[Senate Hearing 110-129]
[From the U.S. Government Publishing Office]
S. Hrg. 110-129
Bioidentical Hormones: Sound Science or Bad Medicine
=======================================================================
HEARING
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/
index.html
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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
HILLARY RODHAM CLINTON, New York ELIZABETH DOLE, North Carolina
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
(ii)
C O N T E N T S
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Page
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
APPENDIX
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
(iii)
BIOIDENTICAL HORMONES: SOUND SCIENCE OR BAD MEDICINE?
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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
presiding.
Present: Senators Smith and Craig.
OPENING STATEMENT OF SENATOR GORDON H. SMITH, RANKING MEMBER
Senator Smith. Good morning, ladies and gentlemen. With the
permission of the Chairman, Senator Kohl--he has asked us to
proceed.
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
therapy.
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
needs.
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
Initiative.
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
therapies.
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
responsibility.
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
dialog.
With that, I will turn to my colleague, Senator Craig, from
Idaho.
OPENING STATEMENT OF SENATOR LARRY CRAIG
Senator Craig. Well, to the Chairman and to you, the
Ranking Member, let me thank you for bringing this hearing
together.
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--
Gordon.
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
option.
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.
STATEMENT OF JACQUES ROSSOUW, CHIEF OF THE WOMEN'S HEALTH
INITIATIVE BRANCH, NATIONAL HEART, LUNG AND BLOOD INSTITUTE,
NATIONAL INSTITUTES OF HEALTH, BETHESDA, MD
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
disease.
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
attacks.
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
complications.
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
publication.
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
age.
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:]
[GRAPHIC(S) NOT AVAILABLE IN TIFF FORMAT]
Senator Smith. Thank you, Doctor.
Steve Galson.
STATEMENT OF STEVE GALSON, DIRECTOR, CENTER FOR DRUG EVALUATION
AND RESEARCH, FOOD AND DRUG ADMINISTRATION, ROCKVILLE, MD
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
products.
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
needs.
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
dehydroepiandosterone.
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
practitioners.
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:]
[GRAPHIC(S) NOT AVAILABLE IN TIFF FOMRAT]
Senator Smith. Thank you very much.
Dr. Galson. Thank you.
Senator Smith. Eileen Harrington.
STATEMENT OF EILEEN HARRINGTON, DEPUTY DIRECTOR, BUREAU OF
CONSUMER PROTECTION, FEDERAL TRADE COMMISSION, WASHINGTON, DC
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
cures.
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:]
[GRAPHIC(S) NOT AVAILABLE IN TIFF FORMAT]
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
synthetic.
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
it.
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
have.
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
duration.
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
basis.
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
hope?
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
here.
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
issues.
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.
STATEMENT OF JOANN MANSON, CHIEF OF PREVENTIVE MEDICINE,
BRIGHAM AND WOMEN'S HOSPITAL, PROFESSOR OF MEDICINE, HARVARD
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
hormones.
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
advertised.
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
post-menopause.
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
cancer.
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
questions.
[The prepared statement of Dr. Manson follows:]
[GRAPHIC(S) NOT AVAILABLE IN TIFF FORMAT]
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
therapy?
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.
STATEMENT OF LEONARD WARTOFSKY, PRESIDENT, THE ENDOCRINE
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
compounds.
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
doctors.
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
positions.
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:]
[GRAPHIC(S) NOT AVAILABLE IN TIFF FORMAT]
Senator Smith. Thank you, Doctor.
I am going to let Dr. Allen testify, and then I have a
question for the both of you.
STATEMENT OF LOYD ALLEN, EDITOR-IN-CHIEF, INTERNATIONAL JOURNAL
OF PHARMACEUTICAL COMPOUNDING, SUGAR LAND, TX
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
briefly.
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
retail.
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:]
[GRAPHIC(S) NOT AVAILABLE IN TIFF FORMAT]
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
it.
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
me.
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
endocrinologists.
Senator Smith. These pharmacies--we call it ``forum
shopping'' in the law--do they doctor-shop to find physicians
who----
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
enforcement.
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
role.
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
concerned.
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
important.
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.
STATEMENT OF T.S. WILEY, WRITER/RESEARCHER, CREATOR OF THE
WILEY PROTOCOL, SANTA BARBARA, CA
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
Texas.
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
unacceptable.
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
dead.
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
not.
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:]
[GRAPHIC(S) NOT AVAILABLE IN TIFF FORMAT]
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
hearing.
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
21.
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
happen.
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
science.
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
effects?
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
country----
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
inspects----
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
standpoint.
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
protocol?
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
serious.
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
medicine.
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;
356:1670-4.
---------------------------------------------------------------------------
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
preparation?
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.
http://www.gethormones.com/physicians.html
http://www.womensinternational.com/resources.html
http://www.naturalwoman.org/
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.''
(http://www.fda.gov/ola/2003/pharmacycompound1023.html)
Current statistics on the number of states that have adopted
this code were available.
http://www.nabp.net/ftpfiles/NABP01/ModelActFINAL.doc
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.
---------------------------------------------------------------------------
http://www.wilsonstemperaturesyndrome.com/index.html
www.netriceuticals.com/
www.naturalhealthconsult.com
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-
Micromedex.
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
USP.
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.
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