance with respect to the term 
that could be used both on over-the-counter and prescription 
products? Is there any effort to do that, to define this?
    Dr. Galson. The term, you are correct, does not mean 
anything to us.
    I was just talking to Dr. Rossouw before the hearing got 
started about the fact that in my remarks I was very careful to 
say ``so-called bioidentical'' hormones. Dr. Rossouw didn't 
mention the term at all.
    We hate this term. We don't think it means anything. We are 
not sure that it should mean anything.
    It implies, by the very words ``identical'' and ``bio,'' 
that it is something that patients should like and should use. 
We just don't think--we think these are drugs, and they deserve 
warning labels like the drugs that we approve.
    Senator Smith. So you have a problem with all the Web sites 
out there using this term that holds out medical promise and 
    Dr. Galson. I certainly do.
    Senator Smith. I certainly hope that the FDA will define 
the term ``bioidentical'' or at least repudiate it; and that 
then the FTC will do its part in getting these Web sites down. 
It just shouldn't be happening in this day and age.
    Do you have any comment about the term ``bioidentical,'' 
Dr. Rossouw?
    Dr. Rossouw. Except to agree with my colleague. It is not a 
medical term. It is a marketing term.
    Senator Smith. Yes. That is the same kind of marketing they 
used to do in the 19th century.
    Let me thank you all. This is, I am sure, not pleasant for 
you, but it is important to the American people that we 
highlight what is out there and that they not just be told, 
``Buyer beware,'' because we are dealing with people's health 
    So, please regard this hearing as done in the spirit of 
trying to get information out there so that people aren't just 
told to beware, that they actually have the opportunity to buy 
products that have health benefits to them and are not scammed 
by things that may actually be harmful to their health.
    So, with that, I thank you for your attendance.
    We will call up our next panel.
    On our second panel, we are pleased to welcome medical 
experts and industry representatives to further outline these 
    Our first witness will be Dr. JoAnn Manson, who is the 
Chief of preventive medicine at Brigham and Women's Hospital in 
Boston. She is also the Elizabeth F. Brigham professor of 
Women's Health and professor of Medicine at Harvard Medical 
School. Dr. Manson is a recognized medical expert in hormone 
therapy and has published a substantial body of work on the 
topic; and has recently served as a medical consultant for the 
``Today'' show.
    That is why I recognize you.
    She will be followed by Dr. Leonard Wartofsky, who is the 
chairman of the Washington Hospital Center's Department of 
Medicine and is the president of the Endocrine Society, an 
internationally recognized association of 11,000 members from 
over 80 countries.
    He will be followed by Dr. Loyd Allen. He is here 
representing the International Academy of Compounding 
Pharmacists. Dr. Allen also serves as the editor-in-chief of 
the International Journal of Pharmaceutical Compounding, among 
several other pharmacy-related posts.
    Our final witness will be T.S. Wiley, who is a researcher, 
published author, creator of the Wiley Protocol, a bioidentical 
hormone regimen that she has developed for women seeking an 
alternative to conventional hormone therapy.
    Dr. Manson, we will start with you.

                   MEDICAL SCHOOL, BOSTON, MA

    Dr. Manson. Thank you.
    Ranking Member Senator Smith, thank you for the opportunity 
to speak to you today about bioidentical and custom-compounded 
    Because of the risks of conventional hormone therapy that 
you have heard about, identified by the Women's Health 
Initiative, including stroke, venous blood clots, breast 
cancer, and other health problems, there has been a growing 
interest in bioidentical and custom-compounded hormones as 
potentially safer alternatives.
    The key question is: Are these products indeed safer or 
more effective than conventional hormone therapy, as proponents 
of these treatments claim?
    Unfortunately, there is little evidence, as you have heard, 
to support this assertion. Moreover, women are not getting 
accurate and unbiased information to help them make an informed 
choice about the use of these hormones.
    In addition, what is the rationale for a different policy 
about FDA regulation of bioidentical hormones when they are 
manufactured en masse and sold by retail pharmacies, where 
there is full FDA regulation, and not for bioidentical products 
that are custom-compounded by pharmacists? There is no clear 
rationale for a difference in regulation.
    Advocates of bioidentical hormones, particularly custom-
compounded ones, assert that these products are more effective 
at relieving menopause symptoms, have fewer side effects, and 
offer a better balance of long-term health benefits and risks 
than other hormone options.
    However, the truth is, we simply don't know that these 
claims are valid. Large-scale, scientifically rigorous studies 
of bioidentical hormones have not been conducted.
    Until we have solid data to indicate otherwise, virtually 
all medical authorities and professional societies agree that a 
conservative and prudent approach is to assume that all hormone 
formulations confer a similar balance of benefits and risks.
    The following are specific concerns about custom-compounded 
hormones due to their lack of FDA oversight.
    As you have heard, quality control is problematic. 
Preparation methods can differ from one pharmacy or pharmacist 
to another, so patients may not receive consistent amounts of 
hormones. In addition, inactive ingredients vary, and 
contaminants may be present.
    Such quality control problems have been demonstrated by a 
government study in 2001. The government purchased and tested 
29 products, including hormone preparations from 12 compounding 
pharmacies, and found that 34 percent of the samples failed one 
or more standard quality tests. Ninety percent of the failing 
samples contained less of the active ingredient than 
    In contrast to this 34 percent failure rate, the failure 
rate for FDA-approved drug therapies was less than 2 percent.
    Another problem is that the value of saliva or blood 
testing of hormone levels to guide dose adjustments for these 
hormones is unsubstantiated.
    Before custom-compounded hormones are prescribed, a saliva 
or blood test is often performed to measure a woman's natural 
hormone levels. The belief is that the test can guide the dose 
of hormones to prescribe.
    However, the value of these tests is highly questionable 
and not supported by scientific evidence. Hormone levels 
fluctuate throughout the day, as well as from day to day, and 
these levels are not clearly linked to severity of menopausal 
symptoms or to the dose of hormones needed to control symptoms.
    Expense and cost are also important issues. Many custom-
compounded hormone products, as well as the associated blood or 
saliva testing, which must be done every few weeks or months 
until hormones are ``balanced,'' are expensive and not covered 
by health insurance.
    Some women's out-of-pocket costs, which can add up to 
thousands of dollars per year, tend to be higher with custom-
compounded hormones than with bioidentical hormones or other 
hormones that are covered by health insurance--the traditional 
hormone therapy.
    Consumers lack reliable product information and can fall 
prey to misleading advertising claims. Unlike retail pharmacy 
prescriptions, compounded products are not required to have a 
warning package insert with information about benefits and 
risks, and as you have heard, do not have a black-box warning 
and are subject to fewer checks on their advertising claims.
    Some women may request bioidentical or custom-compounded 
hormones because they are misled by the following claims often 
made by their proponents.
    One claim is that bioidenticals are not drugs. This is 
false. Bioidentical products are indeed drugs that provide 
hormone doses that are not usually experienced by women after 
menopause. As a result, they cannot be considered natural. 
These are not natural levels that women experience during the 
    It is important to consider that even a woman's natural 
estrogen can confer some health risks, as Dr. Rossouw 
mentioned. For example, women with higher natural estrogen 
levels after menopause, as seen with obesity, have a higher 
risk of breast cancer. Also, women's natural estrogen levels 
climb during pregnancy. This rise is linked to a higher risk of 
blood clots in the legs and lungs.
    So the assertion that bioidentical estrogen has no risks 
because it is natural is untrue. The assertion that 
bioidentical estrogen confers less risk than synthetic forms of 
estrogen is unproven.
    How can we determine whether bioidentical hormones are safe 
and effective? By conducting well-designed clinical trials 
which are scientifically rigorous to gauge the safety and 
effectiveness of these medications.
    Unfortunately, for many bioidenticals, and for custom-
compounded bioidenticals specifically, such trials have not 
been done. Without clinical trials, we simply don't know how 
safe or effective these drugs are.
    Trials of a relatively small size and short duration could 
prove or disprove whether such hormones are effective in 
treating hot flashes, night sweats or other symptoms of 
menopause. These trials would have to be placebo-controlled.
    However, larger-scale trials, even more than 25,000 women--
the scale of the Women's Health Initiative, the both hormone 
trials--would be needed to substantiate or refute the claim 
that bioidentical or custom-compounded products are safer than 
conventional hormone therapy in terms of clinical outcomes such 
as heart attack, stroke, or venous blood clots, or breast 
    Mid-size studies can be done to look at intermediate end-
points such as blood markers of clotting or inflammation and 
also non-invasive imaging of atherosclerosis. Some trials, such 
as the Kronos Early Estrogen Prevention Study and the ELITE 
Trial, are in progress looking at those issues. But they cannot 
address whether there is a difference in clinical outcomes such 
as cardiovascular events or breast cancer.
    In summary, the prudent policy, in the absence of 
scientific evidence to the contrary, is to assume that all 
post-menopausal hormone formulations confer similar risks and 
benefits. However, many proponents of custom-compounded 
bioidentical hormones are making unsubstantiated claims of 
superiority that run directly counter to this policy.
    Given this pervasive and misleading marketing, I have a 
deep concern that women, and even some of their doctors, are 
not getting the objective information necessary to make well-
informed choices about hormone therapy.
    There is an urgent need for increased regulatory oversight 
of custom-compounded bioidentical hormones as is done for 
traditional hormone therapy, including assessment of purity and 
dosage consistency, the inclusion of uniform patient 
information about risks and benefits in the packaging of these 
products, mandatory reporting by drug manufacturers and 
compounding pharmacies of adverse events related to these 
hormones, and clinical trials testing the safety and efficacy 
of these products.
    Thank you very much. I would be happy to answer any 
    [The prepared statement of Dr. Manson follows:]


    Senator Smith. Dr. Manson, I wonder if you would agree with 
the conclusion of some on the first panel that ``bioidentical'' 
is a marketing term and it has no medical definition?
    Dr. Manson. I would agree. I think that there is a great 
difference between the way the term ``bioidentical'' is used by 
scientists and the way it is being used by alternative medicine 
practitioners and in the mass media.
    The scientists use it for hormones that are chemically 
identical to those produced naturally by the body.
    There are three types of natural estrogen that women make. 
In addition, there is progesterone, as well as testosterone, 
and other hormones. Many of these hormones, as we have 
discussed, these bioidentical hormones, are available through 
FDA-regulated medications that are produced en masse and 
available in retail pharmacies.
    These custom-compounded hormones, often we don't even know 
what is in them. They do not have any clear advantage over the 
bioidentical hormones that include the estradiol or 
progesterone that are available through a retail pharmacy.
    Senator Smith. Do you know of any head-to-head studies 
between traditional hormone therapy versus bioidentical hormone 
    Dr. Manson. That is an interesting question. The only 
current trial is the Kronos Early Estrogen Prevention Study, 
and it is ongoing. The results are not yet available. It is a 
head-to-head comparison of oral conjugated equine estrogens, 
which were tested in the Women's Health Initiative, but a lower 
dose is being tested in the Kronos trial, and a transdermal 
estradiol patch.
    Senator Smith. Who is doing that test?
    Dr. Manson. It is being done by the Kronos Longevity 
Research Institute, a private foundation. It is not a drug 
company-sponsored trial.
    Senator Smith. Do you think the Federal Government ought to 
take the lead in it, or participate in it, or----
    Dr. Manson. I think it would be helpful for the Federal 
Government to get involved in providing some support so that 
women can get answers to these questions. So it will be 
comparing the oral conjugated estrogens in low dose with the 
transdermal bioidentical form of estradiol.
    Senator Smith. You spoke in your testimony about the role 
of the physician in prescribing bioidentical hormones. Do they 
have enough information to prescribe them? Are they doing that?
    Dr. Manson. Yes. Some of them are.
    I do not think that, with how busy physicians are these 
days and all of the other issues that they have to attend to, 
that most have really gotten the information that they need 
about what bioidentical hormones are, what custom-compounded 
hormones are--all of these issues and concerns that we have 
been discussing this morning--and that they really have a full 
understanding of what they are prescribing for their patients 
because of just a lack of available information.
    Senator Smith. I mean, the obvious conclusion is some of 
them may unwittingly be practicing some form of quackery by 
getting into this area.
    Dr. Manson. Well, I think that more information is 
necessary. I think that some physicians consider that they have 
adequate information.
    But given the paucity of information out there, it is hard 
to understand how a rationale can be given for prescribing 
these hormones over the retail pharmacy-available hormones, 
unless there is a specific reason, such as a patient is 
allergic to peanuts and there is peanut oil in the natural 
micronized progesterone that is available in retail pharmacies.
    Senator Smith. Maybe a message of this hearing ought to be 
``Doctors beware.''
    Dr. Manson. Absolutely.
    Senator Smith. Thank you, Dr. Manson.
    Dr. Wartofsky, please.

                    SOCIETY, CHEVY CHASE, MD

    Dr. Wartofsky. Senator Smith, thank you for the opportunity 
to testify today. My name is Leonard Wartofsky. I am chairman, 
Department of Medicine at the Washington Hospital Center, and 
Professor of Medicine at Georgetown University.
    But today I am here as President of the Endocrine Society, 
the world's largest professional organization of 
endocrinologists, representing over 14,000 members.
    The Society is deeply concerned about the safety of these 
so-called bioidentical hormones and believes the Federal 
Government should increase regulatory oversight of these 
    As you mentioned in your opening comments, Senator, 
bioidentical hormones have been touted inaccurately, by high-
profile individuals with no medical training, as being safer 
and more effective than traditional hormone therapies.
    You have raised the question of the definition of 
``bioidentical.'' As Dr. Manson said, scientists describe 
compounds as bioidentical that are identical to similar 
compounds produced naturally in the body.
    We do not oppose the use or prescribing of FDA-approved 
bioidentical hormones, which have been available to the public 
for years. Rather, our concern is with custom-compounded 
bioidentical hormones.
    The WHI study uncovered risks to women taking hormone 
replacement, as we heard this morning. We caution physicians 
and patients alike against the unfounded presumption that 
bioidenticals would be any safer.
    In fact, no study as comprehensive as the WHI has assessed 
bioidentical hormones. Until authoritative clinical trials of 
bioidentical hormones are conducted, patient safety is best 
assured by assuming these hormones carry the same benefits and 
the same risks as those studied in the WHI.
    Claims about safety and efficacy come from the belief that 
compounded hormones are precisely and individually custom-
formulated. While theoretically appealing, such customization 
is difficult, if not impossible, to achieve.
    Perhaps most alarming, compounded preparations, as you 
again mentioned this morning, are not required to have the 
black-box advisory warning, as required for FDA-approved 
hormones. This is a serious concern for women and their 
    Compounding pharmacies are not required to adhere to the 
strict manufacturing processes governing FDA-monitored 
facilities, raising concerns about purity, potency and quality.
    In one FDA-conducted post-market survey, 4 out of 11 
compounded hormones failed tests for potency and/or uniformity.
    Our concerns are shared by the broader medical community, 
including multiple other professional medical organizations. 
The AMA recently adopted a policy in support of our society's 
    In conclusion, the society supports legislative action to 
standardize regulation of compounded hormones to include 
requirements for: (1) surveys for purity and potency; (2) 
mandatory reporting of adverse events; (3) a registry of these 
events; (4) inclusion of uniform patient information in the 
packaging; and finally and (5) limits on the use of this term, 
``bioidentical hormones.'' The fact is that scientific evidence 
is lacking at this time to either negate or support claims that 
bioidentical hormones are safer and more effective than other 
commonly prescribed hormones. Until conclusions are based on 
science, the Federal Government must ensure patients receive 
safe and effective drugs with accurate information.
    That concludes my personal remarks, Senator. I would be 
happy to answer any questions.
    [The prepared statement of Dr. Wartofsky follows:]

        Senator Smith. Thank you, Doctor.
    I am going to let Dr. Allen testify, and then I have a 
question for the both of you.


    Dr. Allen. Thank you, Senator Smith. I appreciate and share 
your dedication to improving the health of Americans. I thank 
you for the opportunity to speak to you about my profession, 
pharmacy compounding, and the role that we play in preparing 
compounded hormone treatments.
    In the way they are prescribed, prepared and regulated, 
compounded hormones are just like all other compounded 
medicines, so I will first address pharmacy compounding overall 
    Most of the time, when patients need pharmaceutical 
treatment, doctors prescribe mass-produced, off-the-shelf 
drugs. But for some patients, those drugs are inappropriate. 
When they are, doctors may prescribe compounded medications, 
which are then custom-compounded by licensed and trained 
compounding pharmacists.
    Compounded medicines are most commonly prescribed for a 
number of reasons. Sometimes patients are allergic to the 
inactive ingredients that are in off-the-shelf products. Other 
patients require personalized dosage strengths or delivery 
forms. Also, many times pharmaceutical manufacturers 
discontinue drugs because they aren't profitable but patients 
still rely on them and can have doctors prescribe compounded 
versions of them.
    Hospice care patients, cancer patients, dental patients, 
especially pediatric patients, HIV and AIDS patients, 
ophthalmology patients all tend to have individual medical 
needs and, thus, tend to rely on compounded medicines.
    State boards of pharmacy, State medical boards, the Food 
and Drug Administration, the Federal Trade Commission, the Drug 
Enforcement Agency, and other Federal and State agencies each 
have some degree of oversight over pharmacy compounding. The 
United States Pharmacopeia and the Pharmacy Compounding 
Accreditation Board all play critical roles. Together, they 
have constructed a web of regulations and standards that 
protect patients.
    State boards of pharmacy license pharmacists and pharmacies 
and enforce laws that cover the processes and equipment 
pharmacists use to prepare these medicines, including sterile 
medicines, recordkeeping, and labeling, among other aspects of 
pharmacy practice.
    Since 1820, the United States Pharmacopeia has been the 
national standard-setting body for pharmaceuticals and 
pharmaceutical ingredients, and recognized by Congress as such. 
It, too, has strong enforceable standards for pharmacy 
compounding of both sterile and non-sterile medications. States 
are increasingly codifying USP standards.
    The profession is also taking action. Most notably, the 
United States Pharmacopeia, American Pharmacists Association, 
National Community Pharmacists Association, National Boards of 
Pharmacy, and other associations have launched the Pharmacy 
Compounding Accreditation Board.
    The FDA also regulates aspects of compounding, including 
the suppliers of the ingredients that pharmacists use to 
compound. FDA also has authority to inspect any pharmacy's 
facility, equipment and ingredients. Federal laws also prohibit 
the making of unsubstantiated claims of safety and efficacy.
    A fundamental question is, what is the difference between 
compounded and manufactured medicines?
    First, compounded medications are always prepared pursuant 
to a doctor's prescription. Second, compounded medicines are 
retail only, sold directly to the patient.
    Third, they are not copies of commercially available drugs. 
They are significantly different, as determined by the 
prescriber, whereas manufactured medicines are produced well in 
advance of any prescription and distributed at wholesale.
    So how does this relate to hormone therapy? As I said, like 
compounded medications overall, by definition compounded 
hormones are always prescribed by doctors, prepared pursuant to 
those prescriptions, and dispensed directly to patients at 
    Compounded hormones meet the needs of patients that are 
otherwise unmet by manufactured hormone products. For many 
patients, these products are effective, but for some, they are 
not. That may be because the manufactured drugs simply don't 
relieve the symptoms of menopause. It may also be because 
doctors determine that their patients need a lower dose than 
what is available commercially. The Women's Health Initiative 
recommended that women in search of relief from menopause 
symptoms take the lowest effective dose.
    Doctors may find that some patients respond better to 
different delivery forms or drug combinations. Also, some drugs 
are made with peanut oil, and patients allergic to peanut oil 
may need the active ingredient to be compounded without it.
    Each and every time, though, that doctors prescribe 
compounded hormones, they do it because they determine that 
their patients have needs for medications that are 
significantly different from what is manufactured.
    Compounded hormones, like compounded medicines overall, are 
regulated by State boards of pharmacy. The U.S. Pharmacopeia 
and Pharmacy Compounding Accreditation Board set standards for 
their preparation. FDA regulates the suppliers of the 
ingredients that pharmacists use to compound these medicines. 
the FDA and the Federal Trade Commission regulate the marketing 
practices of pharmacies.
    In conclusion, millions of women have been prescribed 
manufactured hormone products. Many of them have found relief 
from the torturous symptoms of menopause. Some have not and, 
instead, have been prescribed compounded hormones by their 
physicians, and they have found relief.
    I would respectfully urge the members of this committee, 
and Congress overall, to consider the impact of any new 
policies that they would have on them.
    Thank you.
    [The prepared statement of Dr. Allen follows:]

    Senator Smith. Dr. Allen, as I have listened to your 
testimony, it seems to me that you are saying the doctor just 
recommends a certain compound and sends that to the pharmacy, 
and then that is a kit made just for that particular patient.
    What guidance do they have? I mean, is it just based on 
their training as a physician, or is there something deeper 
that they know that traditional therapies don't have?
    Dr. Allen. Pharmacists will only fill a prescription from a 
licensed physician or a health-care practitioner. It is the 
responsibility of the health-care practitioner to care for the 
patient and to prescribe appropriate medications.
    So, yes, you are correct. When the physician determines 
that a specific patient needs a compounded medication, then it 
is originated at the physician's office.
    Now, in some cases----
    Senator Smith. Well, I assume, because they are doctors, 
they are very well-trained, but I don't know if their training 
goes this deeply into how all these things interact.
    I am not a physician. I was trained in law. But I would 
think, based on my training in law, they are out there on their 
own, if they are doing this, if there is some ill effect from 
    Dr. Allen. That is correct. They are trained.
    Basically the physician will prescribe, first of all, the 
drug, the dose, the dosage form, the frequency of 
administration, and the quantity. That would all go on the 
prescription. Then they work with the pharmacist in order to 
compound the medication specifically for that patient.
    Senator Smith. Is there any ever very ill effects from this 
pioneering method that each physician would take?
    Dr. Allen. Well, there are obviously ill effects from 
almost any medication that may be prescribed across the board. 
But with clinical experience, the physicians, you know, 
continue to prescribe medications for these specific patients.
    Senator Smith. So it is sort of an ad hoc building block. 
What has worked in the past? Let's try this and do that?
    Dr. Allen. Yes. It is very similar to just the standard 
practice of medicine. Not everything works for everybody, and 
so the physicians will try a drug product until they find 
something that that specific patient will respond to.
    Senator Smith. I appreciate the education you are giving 
    Dr. Wartofsky and Dr. Allen, your two organizations have 
two very different positions as to who ought to regulate 
bioidentical hormones made by compounding pharmacies. The 
International Academy says States are best to regulate it. The 
Endocrine Society believes that the FDA, the Federal 
Government, is best to regulate it.
    I wonder if you can each tell the committee how your groups 
have reached their very different positions, including what 
evidence or information you found to support the conclusion of 
your academy or society.
    Specifically, did you consider mortality and morbidity 
rates, consumer complaints, State statutory and regulatory 
provisions regarding compounding? How did you come to such 
different places on that?
    Dr. Wartofsky. In the case of the Endocrine Society, I 
mentioned our professional organization of endocrinologists, 
the specialty of medicine that deals with hormone therapies. 
Our members brought to our attention that they were getting 
questions from their women patients about these bioidentical 
hormones. They were lacking information. They were concerned 
about the claims that were being made about these bioidentical 
hormones--custom-compounded hormones.
    Although Dr. Allen is correct that pharmacists should not 
prescribe anything without a prescription written by a 
physician, our information is that there are large pharmacy 
chains that sell these products on the Web; that one can get 
these mail-order; that they, in fact, will provide the names of 
physicians who will write prescriptions for these compounds.
    We believe these physicians are acting without a basis in 
science, as you alluded to, that they are perhaps on the fringe 
of medicine and do not represent our mainstream 
    Senator Smith. These pharmacies--we call it ``forum 
shopping'' in the law--do they doctor-shop to find physicians 
    Dr. Wartofsky. I am sure that is the case, yes.
    Our concern about the need for a Federal regulation is 
because the degree of regulation by the States is highly 
varied. From State to State, there is no consistency.
    The National Association of State Boards of Pharmacy has 
issued guidelines for compounding which, as of recently, were 
adopted and codified by less than a quarter of the States in 
the U.S. So these guidelines are not uniform.
    We have heard this morning how difficult it is for the FDA, 
given everything that is on their plate, to do the kind of 
enforcement and regulation that Dr. Allen indicates that they 
do do, because this is not happening. It just is not feasible, 
given the broad practice of the dispensing of these 
bioidentical hormones.
    So we believe there should be some greater oversight at the 
Federal level with more formal guidelines for regulation under 
which the State boards of pharmacy would operate; that there 
would be consistency throughout the country; and importantly, 
that there would be more teeth put into the regulations with 
    Senator Smith. Dr. Allen, obviously, if these products are 
being sold on the Web and somebody in Oregon can get it from a 
doctor in Arkansas on a Web site, that is clearly an interstate 
commerce issue. That is where the Federal Government comes into 
play. So I wonder how you reach a conclusion that the States 
ought to do it.
    Dr. Allen. Well, basically the individual States recognize 
professions--medicine, pharmacy, nursing, et cetera--in their 
State professional acts. In addition to that, they establish 
certain laws governing that profession and State boards to 
regulate those and enforce those.
    The State boards, then, enact regulations to govern the 
practice of pharmacy. So the practice of pharmacy and medicine 
is something that should be regulated at a State level.
    Now, from the pharmacy standpoint, if a pharmacy sends a 
compounded preparation into another State, they are required to 
be registered with the State board of pharmacy in that State.
    Now, when you are talking about the other aspects of it--
the physician's prescription--that is getting into marketing, 
and that is a different story. Probably should be under the FTC 
or whatever. But the pharmacies--any State that a pharmacy 
sends a compounded prescription to, they must be registered in 
that State.
    Senator Smith. Well, the lack of concrete evidence on the 
whole issue of bioidenticals is what has led me and my staff to 
conclude that we need some more information. That is why I have 
asked the Congressional Research Service to prepare a report on 
the status of laws across all 50 States.
    It seems to me that before we can assess who is in the best 
position to regulate this industry, we need to know more than 
we now know.
    I guess a further question is, does each State track 
adverse related events in pharmacy-compounded products? In 
other words, does the Oregonian who gets the prescription out 
of Ohio--how do they track it, what it has done to them?
    Dr. Allen. Currently, there is no requirement for 
pharmacists to report any adverse reactions for either a 
commercial manufactured product or a compounded preparation.
    Now, the USP in our chapter--it is either 795 or 1075--
there is a statement that adverse reactions should be reported 
to the USP MedMarks reporting system. That is something, I 
think, that can very easily be adapted to this so that it 
becomes a standard of practice.
    Senator Smith. Without the information, though, how do we 
know that people aren't being harmed? Shouldn't the States or 
the FDA track the information?
    I mean, it does seem to me that this is an area where the 
Federal Government really ought to get involved and play a 
    Dr. Allen. Currently, the success of therapy or any adverse 
responses to therapy should be picked up by the physicians and 
changes in therapy made. I would think that a physician would--
it would be incumbent upon them, if the patient is not 
responding or is responding adversely, that there would be a 
change in the therapy of that patient.
    Senator Smith. Do you feel like there are some physicians 
out there that will prescribe anything for a fee? That this may 
not be being done at the highest standards of science?
    Dr. Allen. I can't really answer that question.
    Senator Smith. Dr. Allen, you are going to feel like I am 
picking on you, and I am not trying to. I am asking these 
questions for the record of the U.S. Senate and for my own 
understanding of this issue, because there is reason to be 
    It leads me to my next question.
    Some of the biggest criticisms against compounded products 
that I have heard are their variability in composition, the 
fact that physicians and patients may not know exactly what is 
in the final medication, and the lack of warning labels and 
patient information.
    So, as to the labeling issue, I understand the 
International Academy of Compounding Pharmacists has developed 
a suggested label. That label, however, as has been suggested, 
does not mention the potential risks, any side effects, any 
contraindications of medications that may be present.
    If so, why not? It seems to me like the most basic kinds of 
labeling that consumers ought to have.
    Dr. Allen. You are exactly right.
    Now, to address that issue, the USP standards for 
compounding are currently looking at incorporating additional 
labeling standards for all compounded preparations to at least 
incorporate the level of information that you just mentioned.
    In addition to that, you have referred to black box 
warnings and things like that previously. The U.S. Pharmacopeia 
has had a set of reference books called the ``USP Drug 
Information.'' There have been three volumes: Volume One, Drug 
Information for the Health Care Practitioner; Volume Two, Drug 
Information for the Patient; and then Volume Three, which is 
basically the FDA orange book, et cetera.
    What is feasible is to take the information, the data, from 
Volume Two and put that in a data base in the pharmacy 
compounding computer system software, so that as prescriptions 
are filled for specific drugs, like progesterone or whatever, 
it will automatically print out the information for the 
specific patient, just like the commercial products is being 
done today. So that is something that we are looking at.
    Senator Smith. Well, thank you. I think it is very 
    I think the most vital consumer information is what 
customers ought to be given, and it ought to include the risks, 
the side effects and what kind of consequences there may be for 
using these products. So, I don't think we have that yet.
    But thank you, Dr. Allen.
    Dr. Allen. You are welcome.
    Senator Smith. Ms. Wiley, your testimony, please.


    Ms. Wiley. Mr. Chairman, members of the committee, I am 
T.S. Wiley, and I thank you for inviting me to address you on 
the subject----
    Senator Smith. Can you hit your microphone button? There 
you go.
    Ms. Wiley. I thank you for inviting me to address you on a 
subject to which I have devoted over a decade of my life.
    I have no formal training or indoctrination in the world of 
medicine. I am a writer and a researcher in the areas of 
endocrinology and women's health.
    Over 47 million women in menopause in our country are 
facing the same dilemma we are in this room today: what to do.
    At the turn of the century, women died on average by 47. 
But life expectancy is now well over 80. That means a great 
many of us must go on perhaps 30 years or more without the 
hormones that our minds and bodies have always had.
    The Women's Health Initiative, now the gold standard 
regarding hormone replacement therapy, interestingly enough 
never looked at hormones at all; only drugs with hormone-like 
effects that were dosed in a regimen that in no way resembled 
replacement in human beings.
    The only thing the WHI proved was that static doses of 
synthetic hormone-like drugs caused cardiovascular harm in 
women over 65. This information was not pertinent to women 40 
to 60 looking for answers. Thirteen years ago, I was one of 
those women.
    To me, the answer seemed simple. Since women's hormones are 
rhythmic with ups and downs across the 28-day cycle, I decided 
to copy nature precisely with a bioidentical regimen based on a 
model of hormone replacement seen in Type 1 diabetics who use 
bioidentical insulin--you may argue with the term--biomimetic 
insulin--taken through the skin and fat in doses their bodies 
would have produced it.
    That is all there is to the Wiley Protocol. It is a simple, 
logical model using bioidentical compounded estrogen and 
progesterone in variable dosing.
    I arranged for the reporting of adverse events. We use a 
patient insert with contraindications and warnings, and we test 
for purity and potency quarterly in the pharmacies I work with.
    I have standardized the production, the methods and 
materials, of the compound so it could merit study on a large 
scale in clinical trials, of which there are none right now, 
except, I believe, the one we are planning at the University of 
    Menopausal women are orphans in the health-care system in 
this country. There is no one to take care of us. Doctors 
prescribing the standard of care, HRT, or even bioidentical 
hormones have little support or education in the matter.
    Big pharmaceutical companies and the compounders are now at 
war over who gets to make a fortune on us women.
    Instead of modeling hormone replacement like diabetes care, 
women were given a once-a-day-dose pill of synthetic drugs, 
instead of hormones, because that was easier for the 
pharmaceutical company and the doctors to monitor.
    The last pronouncement from the NIH was just that quite 
simply the drugs--and they weren't hormones--studied by the WHI 
don't work. They are, in fact, dangerous, now that you have 
bothered to look 20 years later.
    So now women just can't have any hormones because big 
pharma couldn't get it right in the first place. That is 
    The majority of Western medicine has been on a wild goose 
chase for the elusive proof that being completely hormoneless 
will save our lives in the face of massive evidence with all of 
our estrogen blocked at every turn we still keep dying of 
cancer. Logically, if high circulating estrogen caused cancer, 
all young women would be dead; all pregnant women would be 
    Now, the most recent move to keep us hormoneless is the 
debate over the value of compounded bioidentical hormones.
    The National Institute of Neurological Diseases and Strokes 
sees the value in compounded hormones.
    A national clinical trial designed to see if high doses of 
compounded progesterone can protect the brain from destruction 
is planned for military use and because 78 million voters are 
in their peak years for stroke and degenerative brain disease.
    Each year, 700,000 Americans suffer strokes and 500,000 
more are diagnosed with neurodegenerative disease.
    Dr. David Wright at Emory University Medical School in 
Atlanta has been testing compounded progesterone for head 
injury. In a 3-year trial of 100 such patients, 80 received 
high-dose progesterone over 72 hours after trauma and 20 did 
    The study on young men--not women--found that those 
receiving compounded progesterone were 50 percent less likely 
to die. There was less disability at the 1-month mark than 
would normally be expected considering the severity of their 
head injuries.
    Marcus Baskett of Commerce, GA, was one of those patients 
in a head-on automobile collision just 3 weeks shy of his high 
school graduation. Early tests of his brain function suggested 
massive and disabling head injury.
    He spent almost 3 weeks in a coma. Then, 4 weeks later, 
Baskett was released with lingering physical injuries but 
little evidence of the severe head trauma. Three years later, a 
21-year-old Baskett is back 100 percent.
    There are uses for compounded bioidentical hormones that 
none of us have ever even imagined. To consider eliminating 
them is to limit the researchers' imagination everywhere.
    [The prepared statement of Ms. Wiley follows:]
    Senator Smith. Thank you very much, Ms. Wiley. You have 
given us another view, and we respect that.
    I guess the thing that leads to my questioning of you is 
clearly the FDA gives a black box warning for hormone therapy 
when even the slightest amounts or smallest amounts of hormones 
are used. They tell you to do it for a short duration.
    You, however, developed a protocol that uses higher amounts 
and for longer periods, as I understand it, recommended for 
lifetime usage. We have heard differing views at this morning's 
    I wonder, your protocol's approach contradicts that held by 
the larger--the greater--medical community on hormone therapy. 
You have said you are not a medical doctor. Can you explain how 
your proposal doesn't put women at greater risk?
    Ms. Wiley. Yes. Hormones, as I am sure Dr. Wartofsky could 
agree, are dose-dependent in their effects on cellular systems 
and different in every organ in the body.
    The normal menstrual rhythm, or the normal production of 
hormones over the course of 28 days in a healthy young woman 
who does not have breast cancer, heart disease, Alzheimer's, 
arthritis, osteoporosis--we could go on for days--in those 
healthy young women, is a rhythmic production with a crescendo 
of estrogen on day 12 and a crescendo of progesterone on day 
    In using bioidentical transdermal hormone creams, it is 
possible, through justification with blood work, to recreate a 
dosing schedule that mimics those normally rolling hormones 
that provoke something called apoptosis, which is cell suicide, 
in the progesterone phase, that in the estrogen phase on day 12 
provoked the progesterone receptor so that apoptosis can 
    Endocrinology is about pulsatility and amplitude. A 
diabetic, for example, would never take the same amount of 
insulin day-in and day-out. The diabetic responds to the meal 
the diabetic ate with the appropriate amount of insulin that 
his body might have produced could he produce it. I only 
suggest that women are treated the same way.
    Senator Smith. You obviously believe that the bioidentical 
products ought to have a medical definition.
    Ms. Wiley. Yes, I do.
    Senator Smith. OK. It is not just a marketing term.
    Ms. Wiley. No. Well, I think ``bioidentical'' is a 
marketing term. I think ``biomimetic'' is more accurate. But 
there are differences in the effects of the molecule of 
estradiol versus conjugated equine estrogens, very big 
differences, certainly on inflammatory response in 
cardiovascular events.
    Senator Smith. Thank you.
    Dr. Manson, have you reviewed the Wiley Protocol?
    Dr. Manson. Yes, I have.
    Senator Smith. Do you have any problems or concerns?
    Dr. Manson. I think it is an interesting theory, and I 
would like to see it tested.
    But I think we have to note that in the post-menopausal 
woman, there are not these levels of estrogen and progesterone 
that are achieved with this treatment, so it is not a natural 
state that is being induced.
    We just don't know what the health effects are, especially 
of very long-term, indefinite use. We don't even know the 
short-term effects.
    I would like to see funding of trials to look at hormone 
regimens that do more closely simulate what happens in a 
woman's natural, pre-menopausal state. I think that is very 
important to have that research and to do those studies. But at 
this point in time, I don't think we can reassure women that 
this is any safer, any more effective, without rigorous 
    I would ask the question, why would any woman agree to 
spend so much out-of-pocket to pay for the hormones, to pay for 
these blood or saliva tests, if she really understood that 
there was no evidence that these treatments were any more 
effective than treatments that could be covered by her health 
insurance; that there was really no rigorous evidence that 
these tests were useful in guiding her hormone therapy 
treatment, and also if she were aware of the concerns about 
dosage consistency and impurities?
    So I think it is clear that women are not getting the 
information that they need, or else it seems very unlikely to 
me that this would become as popular as it has become.
    Senator Smith. Ms. Wiley, would you welcome a Federal 
scientific test of these things?
    Ms. Wiley. Oh, absolutely.
    Senator Smith. A vigorous----
    Ms. Wiley. Absolutely.
    Right now, the University of Texas at Tyler, through the 
nursing school, is entertaining giving us an IRB number, an 
Internal Review Board number, so that we can be watched--the 
women who are on the Wiley Protocol now--in a longitudinal 
observational study. We would love to go head-to-head with the 
commercial products.
    Senator Smith. Are you tracking occurrences of any adverse 
    Ms. Wiley. Absolutely. Dr. Julie Taguchi in Santa Barbara, 
CA, is in touch with all the doctors who will report to us. We 
track them not only through the doctors but through something--
    Senator Smith. There are adverse events?
    Ms. Wiley. We have seen two blood clots in I would say we 
have watched over 1,000 women almost face-to-face in Santa 
Barbara. There are many more that report to us from Santa Fe, 
NM, for example. There are pockets of women all over the 
    Senator Smith. What do you do with the information, you 
know, of an adverse event?
    Ms. Wiley. Dr. Taguchi chronicles it and keeps it.
    We right now have reported on cancer patients who have 
taken the Wiley Protocol post-diagnosis without active cancers. 
That was reported to a large group of doctors at the American 
Academy for the Advancement of Medicine, ACAM.
    Senator Smith. I understand that you require pharmacies to 
be certified----
    Ms. Wiley. Well, I----
    Senator Smith [continuing]. Before they can dispense drugs.
    Ms. Wiley. I found that for the Wiley Protocol I expected a 
certain rigor in compounding. I perceived that there is a 
process that makes these hormones uniquely standardized. In 
other words, a woman in New Mexico can pick up the same Wiley 
Protocol as a woman in New York City if, in fact, she goes to a 
pharmacy that has agreed and committed to make them in this 
certain way.
    I went for standardization because, obviously, it removes 
variables for the doctors in discerning what is going on with 
their patients. More importantly, I was aware that no large 
pharmaceutical company is going to sponsor clinical trials for 
the Wiley Protocol, and that clinical trials would be useless 
without a standardized compound.
    So by engaging enough pharmacies and asking them to donate 
a percent of their volume that they do in the Wiley Protocol, 
ultimately, to a national trial, I would have a standardized 
product that could be looked at.
    Senator Smith. Do you have any relationship to the FDA? Do 
they monitor what you do?
    Ms. Wiley. No. Other than they monitor the bulk substances 
that the Wiley Protocol, you know, derives from.
    Senator Smith. But they have investigated your products, I 
assume, and----
    Ms. Wiley. I believe they only investigate the bulk 
material that pharmacists use, and then that is, as Dr. Allen 
said, a pharmacy-to-pharmacy case, whether or not FDA 
    Senator Smith. Those women who sign up for the Wiley 
Protocol, you have found overwhelmingly good results?
    Ms. Wiley. Surprisingly good results.
    I don't know what I anticipated. I was just interested. The 
oncologist I have worked with for over 7, 8 years, and a very 
large group of doctors both in Santa Barbara and around the 
country, we are all surprised at how remarkably well the women 
seem to do.
    Senator Smith. Dr. Allen, how does the Wiley Protocol fit 
within your academy's view of things?
    Dr. Allen. Well, I can address it from the formulation 
    Physicians in prescribing a compounded preparation may want 
a certain effect, and so the pharmacist has some leeway in the 
different excipients, or non-active ingredients, that can be 
included. So for the Wiley Protocol, it is, as was explained, a 
set formulation so that it can be compared----
    Senator Smith. Which would be different from your members 
who might be coming up with their own formulations and having 
pharmacies produce them?
    Dr. Allen. Yes. The individual physician, based upon what 
they want in their specific prescription for their specific 
patients, they have some flexibility in the different 
excipients that can be used, yes.
    Senator Smith. Dr. Manson and Dr. Wartofsky, if compounded 
products could be standardized, as Ms. Wiley has done with her 
products, would that alleviate your concerns?
    Dr. Wartofsky. I would have----
    Senator Smith. Push your button there.
    Dr. Wartofsky. Sorry. I would have residual concern. The 
concern with compounded products is that they may not be of 
sufficient content, quality, purity, so that women might be 
either underdosed or overdosed.
    So Dr. Allen's comment that the doctor should pick up these 
adverse effects really doesn't apply because some of these 
effects may take years, if not decades. For example, if an 
estrogenic compound is underdosed and leads to bone mineral 
loss and osteoporosis, that will show up 10, 20 years later. 
The doctor will not pick that up.
    Ms. Wiley's standardization of her formulation that is 
going out across the country to different pharmacies to me is 
counterintuitive to customization. If she is customizing the 
dosage for the individual patient, how does this fit a standard 
    Her analogy to diabetes and insulin doesn't hold. In the 
case of diabetes, we have a very specific marker to follow in 
terms of the efficacy of insulin: the blood sugar.
    As Dr. Manson mentioned, the test to measure hormones by 
saliva or blood tests are notoriously inaccurate and thrown 
off. So it is really impossible, as I mentioned in my 
statement, to truly customize to an individual woman what her 
estrogen levels or progesterone levels should be by some 
standard formulation analogous to insulin and blood sugar.
    Ms. Wiley. May I respond?
    Senator Smith. Yes. Let me get Dr. Manson. Then we will 
give you the last word, like Bill O'Reilly. [Laughter.]
    Dr. Manson. I agree with all of the concerns expressed by 
Dr. Wartofsky. But I also want to emphasize that some of the 
risks of having an inadequate dose of the progesterone are very 
    Women who have a uterus who are taking estrogen have 
increased growth of the lining of the uterus. It is very 
important that they receive an adequate dose of a progestogen, 
whether it is natural or synthetic, in order to avoid uterine 
cancer, endometrial cancer. So if there is an inadequate dose 
of the progestogen, then they are at an increased risk of 
uterine cancer.
    So I think there are some very serious concerns about not 
having uniformity of dose or consistency, knowing exactly what 
doses are there.
    Also, if women are being told about the lack of scientific 
studies, the lack of evidence that these custom-compounded 
hormones are any safer or more effective then, again, it seems 
unlikely that they would be paying as much out-of-pocket for 
them and having these tests done that have not been proven to 
have validity.
    Senator Smith. Ms. Wiley?
    Ms. Wiley. Well, first of all, I am flattered that anyone 
could insinuate low doses with the Wiley Protocol because we 
use quite a bit at the Wiley Protocol.
    I don't ever involve myself with individual patient 
response. That belongs to their doctor.
    However, by testing potency four times a year at the 
registered pharmacies to make sure what is on the label is in 
the syringe--and we use syringes--by following these women with 
what seems to be a standardized dose--it is one dose not fits 
all, but starts all--the customization actually is true.
    These women are all on a rhythm. I am very concerned about 
the curves in the rhythm. However, their doctors customize 
this--because it is a compounded product and not FDA-approved--
they customize the Wiley Protocol by raising or lowering the 
dose a couple of lines, maintaining the curves which 
conceptually was my concern.
    As far as tests, we never use saliva. I, too, agree with 
all of you. It is not reliable.
    However, we do use blood testing that has been standardized 
and considered a reasonable approach in medicine since the 
early 1950's--blood tests. We test for estradiol blood levels 
on day 12 and progesterone both, and then we test again for 
both on day 21.
    Now, as far as expense goes, the Wiley Protocol is $75 a 
month, and most insurance companies do cover it, OK?
    The testing is not onerous either. In the first 3 months, 
the woman's levels are checked to make sure she has optimum 
response, and her doctor can adjust it to her needs given 
symptoms, matching numbers.
    So I think we have created something that is standardized 
and simultaneously customized for the first time in compounded 
    Senator Smith. Well, thank you, Ms. Wiley.
    Thanks to all of our witnesses. We respect your time and 
don't hesitate in telling you that you have each contributed, I 
think, wonderfully to the understanding of this Senator and to 
the U.S. Senate record.
    This is an important issue, and what is at stake is women's 
health. That matters to this committee and it certainly ought 
to be of concern to Federal agencies charged with consumer 
protection and legitimacy in medicine.
    This hearing has been most enlightening, and for that we 
thank you. We wish you all a very good day.
    We are adjourned.
    [Whereupon, at 11:47 a.m., the Committee was adjourned.]
                            A P P E N D I X


         Responses to Senator Smith Questions from JoAnn Manson

    Question What does the April 19, 2007 New England Journal 
of Medicine report\1\ mean for hormone therapy and women's 
health in general?
    \1\ Ravdin PM, Cronin KA, Howlader N, Berg CD, Chlebowski RT, Feuer 
EJ, Edwards BK, Berry DA. The decrease in breast-cancer incidence in 
2003 in the United States. New England Journal of Medicine 2007; 
    Answer. This study compared time trends in breast cancer 
incidence with time trends in hormone therapy use in the United 
States. The researchers speculated that the 7 percent decline 
in the incidence of breast cancer that occurred from 2002 to 
2003 in this country was most likely a result of the dramatic 
reduction in the use of hormone therapy following the 
publication of the WHI estrogen-plus-progestin trial results in 
July 2002. However, studies of this type (i.e., time-trend 
ecologic studies, which compare variations in aggregate 
exposures and outcomes over time within a population) cannot 
definitively establish the existence of cause-and-effect 
relationships. We need more research to tease out the factors 
causing the drop in breast cancer rates. Declining use of 
hormone therapy is likely part of the answer, but the 
decreasing prevalence of use of screening mammography may also 
play a role.\2\ If so, some of the apparent decline in breast 
cancer rates could simply reflect underdiagnosis, because fewer 
women are getting screened for the disease. A key question is 
whether deaths from breast cancer will also decline, and it 
will take years to answer this definitively. Additionally, 
another recent study suggests that breast cancer rates have 
been declining since 1999\3\--that is, well before the mid-2002 
drop in hormone therapy use.
    \2\ Breen N, K AC, Meissner HI, Taplin SH, Tangka FK, Tiro JA, 
McNeel TS. Reported drop in mammography: is this cause for concern? 
Cancer 2007 [e-published on 14 May 2007]
    \3\ Jemal A, Ward E, Thun MJ. Recent trends in breast cancer 
incidence rates by age and tumor characteristics among U.S. women. 
Breast Cancer Research 2007; 9:R28.
    Nonetheless, the results of the New England Journal of 
Medicine report underscore the importance of adhering to 
current clinical guidelines regarding the use of hormone 
therapy. To minimize the increase in breast cancer risk 
associated with hormone therapy, use of such therapy, 
particularly estrogen plus progestogen, should be limited to no 
more than five years (and ideally no more than two or three 
years). It should be noted that available data, including the 
WHI trials, more strongly implicate estrogen plus progestogen 
than estrogen alone in raising breast cancer risk. (Indeed, the 
WHI estrogen-alone trial found no increase in risk of breast 
cancer after 7 years of estrogen use among women with 
hysterectomy.) Some data suggest that less frequent use of a 
progestogen (e.g., as in cyclic regimens, where the progestogen 
is taken for only 10-14 days per month, or even less 
frequently) may carry less risk than more frequent use of a 
progestogen (e.g., as in continuous regimens, where it is taken 
every day), but more research is needed on this topic.
    Question. Can you clarify for the record your position on 
the use of the term ``bioidentical''--in what circumstances 
would its use be appropriate or accurate?
    Answer. ``Bioidentical'' hormone preparations properly 
refer to medications that contain hormones that are an exact 
chemical match to those made naturally by women's bodies. 
Bioidentical preparations fall into two broad categories: (1) 
FDA-approved medications that are available at commercial 
pharmacies in a range of standard doses, and (2) custom-
compounded medications prepared according to an individualized 
prescription from a doctor by compounding pharmacies. This 
distinction must be made clear to women who are considering the 
use of bioidentical products. A growing number of bioidentical 
products have FDA approval and are widely available through 
retail pharmacies, so most women have no need to take on the 
unique risks of custom-compounded products to satisfy their 
preference for bioidentical over traditional hormone 
formulations. Another important point is that no type of 
menopausal hormone therapy, including bioidentical products, 
should be called ``natural,'' because all lead to substantially 
higher blood levels of estrogen and/or progesterone than the 
levels that occur naturally in women after menopause. (also see 
response to question #3)
    Question. Could you clarify for the record your position on 
the use of FDA-approved bioidentical versus custom-compounded 
hormone therapy products?
    Answer. Provided that they are appropriate candidates for 
hormone therapy, women who prefer to use FDA-approved 
bioidentical hormone preparations (such as estradiol and 
micronized progesterone) rather than traditional hormone 
products (such as conjugated equine estrogens and synthetic 
progestins), or transdermal over oral delivery systems, can be 
encouraged to do so, as these products may offer some 
advantages over traditional ones. That said, until we have 
solid data from randomized clinical trials that indicate 
otherwise, the conservative and prudent approach is to assume 
that all FDA-approved hormone formulations confer a roughly 
similar balance of benefits and risks.
    There is no evidence that custom-compounded bioidentical 
hormone products are safer than FDA-approved bioidentical 
products, and healthcare providers should clearly convey this 
message to their patients. Indeed, custom-compounded 
bioidentical products carry unique risks--insufficient quality 
control; unreliable information about benefits and risks; 
misleading advertising claims; and are often accompanied by 
unreliable and expensive saliva and blood tests;--and should 
not be used by most women. Few women have a legitimate need to 
select a custom-compounded hormone product over other hormone 
options. The main valid reasons for a woman to choose a custom-
compounded hormone product are allergies to certain ingredients 
(e.g., peanut oil in Prometrium) or intolerance to doses of 
commercially available products. With the recent availability 
of many different dose levels, there should be even less need 
than in the past to select a custom-compounded hormone product.
    Question. When you spoke of the need for clinical trials on 
bioidentical hormones, did you mean head-to-head studies 
between FDA-approved bioidentical hormone products and 
traditional conjugated equine products, or did you mean custom-
compounded bioidentical hormones and traditional products? If 
you were referring to custom compounding, how could you have a 
controlled trial without having a ``standardized'' compound 
    Answer. There are two types of double-blinded randomized 
clinical trials that need to be done. First, we need clinical 
trials that directly compare FDA-approved bioidentical hormone 
products to traditional hormone therapies such as conjugated 
equine estrogens or other synthetic products. These studies 
should compare different hormone formulations, as well as 
routes of delivery (such as pill, patch, or cream), with 
respect to their effects on blood-based biomarkers (including 
levels of cholesterol, C-reactive protein and other markers of 
inflammation, and markers of thrombosis), intermediate 
endpoints (such as noninvasive measures of atherosclerotic 
build-up or mammographic density), and, eventually, hard 
clinical endpoints (such as heart attack or breast cancer). 
Second, we need clinical trials that directly compare FDA-
approved bioidentical hormone products with custom-compounded 
bioidentical hormones to determine which type of therapy, if 
either, is more effective at relieving menopausal symptoms and 
improving quality of life and sleep. In the FDA-approved 
bioidentical hormone arm of such a trial, the dosing should be 
determined in the usual way--i.e., start with the lowest 
possible dose and then adjust the dose based on the symptoms 
subsequently reported by the participant. In the custom-
compounded bioidentical hormone arm, the initial and subsequent 
dosing would be based on results of ongoing blood and saliva 
tests until hormone levels are ``stabilized'' according to a 
preset protocol. Both types of clinical trials are affordable 
and feasible; they can be conducted with relatively few women 
and in a short time span, providing answers to many of the 
research questions in 6 to 12 months of follow-up. If initial 
trials look promising, then serious consideration should be 
given to mounting a large-scale clinical trial to compare the 
effect of these various hormone products on clinical events.

      Responses to Senator Smith Questions from Leonard Wartofsky

    Question. In your testimony you referenced internet 
pharmacies going beyond proper professional bounds and doctors 
on the ``fringe'' who were prescribing compounded 
bioidenticals. Can you give the Committee any further 
information on these problems you've identified, i.e. where and 
how frequently this is happening?
    Answer. Unfortunately, no hard data exists detailing how 
frequently physicians in the broader medical community are 
prescribing compounded bioidentical hormones. However, the vast 
majority of The Endocrine Society members support our position 
statement, providing evidence that most endocrinologists do not 
prescribe these. Opportunities do exist for patients to obtain 
compounded bioidentical hormones without a prescription from 
their regular physicians. We have attached links to three 
websites that provide women with the names of physicians who 
are willing to prescribe bioidentical hormones for them if 
their primary physician is unwilling to do so. Although 
compounding pharmacies claim that they are only filling the 
prescriptions that are generated by physicians, pharmacies such 
as these provide the means for women to get a prescription 
without the assistance or oversight of the physicians with whom 
they have a medical relationship.
    Question. In your testimony you mentioned the National 
Association of State Boards of Pharmacy had guidelines on 
compounding that were only adopted by a quarter of states to 
date--is that statistic available in a report or paper you 
could share with the Committee?
    Answer. The National Association of State Boards of 
Pharmacy issued ``Good Compounding Practices Applicable to 
State Licensed Pharmacies,'' which may be viewed through the 
link below. The model code provides State Boards of Pharmacy 
with a framework for developing requirements for compounding 
pharmacies. As of 2003, only 10 states had adopted this code, 
which was identified through the 2003 testimony of Steven 
Galson, Acting Director, Center for Drug Evaluation and 
Research, FDA, before the Senate Committee on Health, 
Education, Labor, and Pensions, ``Some of the stakeholder 
groups with whom we have interacted are engaged in activities 
intended to provide greater confidence in the quality of 
compounded medications. For example, the NABP has a model code 
governing pharmacy compounding that substantially has been 
adopted by ten states. The model code provides State Boards of 
Pharmacy with a framework for developing requirements for 
compounding pharmacies.''
Current statistics on the number of states that have adopted 
this code were available.
    Question. You have mentioned some concerns about compounded 
products that can be attained over the internet. Could you 
explain those concerns and share any examples of bad actors 
known to the Endocrine Society? What more needs to be done to 
ensure product quality and safety the area of internet 
available compounded products?
    Answer. As we mentioned above, there are compounding 
pharmacies that will provide women with the names of physicians 
who have already agreed to provide prescriptions for compounded 
hormones, even if they are not regular patients. In my work on 
thyroid conditions, I have come across a number of websites 
that are providing questionable advice and medical supplements 
for ``Wilson's Syndrome.''* We have attached links to a few 
websites as examples that can easily be accessed through a 
Google search.
    * An invented ``syndrome'' by a Florida physician, Dr. Wilson, to 
promote sale of his products.
    However, we cannot say with any certainty whether the 
practices of these organizations or those mentioned in Question 
#1 go beyond the bounds of the ethical or legally allowed 
practices of the medical community. We do believe that the 
decision about the best hormone therapy for a patient should 
only be made by the patient and her physician. Only when this 
happens can a woman be assured that she is receiving the best 
therapy for her individual needs. In order to ensure that women 
have access to safe and effective treatments, greater 
regulation of the production and marketing of compounded 
bioidentical hormones is needed.*An invented ``syndrome''by a 
Florida physician, Dr. Wilson, to promote sale of his products.

     Response to Senator McCaskill question from Leonard Wartofsky

    Question. What are the growth or development risks to 
children of exposure to bioidentical hormones their parent or 
caregiver is using?
    Answer. A small number of cases of children's virilization 
have been reported since 1999 as a result of exposure to 
topical testosterone preparations used by their fathers. The 
articles referenced below provide case reports of the effects 
of these testosterone preparations on small children. In the 
study conducted by Kunz, et al, 5 of the 6 caretakers obtained 
the products through Internet sites or interstate 
pharmaceutical commerce, often without a prescription. The 
children suffered from masculinization of the genitals and 
enlargement of the clitoris or penis, rapid linear growth and 
bone maturation, development of pubic hair and acne, and 
aggressive behavior. In almost all cases, the symptoms 
regressed after the men ceased use of the topical preparations.
    Brachet C, Vermeulen J, Heinrichs C.
    Children's virilization and the use of a testosterone gel 
by their fathers.
    Eur J Pediatr. 2005 Oct;164(10):646-7. Epub 2005 Jul 16.
    Kunz GJ, Klein KO, Clemons RD, Gottschalk ME, Jones KL.
    Virilization of young children after topical androgen use 
by their parents.
    Pediatrics. 2004 Jul;114(1):282-4.

        Responses to Senator Smith Questions from Loyd V. Allen

    Question. In your testimony, you discussed the issue of 
labeling compounded products and expressed that you were 
generally supportive of a labeling requirement. I understand 
that there is potential for developing a centralized database 
for pharmacists to use in order to provide a patient printout 
that provides uniform information about his or her medication. 
Can you share with the Committee how this would work, why it 
would be helpful, and when nationwide availability of such a 
database could be feasible?
    Answer. The U.S. Pharmacopoeia (USP) has developed the USP-
DI, or USP Drug Information database. The database was 
developed by physicians and pharmacists over several years and 
is very comprehensive. It consists of three volumes: Volume I 
is Drug Information for the Health Care Professional; Volume II 
is Advice for the Patient (Drug Information in Lay Language); 
and Volume III is Approved Drug Products and Legal 
Requirements. These are currently being published by Thomson-
    The specific database that can be of benefit for 
compounding pharmacy and patients is Volume II Advice for the 
Patient. This database is at the USP offices in Rockville, MD 
and can be modified to meet the needs for pharmacy compounding. 
The database can be reformatted and licensed to the various 
software vendors that supply the software programs to 
compounding pharmacists. As the label for a compounded 
prescription is printed, the patient advisory leaflet 
information that is given to the patient can also be printed. 
This is similar to what is currently used for commercially 
manufactured prescriptions that print the patient advisory 
leaflet for the commercial product along with the label for 
dispensing to the patient.
    This is a workable solution and could be implemented 
relatively quickly as the database is already available.
    Question. There was considerable discussion in the hearing 
about the use of the term ``bioidentical'' when describing that 
particular type of hormone therapy. What is your opinion on the 
use of bioidentical as a descriptive?
    Answer. The word ``bioidentical'' is a contraction of the 
worlds ``bios,'' meaning ``life,'' and ``identical,'' meaning 
``the same as''. Therefore, ``bioidentical'' means ``the same 
as life'' or identical to what is in the living body. This is 
in contrast to those substances that are not the same as those 
that naturally occur in the human body, such as synthetic 
conjugated hormones. The term bioidentical is descriptive of 
reality but has been misused.
    To resolve this, since we commonly use the official term 
``Human Insulin'' for insulin that is identical to that which 
occurs in the human body, it may be better to use the term 
``Human Hormones'' to designate those that are identical to 
those in the body. The non-human hormones (conjugated 
estrogens, etc.) could not use this designation. (This is 
appropriate because human insulin is derived from non-human 
sources but is altered to be chemically identical to that in 
the body, just like bioidentical hormones are derived from yams 
and soy but are chemically altered to be identical to those in 
the body, i.e. bioidentical). The American Diabetes Association 
and the American Medical Association both use the term ``Human 
Insulin,'' and the official name in the USP is Human Insulin 
    The term ``natural'' is another term that has been used in 
a confusing manner. Human hormones are those that occur 
naturally in the body. However, the starting point for the 
chemical preparation of some of these human hormones is the 
naturally grown soy beans, yams, etc. The precursor chemical is 
extracted from these plants and is then chemically modified to 
the hormones that are bioidentical to those human hormones that 
are naturally in the body. This tends to be confusing to many 
people. If one also looks at the marketing of some low dose 
progesterone products available in the market place, they use 
the term natural, generally referring to the source of the 
hormone. So, the term ``natural'' can refer to either the human 
hormones that occur naturally in the body or to the natural 
source from which they are derived.
    Question. How safe is ``bioidentical'' hormone therapy from 
a pharmacist's viewpoint?
    As a pharmacist, many things that occur naturally in the 
body are used therapeutically, including water, electrolytes 
(sodium, potassium, etc.), thyroid, pancreatic enzymes and 
insulin. We are simply replacing what the body has lost.
    Bioidentical hormones are available in commercially 
manufactured (e.g., Prometriuim, Estragel, Androgel) and 
compounded forms. These have been recognized as safe and 
effective by the Food and Drug Administration. Since these 
hormones are the same as what the body has been producing for 
years, they should be safe, effective and without adverse 
problems provided the dosing is done properly, which is worked 
out between the physician, patient and the pharmacist. So yes, 
in my opinion they are safe and effective when properly used.
    Question. We have discussed how you believe that the states 
are in the best position to regulate the practice of pharmacy 
compounding. I am told one of the challenges facing state 
boards of pharmacy is the lack of sufficient staffing (and 
funding) to do the type of inspections and investigations that 
could provide a higher level of oversight.How many additional 
staff members would each state need to start making a greater 
enforcement impact, and how much would it potentially cost to 
provide the personnel and training that they need?
    Answer. The practice of pharmacy should be regulated by the 
state boards of pharmacy. As pharmacy practice changes, the 
state boards adapt to these changes. The standards of the USP 
related to pharmacy compounding are being implemented by the 
states, either directly or by rewriting them on a state-by-
state basis. Enclosed please find a document prepared about 
three years ago, entitled ``Reasons the FDA Should Not Be 
Involved In Pharmacy Compounding.''
    The individual state boards of pharmacy may need some 
supplemental funding for additional inspectors, depending upon 
the needs of the individual states. This may range from 1 to 5 
additional inspectors per state with an overall average 
estimate of 2 per state, or 100 new inspectors. At salary plus 
benefits of about $100,000 per year per position this amounts 
to $10 million dollars. This could be provided initially in the 
form of grants for the first few years, similar to other 
programs provided by the Federal Government, as the states 
eventually assume funding for these and the federal funds are 
decreased and eventually eliminated as the program becomes 
totally supported at the state level.