[House Hearing, 109 Congress]
[From the U.S. Government Publishing Office]
RU-486: DEMONSTRATING A LOW STANDARD FOR WOMEN'S HEALTH?
=======================================================================
HEARING
before the
SUBCOMMITTEE ON CRIMINAL JUSTICE,
DRUG POLICY, AND HUMAN RESOURCES
of the
COMMITTEE ON
GOVERNMENT REFORM
HOUSE OF REPRESENTATIVES
ONE HUNDRED NINTH CONGRESS
SECOND SESSION
__________
MAY 17, 2006
__________
Serial No. 109-202
__________
Printed for the use of the Committee on Government Reform
Available via the World Wide Web: http://www.gpoaccess.gov/congress/
index.html
http://www.house.gov/reform
RU-486: DEMONSTRATING A LOW STANDARD FOR WOMEN'S HEALTH?
RU-486: DEMONSTRATING A LOW STANDARD FOR WOMEN'S HEALTH?
=======================================================================
HEARING
before the
SUBCOMMITTEE ON CRIMINAL JUSTICE,
DRUG POLICY, AND HUMAN RESOURCES
of the
COMMITTEE ON
GOVERNMENT REFORM
HOUSE OF REPRESENTATIVES
ONE HUNDRED NINTH CONGRESS
SECOND SESSION
__________
MAY 17, 2006
__________
Serial No. 109-202
__________
Printed for the use of the Committee on Government Reform
Available via the World Wide Web: http://www.gpoaccess.gov/congress/
index.html
http://www.house.gov/reform
U.S. GOVERNMENT PRINTING OFFICE
31-397 WASHINGTON : 2007
_____________________________________________________________________________
For Sale by the Superintendent of Documents, U.S. Government Printing Office
Internet: bookstore.gpo.gov Phone: toll free (866) 512-1800; (202) 512�091800
Fax: (202) 512�092250 Mail: Stop SSOP, Washington, DC 20402�090001
COMMITTEE ON GOVERNMENT REFORM
TOM DAVIS, Virginia, Chairman
CHRISTOPHER SHAYS, Connecticut HENRY A. WAXMAN, California
DAN BURTON, Indiana TOM LANTOS, California
ILEANA ROS-LEHTINEN, Florida MAJOR R. OWENS, New York
JOHN M. McHUGH, New York EDOLPHUS TOWNS, New York
JOHN L. MICA, Florida PAUL E. KANJORSKI, Pennsylvania
GIL GUTKNECHT, Minnesota CAROLYN B. MALONEY, New York
MARK E. SOUDER, Indiana ELIJAH E. CUMMINGS, Maryland
STEVEN C. LaTOURETTE, Ohio DENNIS J. KUCINICH, Ohio
TODD RUSSELL PLATTS, Pennsylvania DANNY K. DAVIS, Illinois
CHRIS CANNON, Utah WM. LACY CLAY, Missouri
JOHN J. DUNCAN, Jr., Tennessee DIANE E. WATSON, California
CANDICE S. MILLER, Michigan STEPHEN F. LYNCH, Massachusetts
MICHAEL R. TURNER, Ohio CHRIS VAN HOLLEN, Maryland
DARRELL E. ISSA, California LINDA T. SANCHEZ, California
JON C. PORTER, Nevada C.A. DUTCH RUPPERSBERGER, Maryland
KENNY MARCHANT, Texas BRIAN HIGGINS, New York
LYNN A. WESTMORELAND, Georgia ELEANOR HOLMES NORTON, District of
PATRICK T. McHENRY, North Carolina Columbia
CHARLES W. DENT, Pennsylvania ------
VIRGINIA FOXX, North Carolina BERNARD SANDERS, Vermont
JEAN SCHMIDT, Ohio (Independent)
------ ------
David Marin, Staff Director
Lawrence Halloran, Deputy Staff Director
Teresa Austin, Chief Clerk
Phil Barnett, Minority Chief of Staff/Chief Counsel
Subcommittee on Criminal Justice, Drug Policy, and Human Resources
MARK E. SOUDER, Indiana, Chairman
PATRICK T. McHenry, North Carolina ELIJAH E. CUMMINGS, Maryland
DAN BURTON, Indiana BERNARD SANDERS, Vermont
JOHN L. MICA, Florida DANNY K. DAVIS, Illinois
GIL GUTKNECHT, Minnesota DIANE E. WATSON, California
STEVEN C. LaTOURETTE, Ohio LINDA T. SANCHEZ, California
CHRIS CANNON, Utah C.A. DUTCH RUPPERSBERGER, Maryland
CANDICE S. MILLER, Michigan MAJOR R. OWENS, New York
VIRGINIA FOXX, North Carolina ELEANOR HOLMES NORTON, District of
JEAN SCHMIDT, Ohio Columbia
Ex Officio
TOM DAVIS, Virginia HENRY A. WAXMAN, California
Marc Wheat, Staff Director
Michelle Gress, Professional Staff Member
Malia Holst, Clerk
Richard Butcher, Minority Professional Staff Member
C O N T E N T S
----------
Page
Hearing held on May 17, 2006..................................... 1
Statement of:
Harrison, Donna J., M.D., member, Mifeprex Subcommittee of
American Association of Prolife Obstetricians and
Gynecologists.............................................. 135
Patterson, Monty L., Livermore, CA........................... 117
Rarick, Lisa D., M.D., RAR Consulting, LLC................... 128
Snead, O. Carter, associate professor, University of Notre
Dame Law School, and former general counsel for the
President's Council on Bioethics........................... 338
Wood, Susan F., former Assistant Commissioner for Women's
Health and Director of the Office of Women's Health, Food
and Drug Administration.................................... 122
Woodcock, Janet, M.D., Deputy Commissioner for Operations,
Food and Drug Administration, U.S. Department of Health and
Human Services............................................. 87
Letters, statements, etc., submitted for the record by:
Cummings, Hon. Elijah E., a Representative in Congress from
the State of Maryland, prepared statement of............... 75
Harrison, Donna J., M.D., member, Mifeprex Subcommittee of
American Association of Prolife Obstetricians and
Gynecologists, prepared statement of....................... 137
Patterson, Monty L., Livermore, CA, prepared statement of.... 120
Rarick, Lisa D., M.D., RAR Consulting, LLC, prepared
statement of............................................... 131
Ruppersberger, Hon. C.A. Dutch, a Representative in Congress
from the State of Maryland, prepared statement of.......... 85
Snead, O. Carter, associate professor, University of Notre
Dame Law School, and former general counsel for the
President's Council on Bioethics, prepared statement of.... 340
Souder, Hon. Mark E., a Representative in Congress from the
State of Indiana:
Information concerning lower standards for RU-486........ 112
Judicial Watch Report.................................... 3
Prepared statement of.................................... 69
Waxman, Hon. Henry A., a Representative in Congress from the
State of California, prepared statement of................. 81
Wood, Susan F., former Assistant Commissioner for Women's
Health and Director of the Office of Women's Health, Food
and Drug Administration, prepared statement of............. 125
Woodcock, Janet, M.D., Deputy Commissioner for Operations,
Food and Drug Administration, U.S. Department of Health and
Human Services, prepared statement of...................... 90
RU-486: DEMONSTRATING A LOW STANDARD FOR WOMEN'S HEALTH?
----------
WEDNESDAY, MAY 17, 2006
House of Representatives,
Subcommittee on Criminal Justice, Drug Policy, and
Human Resources,
Committee on Government Reform,
Washington, DC.
The subcommittee met, pursuant to notice, at 2:04 p.m., in
room 2203, Rayburn House Office Building, Hon. Mark E. Souder
(chairman of the subcommittee) presiding.
Present: Representatives Souder, Schmidt, Shays, Cummings,
Davis, Watson, Ruppersberger, Norton, and Waxman.
Staff present: Marc Wheat, staff director and chief
counsel; Michelle Gress, professional staff member and counsel;
Malia Holst, clerk; Karen Lightfoot, minority senior policy
advisor and communications director; Sarah Despres, Tony
Haywood, Kimberly Trinca, Naomi Seiler, minority counsels;
Richard Butcher, minority professional staff member; and Teresa
Coufal, minority assistant clerk.
Mr. Souder. The subcommittee will come to order. We are
here today because there is a drug on the market associated
with the deaths of at least 8 women, 9 life-threatening
incidents, 232 hospitalizations, 116 blood transfusions, and 88
cases of infection. There are more than 950 adverse event cases
associated with RU-486 out of only 575,000 prescriptions, at
most. Adverse events are typically under-reported, since they
are offered voluntarily by consumers and health care
professionals, so it is most likely that there are many more
cases that we don't even know about.
It is very clear that there is a serious problem with RU-
486. In failing to address this problem by disguising it,
ignoring it, minimizing it, or causing confusion, it is a
shameful failure for anyone with the ability and desire to
protect women from needless harm.
RU-486 is a common name for Mifeprex. It is produced by
Danco Laboratories, a corporate entity located in the Cayman
Islands which produces only that single drug and nothing else.
Mifeprex is approved by the FDA for the termination of
pregnancy through 49 days of development. It is used in
combination with another drug called Misoprostol, which causes
uterine contractions that expel the dead fetus. This is an off-
label use for the Misoprostol, which contains a black box
warning against using the drug during pregnancy.
At least five of the deaths following the use of RU-486
have been the result of toxic shock-like syndrome initiated by
the bacteria Clostridium Sordellii. This bacteria is thought to
exist in low numbers in the reproductive tracts of many women
and is normally combatted by the immune system. Experts in
immunology, pharmacology, and maternal-fetal medicine have
suggested that because RU-486 interferes with the innate immune
response, the bacteria, if present, is allowed to flourish,
causing a widespread multi-organ infection in the woman. These
infections are not accompanied by a fever and the symptoms
match those that are expected after taking the RU-486 regime,
including cramping, pain, bleeding, nausea, vomiting. Each of
the women infected with C. Sordellii after taking RU-486 were
dead within 5 to 7 days.
To investigate the nature of this bacteria, the CDC and FDA
held a scientific workshop last week called ``Emerging
Clostridial Disease.'' The workshop panelists noted that the
rapid growth of the C. Sordellii bacteria in the RU-486 context
likely forecloses effective treatment and that there is no
currently identifiable window of opportunity for treatment once
a woman is infected, even with major interventions such as a
hysterectomy. The fatality rate has been 100 percent for the
women who have contracted C. Sordellii infection after using
RU-486.
Any other drug associated with a 100 percent fatal septic
infection that kills otherwise healthy adults within days, with
no apparent window for treatment, and associated with an
exponential amount of severe reactions would normally prompt an
immediate withdrawal. But we are talking about a drug regimen
that is administered to cause an abortion, manufactured by a
drug company based in the Cayman Islands with no other drugs on
the market, and therefore no incentive to voluntarily withdraw
its product, no matter how dangerous.
Many abortion advocates feel they have to defend RU-486
because it is an alternative to surgical abortion. However,
with eight deaths that we know about, RU-486 is 10 to 14 times
more likely to be fatal than surgical abortion during the first
7 weeks of pregnancy, the period during which the drug is
administered. To continue defending this dangerous drug in
light of the mounting scientific evidence, injury, and death is
to allow one's zeal for abortion to truly distort their view
about what is right for women's health. The 10-times-more-
deadly danger posed by RU-486 should not be considered an
acceptable risk that justifies keeping this drug on the market.
The approval of RU-486 was made under extreme political
pressure from the Clinton administration, which is well
documented in a recent report by Judicial Watch entitled ``The
Clinton RU-486 Files.'' I ask that this report be included in
the hearing record.
[The information referred to follows:]
[GRAPHIC] [TIFF OMITTED] T1397.001
[GRAPHIC] [TIFF OMITTED] T1397.002
[GRAPHIC] [TIFF OMITTED] T1397.003
[GRAPHIC] [TIFF OMITTED] T1397.004
[GRAPHIC] [TIFF OMITTED] T1397.005
[GRAPHIC] [TIFF OMITTED] T1397.006
[GRAPHIC] [TIFF OMITTED] T1397.007
[GRAPHIC] [TIFF OMITTED] T1397.008
[GRAPHIC] [TIFF OMITTED] T1397.009
[GRAPHIC] [TIFF OMITTED] T1397.010
[GRAPHIC] [TIFF OMITTED] T1397.011
[GRAPHIC] [TIFF OMITTED] T1397.012
[GRAPHIC] [TIFF OMITTED] T1397.013
[GRAPHIC] [TIFF OMITTED] T1397.014
[GRAPHIC] [TIFF OMITTED] T1397.015
[GRAPHIC] [TIFF OMITTED] T1397.016
[GRAPHIC] [TIFF OMITTED] T1397.017
[GRAPHIC] [TIFF OMITTED] T1397.018
[GRAPHIC] [TIFF OMITTED] T1397.019
[GRAPHIC] [TIFF OMITTED] T1397.020
[GRAPHIC] [TIFF OMITTED] T1397.021
[GRAPHIC] [TIFF OMITTED] T1397.022
[GRAPHIC] [TIFF OMITTED] T1397.023
[GRAPHIC] [TIFF OMITTED] T1397.024
[GRAPHIC] [TIFF OMITTED] T1397.025
[GRAPHIC] [TIFF OMITTED] T1397.026
[GRAPHIC] [TIFF OMITTED] T1397.027
[GRAPHIC] [TIFF OMITTED] T1397.028
[GRAPHIC] [TIFF OMITTED] T1397.029
[GRAPHIC] [TIFF OMITTED] T1397.030
[GRAPHIC] [TIFF OMITTED] T1397.031
[GRAPHIC] [TIFF OMITTED] T1397.032
[GRAPHIC] [TIFF OMITTED] T1397.033
[GRAPHIC] [TIFF OMITTED] T1397.034
[GRAPHIC] [TIFF OMITTED] T1397.035
[GRAPHIC] [TIFF OMITTED] T1397.036
[GRAPHIC] [TIFF OMITTED] T1397.037
[GRAPHIC] [TIFF OMITTED] T1397.038
[GRAPHIC] [TIFF OMITTED] T1397.039
[GRAPHIC] [TIFF OMITTED] T1397.040
[GRAPHIC] [TIFF OMITTED] T1397.041
[GRAPHIC] [TIFF OMITTED] T1397.042
[GRAPHIC] [TIFF OMITTED] T1397.043
[GRAPHIC] [TIFF OMITTED] T1397.044
[GRAPHIC] [TIFF OMITTED] T1397.045
[GRAPHIC] [TIFF OMITTED] T1397.046
[GRAPHIC] [TIFF OMITTED] T1397.047
[GRAPHIC] [TIFF OMITTED] T1397.048
[GRAPHIC] [TIFF OMITTED] T1397.049
[GRAPHIC] [TIFF OMITTED] T1397.050
[GRAPHIC] [TIFF OMITTED] T1397.051
[GRAPHIC] [TIFF OMITTED] T1397.052
[GRAPHIC] [TIFF OMITTED] T1397.053
[GRAPHIC] [TIFF OMITTED] T1397.054
[GRAPHIC] [TIFF OMITTED] T1397.055
[GRAPHIC] [TIFF OMITTED] T1397.056
[GRAPHIC] [TIFF OMITTED] T1397.057
[GRAPHIC] [TIFF OMITTED] T1397.058
[GRAPHIC] [TIFF OMITTED] T1397.059
[GRAPHIC] [TIFF OMITTED] T1397.060
[GRAPHIC] [TIFF OMITTED] T1397.061
[GRAPHIC] [TIFF OMITTED] T1397.062
[GRAPHIC] [TIFF OMITTED] T1397.063
[GRAPHIC] [TIFF OMITTED] T1397.064
Mr. Souder. RU-486 was forced through the FDA using an
extraordinary provision called Subpart H, reserved only for
drugs that treat life-threatening illnesses and for which
existing treatments are insufficient. It was obvious even to
the drug's sponsor that RU-486 did not fall within the narrow
scope of Subpart H, saying the FDA's imposition of Subpart H
was unlawful, unnecessary, and undesirable. But that did not
deter the FDA in its extraordinary political complicity with
President Clinton's administration from forcing an abortion
pill onto the market, no matter how distorted the approval
process was or what the price.
We are paying that price now. Almost 1,000 women have
suffered adverse effects after taking RU-486. We know that
eight have died. We have a responsibility to consider the
dangers that this drug poses and question whether the FDA has
the authority to remove it from the market in the light of the
severe problems associated with this drug and the
manufacturer's failure to comply with post-marketing
restrictions.
I anticipate that the defenders of RU-486 will try to
detract from the cold, hard facts or cause confusion by talking
about other septic infections in other pregnancy situations.
This tactic ignores what the panelists reported at last week's
CDC conference, that Mifeprex compromises the innate immune
system, providing an environment for rapid growth of the deadly
infection.
C. Sordellii infection in the RU-486 context is 100 percent
fatal, with no opportunity for intervention. To ignore the
immune system connection with Mifeprex, or to say that there
have been only five such deaths and advocate only for better
surveillance and informed consent will be no comfort to the
family of the next women who dies suddenly after taking RU-486.
To the shallow objection that those of us who are pro-life
have no business looking into the problems associated with RU-
486, let me respond that this is a smokescreen and is
incredibly shameful. Anyone who honestly cares about women's
health has to take a critical look at the potential dangers of
this drug. To argue otherwise, on the basis that it is simply
an abortion issue, is to demonstrate a blind allegiance to
abortion at any cost, including women's lives.
Representing the FDA on the first panel is Dr. Janet
Woodcock, Deputy Commissioner for Operations.
On our second panel, we will hear from Monty Patterson, the
father of Holly Patterson, who was 18 years old when she died
after taking RU-486; Dr. Susan Wood, former FDA Assistant
Commissioner for Women's Health; Dr. Lisa Rarick of RAR
Consulting; Dr. Donna Harrison, a member of the Mifeprex
Subcommittee of the American Association of Prolife
Obstetricians and Gynecologists, and Carter Snead, Associate
Professor of Law at Notre Dame and former General Counsel for
the President's Council on Bioethics.
I wish to note that the medical director for Danco, the
Cayman Islands-based manufacturer for RU-486, initially agreed
to testify at this hearing, but pulled out 2 days ago. I intend
to followup with Danco to request answers in a sworn affidavit
to critical questions regarding Danco's failure to comply with
the post-marketing restrictions for RU-486.
Last of all, I want to note that I notified the FDA last
December that this subcommittee would conduct a hearing into
RU-486. FDA's compliance with this oversight committee's
document requests has been quite frustrating. We were getting
critical documents related to our December request as late as
last night. This hearing is not the end of our document
requests and I invite better cooperation from the agency moving
forward. Now that we are here and we have most of the documents
we requested 5 months ago, it is time to seek some answers
about what can be done to protect women from this deadly drug.
[The prepared statement of Hon. Mark E. Souder follows:]
[GRAPHIC] [TIFF OMITTED] T1397.065
[GRAPHIC] [TIFF OMITTED] T1397.066
[GRAPHIC] [TIFF OMITTED] T1397.067
[GRAPHIC] [TIFF OMITTED] T1397.068
Mr. Souder. Now I yield to the ranking member, Mr.
Cummings, for his opening statement.
Mr. Cummings. Thank you very much, Mr. Chairman. I want to
join you in welcoming all of our witnesses testifying this
afternoon on a very important subject, protecting women's
health.
And particularly, I want to acknowledge Mr. Monty
Patterson, who lost his 18-year-old daughter, Holly, when she
died as a result of a rare bacterial infection. I offer my
sincere condolences to the Patterson family and want to commend
Mr. Patterson and his family for their efforts to become well-
versed in this subject area in the wake of a terrible family
tragedy.
As you know, Mr. Chairman, C. Sordellii is a bacterium that
normally resides in soil. Although cases of human illness are
rare, the effect is usually fatal when the bacteria produces
toxins that cause rapid onset of shock that physicians are
powerless to curtail.
To date, medical literature reflects a total of
approximately 30 reported fatalities from C. Sordellii
infection. Cases of infection have involved both males and
females of all ages. At least eight of the reported fatalities
occurred in women who had just given birth, and two occurred
after miscarriages.
The selective focus of today's hearing centers on five
fatal cases that have occurred over the past 5 years and also
involved pregnancy. Four of these cases occurred in California,
the other in Canada. The key factor linking this small subset
of cases is that they occurred in women who underwent medical
abortion.
Last week, the Centers for Disease Control, as you said,
convened a scientific meeting on C. Sordellii and another
related bacterium. The meeting served to underscore just how
little is known about the cause of human C. Sordellii
infections. Although a number of theories were advanced and
debated, the meeting produced no solid answers as to how the
infection is acquired. The only consensus was that much more
needs to be learned if additional deaths are to be prevented.
Despite the overwhelming scientific uncertainty among
experts, a number of policymakers and policy shapers apparently
have already arrived at the conclusion that the drug
Mifepristone, also known as RU-486 and marketed in the United
States under the name Mifeprex, is the likely cause of the
infection in the five cases involving patients who underwent
medical abortion. Consequently, they are advocating the FDA's
immediate withdrawal of Mifeprex from the market. What is the
basis for this belief? Is it science, or is it something else?
It is difficult to overlook the fact that adherents to this
point of view generally opposed the introduction of
Mifepristone into the United States in the first place, or to
ignore the fact that they did so on an ideological grounds,
knowing that there had been no reported fatalities among as
many as 2 million users of the drug in Europe.
To bolster their argument, proponents of withdrawing FDA
approval suggest that the FDA, in effect, rushed the drug to
market. But the record shows that the approval process was
thorough and unusually lengthy. However, it resulted in more
stringent restrictions on distribution than apply to most other
drugs.
Mr. Chairman, I hope it is fair and correct to presume that
not one participant in today's hearing takes the health of
women lightly. As a matter of fact, every single one of us take
women's health very seriously. My own concern for both women's
health and women's rights leads me to wonder, however, why the
narrow focus on these cases and on this drug as the suspected
culprit? Why not concern ourselves with all the possible causes
of infection in not only these 5 cases, but also the other 9 or
10 reported cases in which pregnancy was the common
denominator?
If ensuring a high standard of health care for American
women is our pure objective, it just seems to me, Mr. Chairman,
that our focus should be seeking the truth concerning the cause
of C. Sordellii infection rather than attempting to bully the
FDA into taking action, unsupported by science, that would have
just one certain impact, limiting access to abortion for many,
many women.
Therefore, I hope today's hearing can serve the purpose of
promoting thorough scientific inquiry and supporting a research
agenda that will lead us to answers that can prevent infection
and death from infection.
Concentrating on five cases involving medical abortion to
the exclusion of a larger number of equally tragic cases
appears to serve the narrow purpose of whittling away at a
women's constitutional right to choose by limiting practical
access to abortion. I only hope that, in this case, appearances
are deceiving.
I look forward to the testimony and I thank the witnesses
for being with us, and with that, Mr. Chairman, I yield back.
[The prepared statement of Hon. Elijah E. Cummings
follows:]
[GRAPHIC] [TIFF OMITTED] T1397.069
[GRAPHIC] [TIFF OMITTED] T1397.070
[GRAPHIC] [TIFF OMITTED] T1397.071
[GRAPHIC] [TIFF OMITTED] T1397.072
Mr. Souder. I now yield to other Members wishing to make
opening statements. Mr. Waxman, do you have an opening
statement? I am going to ask for this process. It has been a
practice if Members are members of the full committee but not
the subcommittee, that we let them participate, and I ask
unanimous consent that Mr. Shays be allowed to participate, and
he will go to the back of the rest of everybody else's opening
statements.
I yield to Mr. Waxman.
Mr. Waxman. Thank you very much, Mr. Chairman. I appreciate
this chance to make an opening statement and to attend this
hearing because this is an important hearing. It gives us a
chance to talk about the deaths of several women who had taken
Mifepristone, RU-486--we all have been stumbling over that
word--which is the medical abortion pill. These deaths were
tragic and I also want to join in extending my deepest
sympathies to the Patterson family, who lost their daughter,
and thank you for coming today.
We are going to discuss these cases as part of a broader
pattern of C. Sordellii infection. This is an infection that
has killed men, women, and children. It has killed women who
have just given birth, women who had miscarriages, and women
who had not even been pregnant. As with any infection we do not
yet understand well, we need better research and surveillance
to fight it.
But before we begin this discussion, I would like to say
something about another reason I believe we are here. There are
people who have wanted RU-486 to be pulled off the market since
the day it was approved. In fact, they didn't want it to be
approved. I respect their judgment because they are very
strongly against an abortion, whether it be by RU-486 or by a
medical procedure.
But that is not the issue of safety and it is not an issue
of science and it is not an issue of data. That makes it an
ideological opposition to a woman's right to choose abortion.
And, in fact, many of those who want to take this drug off the
market want women to have virtually zero access to any kind of
abortion, whether it be medical or surgical.
I need not remind people what happened before abortion
became legal and safe in the United States. Hundreds of
thousands of women per year sought out illegal abortions or
tried to induce abortions themselves. Tens of thousands
suffered major infections and other injuries. And even after
the introduction of antibiotics, hundreds of women died every
year before abortion was made legal and safe.
There are many who want us to have States' rights to pass
the kind of law that was just adopted in South Dakota, to ban
all abortions, even in the case of rape or incest, or even to
preserve the health and well-being of the mother. That is the
ultimate expression of their point of view, but it is not the
point of view I share and it is not the point of view that I
think most people would share.
This drug, which is the subject of today's hearing, has
some promising characteristics. It offers women an alternative
to surgery for early termination of pregnancy. It is available
to many women who do not have access to surgical abortions. And
it has been widely and safely used in Europe.
On the other hand, questions have been raised about whether
there may be a link between the drug and the tragic deaths of
several young women. That is the question. Is there a link
between this drug and those deaths? And that is a scientific
issue, not an ideological one, and it is an issue that we ought
to leave to the Food and Drug Administration scientists to look
at the evidence.
Now, it has been asserted by the chairman that the side
effects may be understated because there is voluntary
disclosure. Well, that is true of all drugs--there is voluntary
disclosure of adverse effects--but not this drug, because the
drug had a lengthy period of time during which it was under
surveillance at the Food and Drug Administration. It was
approved ultimately under Subpart H, which put a lot of
restrictions in place on the use of this drug which are not in
place for the use of other drugs that are available on the
market today in the United States. And one of the limits to its
use was that a physician had to agree in advance to report any
adverse consequences from use of this drug to the manufacturer
and the manufacturer is obligated under law to report it to the
FDA. So we have a pretty clear picture of what has been going
on.
This is not like the Plan B drug, which has not been
approved by the FDA for over-the-counter use because of
political pressure on the FDA. This drug was not approved by
political pressure, it was approved under the usual standards
of safety and efficacy.
Now, other drugs have been approved under that status and
have been taken off when we saw that there were consequences to
it which changed the balance of whether it was a safe and
efficacious drug, and that is the issue of whether this drug
should remain available to women. It should be resolved based
on scientific assessment of its benefits and dangers. If the
best scientific evidence turns out to demonstrate that the
risks do, in fact, outweigh the benefits, then the FDA should
make a decision accordingly. But it should be kept on the
market or removed using the same legal and scientific standards
that are used for all other drugs.
For today, let us take a close and serious look at C.
Sordellii infection. We must encourage our scientists to figure
out why these women and the other victims of this bacteria,
which had no relationship that we know of to RU-486, why they
died, and we should do everything we can to improve detection
and treatment. But in the end, we need to make sure any
regulatory decision about RU-486 is based on the science and
the law and not the politics of the abortion debate.
Thank you, Mr. Chairman.
[The prepared statement of Hon. Henry A. Waxman follows:]
[GRAPHIC] [TIFF OMITTED] T1397.073
[GRAPHIC] [TIFF OMITTED] T1397.074
Mr. Souder. Ms. Holmes Norton, do you have an opening
statement?
Ms. Holmes Norton. Thank you very much, Mr. Chairman. Mr.
Chairman, first, I want to say that if there is a drug, if it
is a contraceptive drug, if it is a drug related in any way to
the health of women, that scientists tell us causes death or
injury of any kind, that drug should have no approval.
I don't think this committee is qualified to make that
judgment. I think that judgment has to be committed to the kind
of scientific study you would do if you were serious about
these eight deaths. The most important thing we can do is to
find out causation here, because then we know how to prevent
the deaths or injury. Anything that stands in the way of that
link is not a serious attempt to deal with it. Anything that
jumps over the appropriate scientific inquiry is not serious
about these eight deaths.
I think RU-486 has been very important in preventing
abortions and in getting to where American women are going to
get anyway. We simply will never be able to keep this kind of
drug, which has not been shown to be harmful by scientists, out
of the hands of people. So if it is going to get into the hands
of people, one thing we want to know is what causes it.
What we don't want is to investigate scientists, for
example, who give us answers contrary to our personal or moral
or religious beliefs. We want to leave them free and unfettered
to tell us what the scientific method reveals to them.
Finally, Mr. Chairman, I particularly regret not being able
to stay throughout this hearing because of other hearings, but
I do want to go on the record indicating the unthinkable series
we have witnessed during this term that show the unmitigated
politicization of the one area that Americans always held off
from politics, and that is science itself. Whether Schiavo or
creationism renamed intelligent design or stem cell research
or, God help us, global warming itself, there are views
floating around this Congress that essentially reach
conclusions on these matters of huge scientific moment based on
their own personal belief.
I never thought that the country that has stood at the
forefront of science in the world would ever reduce science to
personal, political, and religious views and opinions and I
don't believe that, in effect, that is what the country is
going to let us do when they see the long list before them of
bills, of things we now can't do, of things we do do, only
because of the personal, political, and religious views of some
Members. When they see that the attempts that have been made
during this session of Congress and during this administration
to burden scientists with the personal views of Members of
Congress, it is a shameful day for American science and I think
we have to wipe it away if we do nothing else.
Thank you, Mr. Chairman.
Mr. Souder. Mr. Davis.
Mr. Davis of Illinois. Thank you very much, Mr. Chairman,
and I shall be brief. Let me just thank you for calling this
hearing. I think that every single one of us are indeed
concerned about the health, safety, and well-being of every
single individual as they make use of a drug, medical
procedure, or pattern of treatment. I would hope especially
given the fact that we are talking about safety of a drug, that
we discuss and debate the science and not the ideological
expressions of individuals who may be bent one way or another
around the question and the issue of abortion.
And so I look forward to the witnesses and look forward to
the information that is going to be presented and I yield back
the balance of my time.
Mr. Souder. Mr. Ruppersberger.
Mr. Ruppersberger. Thank you, Mr. Chairman, for having this
hearing. We know the issue of abortion is a very difficult
issue for many citizens in this country and there are different
people that have different points of view. One of the issues it
looks like--you can't hear? That is probably a good thing.
[Laughter.]
Starting again, we know the abortion issue is a very
difficult issue and we also know that individuals, no matter
which side of the issue you are on with respect to abortion, is
something that you are probably not going to change. It would
be more positive for our whole country if we could come to some
resolution, but I don't think that is going to happen.
But I think in today's hearing it is important that we
really don't use the political issue of abortion but focus on
this RU-486. With that in mind, RU-486 underwent a vigorous, a
rigorous 4-year review process at the FDA, more rigorous than
most drugs. As you know, it was considered under a select set
of regulations called Subpart H, which allowed the FDA to add
more conditions on the drug's distribution and use.
But since its approval in the year 2000, nearly 600,000
women in the United States have used RU-486. It has proven to
be a safe and effective means of terminating early pregnancy.
Because of this medical option, millions of women worldwide,
including survivors of sexual assault, have had the right to
end an early pregnancy with privacy and dignity.
Tragically, there have been four confirmed deaths in the
United States from bacterial infection in women who used RU-
486. At this point, we do not know what caused these infections
or if these deaths are at all related to the use of RU-486.
Fortunately, the CDC and FDA have moved quickly to
investigate these incidents. Early this month, RU-486
scientists from the Nation's leading public health agencies
gathered in Atlanta to discuss the bacteria that caused these
deaths and the risk it poses to pregnant women. Career
scientists and doctors are the best equipped to investigate
this issue and I know they will get to the bottom of it. We
must rely on accepted medical standards for determining the
safety and efficacy of a medication. The future of RU-486
should lie with the FDA and the medical community, not with
Congress, who do not have yet the full picture and have
scientific data before us to make a decision on women's health.
I yield back.
[The prepared statement of Hon. C.A. Dutch Ruppersberger
follows:]
[GRAPHIC] [TIFF OMITTED] T1397.075
Mr. Souder. Ms. Watson.
Ms. Watson. I want to thank you, Mr. Chairman. I applaud
the subcommittee for bringing this topic up to educate the
American public.
It is very important that the FDA, our drug watchdog
agency, is engaged with the scientific community and the
population at large in order to provide informed choices for
the women of the United States. Mifepristone, or RU-486, has
been utilized for nearly two decades by women all over the
globe. This drug provides an early abortion option that does
not require surgery. It has been reported that since the FDA
approved RU-486 in 2000, significantly more than half a million
American women have used this medication.
Mr. Chairman, let us be very clear during this hearing
today. Ideological debate pro or anti-abortion is a discussion
that we have been afforded the free speech right to talk about.
Medical process and drug effectiveness should not be subject to
any debate of that style. It is imperative to the health of our
Nation that Congress, the FDA, health care delivery
professionals, and the scientific community and patients
approach the utilization of any drug from an educated,
scientifically tested, and unbiased perspective.
So I am interested to hear the testimony of our witnesses
because oversight is a serious responsibility that we undertake
on behalf of the American people, and the use of RU-486 is a
subject that must be treated with unbiased integrity and regard
for the overall health of women.
Four women have died of sepsis. All four were infected by
the same type of bacteria. What does the medical and scientific
community say to this situation? Is Mifeprex responsible? So
our decision should be based on education and scientific
investigation and I look forward to hearing about that
information.
I yield back my time, Mr. Chairman. Thank you very much.
Mr. Souder. Thank you. Mr. Shays.
Mr. Shays. Thank you, Mr. Chairman. I want to thank you,
one, for having a hearing on this issue, to encourage you to
use that same logic to have a hearing on Plan B, which is a
related drug that doesn't require an abortion but can
accomplish the same task. I want to say that I have
extraordinary respect for you, and in spite of your bias one
way and my bias the other, I am convinced that this will be a
fair hearing and I appreciate that.
I guess I would just end by saying that I appreciate
particularly the thoughtful statement of your ranking member,
Mr. Cummings, and the ranking member of the full committee. I
think others have said the same thing, but I think they covered
it well. If I could have written a statement in time, I would
have been pleased to have written either of those two
statements, so I would like to stand on their statements.
Again, thank you for allowing me to participate.
Mr. Souder. Thank you, and the record needs to show that
there have been 8 women, at least, who have died, 950 adverse
events, and not all are necessarily associated with the other
infection.
Also, I would like to ban abortion, but this isn't about
abortion. We can't ban abortion. This is a health question.
Just because scientists disagree doesn't mean that one person
is trying to put an ideological view on it and other people
have a scientific view.
In a number of issues lately, I have been accused of being
anti-science because the scientists I support disagree with the
scientists who another group support. In fact, this drug was
cleared in an expedited process, not using mostly U.S.
research, and we have a right to look into this drug and we
should be looking into this drug. Scientists disagree and we
should hear the debate. Just because one group of scientists is
political doesn't mean that the other group of scientists
aren't political, too. We all know that science requires
judgments, as well. If it was just an ideological view, we
couldn't hold this hearing. We are not hearing from ideological
people, we are hearing from medical people, we are hearing from
researchers, and we will hear the debate and I am looking
forward to that debate.
I ask unanimous consent that all Members have 5 legislative
days to submit written statements and questions for the hearing
record and that any answers to written questions provided by
the witnesses also be included for the record. Without
objection, it is so ordered.
I also ask unanimous consent that all exhibits, documents,
and other materials referred to by Members and the witnesses
may be included in the hearing record, that all Members be
permitted to revise and extend their remarks, and without
objection, it is so ordered.
Our first panel is composed of Janet Woodcock. Dr. Woodcock
is Deputy Commissioner for Operations at the FDA. If you could
come forward, remain standing. As an oversight committee, it is
our standard procedure to swear in our witnesses. If you will
raise your right hand.
[Witness sworn.]
Mr. Souder. Let the record show that the witness responded
in the affirmative.
We thank you for coming today and we are looking forward to
your testimony.
STATEMENT OF JANET WOODCOCK, M.D., DEPUTY COMMISSIONER FOR
OPERATIONS, FOOD AND DRUG ADMINISTRATION, U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
Dr. Woodcock. Good afternoon, Mr. Chairman, Congressman
Cummings, and Members of the subcommittee. I am Janet Woodcock,
Deputy Commissioner for Operations at the Food and Drug
Administration. Today, I will discuss the approval history and
the current regulatory status of the product Mifepristone,
currently marketed in the United States under the trade name
Mifeprex and indicated for termination of early pregnancy.
First, I would like to correct any misconceptions that may
exist about the initial approval of the drug. Mifeprex was
approved in September 2000 after extensive FDA review of the
application, which included three adequate and well-controlled
trials documenting the efficacy and safety profile of the drug
when used for this indication. In addition, post-market
experience in Europe included over 620,000 exposures for
pregnancy termination, of which 415,000 were in combination
with Misoprostol. These data fully conform with FDA's standards
for approval.
In order to assure that Mifeprex was used by qualified
specialists, FDA and the sponsor agreed that the drug would be
approved under 21 CFR 314.520. This section of Subpart H
concerns safety, not effectiveness. This infrequently used
regulatory provision allows approval of a drug with
restrictions to assure safe use. In this case, distribution of
Mifeprex is restricted to physicians qualified to supervise
medical abortion and its complications and who have agreed to
fully inform patients and obtain their written agreement to
provide an FDA-approved patient information sheet and agreed to
report serious adverse events to the sponsor.
This product met the requirements of all applicable laws
and regulations, including Subpart H. As FDA made clear in the
preamble to the final rule, the Subpart H regulations were
intended to apply to serious or life-threatening conditions,
such as depression, not only to diseases. Approval of Mifeprex
under restricted distribution had nothing to do with
accelerated approval based on a surrogate end point, which is a
separate provision of the regulations.
FDA has monitored reports of Mifeprex-related adverse
events very carefully after marketing. As of March 31, 2006,
950 cases related to the approved use were submitted to FDA.
Consistent with the clinical trials' experience and the drug
label, heavy vaginal bleeding was the most frequently reported
adverse event, with 422 cases, followed by incomplete abortion,
with approximately 400 cases. Other serious events included 88
instances of infection, with 18 of them considered severe, and
27 ectopic pregnancies. This adverse event profile was
consistent with prior experience with medical termination of
pregnancy.
Since approval, FDA has evaluated nine reports of death in
the United States potentially associated with the approved
indication. Three of these have either been found or appear to
be unrelated to medical abortion. An additional death was due
to a ruptured ectopic pregnancy. The use of Mifeprex is
contraindicated in ectopic pregnancy. Five deaths were due to a
rapidly fatal toxin mediated shock syndrome. One of these was
caused by infection with Clostridium Perfringens. The four
additional deaths, all in California, were caused by infection
with a rare anaerobic bacterium, Clostridium Sordellii. An
additional Clostridium Sordellii fatality previously occurred
in a clinical trial in Canada.
This rapidly fatal toxin mediated shock syndrome was not
anticipated to be a complication of medical abortion. It has
not been reported in the extensive European experience to date,
estimated over 1.5 million uses of the drug. Eight previous
U.S. cases of fatal shock due to C. Sordellii, primarily after
vaginal delivery or Caesarian delivery, have been reported in
the obstetrical literature.
FDA responded aggressively to the reports, with extensive
followup and expert consultation. Last week, NIH, CDC, and FDA
cosponsored a scientific workshop on potential emerging
Clostridium infections. CDC researchers identified three
additional C. Sordellii cases, two fatal, that occurred after
spontaneous abortion. CDC has also instituted an investigation
in California looking into 321 unexplained pregnancy-associated
deaths between 2000 and 2003. They have excluded 303 cases from
being related to toxic shock-related syndrome and are further
investigating 18 more.
Given that the information on this infection and its
epidemiology is still emerging, it is not possible at this time
to determine whether the current Mifepristone/Misoprostol
regimen for medical abortion results in an increased risk of C.
Sordellii infection or whether the reporting requirements under
the Mifeprex approval and subsequent intensive investigations
have uncovered what is an emerging risk in pregnancy overall.
FDA is collaborating with the CDC and NIH on further research
into this infection and will continue to provide timely public
information.
I will be happy to answer your questions.
[The prepared statement of Dr. Woodcock follows:]
[GRAPHIC] [TIFF OMITTED] T1397.076
[GRAPHIC] [TIFF OMITTED] T1397.077
[GRAPHIC] [TIFF OMITTED] T1397.078
[GRAPHIC] [TIFF OMITTED] T1397.079
[GRAPHIC] [TIFF OMITTED] T1397.080
[GRAPHIC] [TIFF OMITTED] T1397.081
[GRAPHIC] [TIFF OMITTED] T1397.082
[GRAPHIC] [TIFF OMITTED] T1397.083
[GRAPHIC] [TIFF OMITTED] T1397.084
[GRAPHIC] [TIFF OMITTED] T1397.085
[GRAPHIC] [TIFF OMITTED] T1397.086
[GRAPHIC] [TIFF OMITTED] T1397.087
[GRAPHIC] [TIFF OMITTED] T1397.088
[GRAPHIC] [TIFF OMITTED] T1397.089
[GRAPHIC] [TIFF OMITTED] T1397.090
[GRAPHIC] [TIFF OMITTED] T1397.091
[GRAPHIC] [TIFF OMITTED] T1397.092
[GRAPHIC] [TIFF OMITTED] T1397.093
[GRAPHIC] [TIFF OMITTED] T1397.094
[GRAPHIC] [TIFF OMITTED] T1397.095
Mr. Souder. Let me ask this first question as a multi-part.
This drug went through a different type of an approval process
than others, Subpart H in the approval process, and it allows
the FDA to impose certain restrictions on the distribution of
Mifeprex, which you covered in your written testimony. How do
you monitor Danco's compliance with each of these restrictions
and what do you do when they are not in compliance?
Furthermore, are they absolutely required to report all the
incidents?
Dr. Woodcock. Yes. FDA has, once the drug was approved
under these provisions, put into place an inspectional system
for FDA to inspect the manufacturer to assure they were
complying with the provisions of the approval, and we have done
frequent inspections to oversee their compliance with this
program.
Mr. Souder. And are they required under the law to report
all adverse effects?
Dr. Woodcock. All manufacturers are required under the law
to report adverse events that they find out about with drugs
that they manufacture or distribute to the FDA.
Mr. Souder. Are you tracking that?
Dr. Woodcock. Yes.
Mr. Souder. And then if you are, how did the manufacturer
not know about some of the things that you referred to, or did
you discover those through the manufacturer? Have they reported
any of these? Do you view them as cooperative?
Dr. Woodcock. The vast majority of reports that we have
received, which are over 1,000, counting duplicates, have come
directly from the manufacturer. The physicians who have signed
the physician agreement are instructed to report adverse events
to the manufacturer.
Mr. Souder. We heard a number of the opening statements
refer to that there is a regimen, but yet RU-486 is frequently
used past the 49 days as it is recommended and it is
administered at a dosage of 200 rather than the FDA-approved
600 dosage. It is often prescribed without the required patient
agreement form and its counterpart, Misoprostol, is used
vaginally despite its approval for oral use only. Furthermore,
although the manufacturer is required to have the ability to
track its use to the patient level, the manufacturer estimates
to arrive at usage rates for the purposes of safety and
promotional material, WHO, Planned Parenthood, and a number of
these are not following your regimen. Would it be fair for one
to conclude from this evidence that RU-486 is not being used
according to the restriction that you imposed on it in Subpart
H?
Dr. Woodcock. There is no restriction in the approval
letter or in the physician agreement that says the physician
must use a specified dose or regimen. The manufacturer, who FDA
regulates, is complying with the restrictions that were placed
on the drug distribution at the time of approval.
Mr. Souder. So you are saying that individuals are--let me
ask this. Would it be fair for one to conclude that the
restrictions placed on RU-486 have failed to ensure that the
drug will be used in a manner consistent with the FDA's opinion
on safe use? In other words, when you cleared the drug, it was
cleared on the basis of the usage. Now what you are telling me
is there is no checking to see that it is being used in the way
you approved it, and could not that explain some of the
problem?
Dr. Woodcock. The restriction program was pub in place to
ensure that physicians who prescribe the drug could date a
pregnancy--that is a very important aspect of using this
regimen--could rule out with professional experience an ectopic
pregnancy, and were manage the complications of medical
abortion, which include requirements for surgical intervention.
So that was the purpose of the restriction program.
FDA reviews data that is submitted to it when FDA approves
a dose and a regimen in an approved indication for use of the
drug. Subsequently, based on medical literature, physicians may
deviate from the recommended dose and this occurs very
frequently. The restricted distribution program had to do with
distribution to physicians who were qualified. So the drug is
not available in pharmacies. It cannot be prescribed by
physicians who are not qualified and have not gone through the
program.
Mr. Souder. So let me see if I can understand, see if this
is an oversimplification of what you just said. You said you
tested it with one regimen. Then you didn't put that in force
because you concluded after the tests, based on information
that regimen wasn't essential to the safety of the individuals?
Dr. Woodcock. FDA----
Mr. Souder. Because the regimen dealt with other subjects
other than the safety.
Dr. Woodcock. FDA reviewed the data based on the safety and
effectiveness information that was included in the application.
That was the recommended regimen, the approved regimen that is
in the drug label. The patient agreement and so forth discuss
that regimen. All the approved patient labeling discusses that
regimen. It is quite common in the United States, however--a
recent article showed that about 21 percent of drug usage in
the United States deviates somewhat from the label directions--
--
Mr. Souder. Let me, because my time is up, when I came as a
freshman, I was vice chair of Mr. Shays' subcommittee and I
remember on the secondary use of drugs one of the huge
questions is the FDA, however, does not give its blessing to
non-approved regimens and non-prescribed ways of doing it. And
I would also like to insert in the record at this point a
history of other drugs where with one or two deaths, they have
been pulled off the market. Usually, scientific research does
not go forth while there is a question on a drug, and I think
an exception has been made in this for political reasons. It is
exactly the reverse of what has been charged.
[The information referred to follows:]
[GRAPHIC] [TIFF OMITTED] T1397.096
[GRAPHIC] [TIFF OMITTED] T1397.097
Mr. Souder. I yield to Mr. Cummings.
Mr. Cummings. Thank you very much, Mr. Chairman.
First of all, thank you for being with us, Dr. Woodcock.
Dr. Woodcock, there have been allegations that there was
something unusual about the approval of Mifeprex. You were the
Director of the Center for Drug Evaluation and Research back
then, is that not correct?
Dr. Woodcock. That is true.
Mr. Cummings. And did the FDA treat Mifeprex using the
appropriate scientific and legal standards for safety and
efficacy?
Dr. Woodcock. We used the scientific and legal standards
that we use for every drug that we evaluate.
Mr. Cummings. Now, anti-choice advocates have criticized
the approval on a number of grounds, including the fact that
there was no double-blind placebo controlled study of this
drug. But it is hard for me to imagine how someone could
conduct a placebo-controlled study of an abortion drug. That
would mean giving the women seeking an abortion a placebo that
would not terminate the pregnancy, is that right?
Dr. Woodcock. I suppose. The need for a placebo occurs when
there is a tremendous variability in the outcome, and so you
can't tell whether the outcome was due to the intervention or
other events. For many types of interventions, such as
anesthesia, all right, we don't have a randomized control group
because you can easily tell whether people are unconscious and
they don't become unconscious spontaneously very often. The
same is true for contraceptives, where we have a very good
background rate of pregnancy with unprotected intercourse. So
in various situations, a totally accurate control is what is
called a historical control, where we know what happens in that
situation without an intervention.
Mr. Cummings. There seems to be confusion about the way
that Mifeprex was approved. It was approved under provisions
known as Subpart H, is that correct?
Dr. Woodcock. Yes.
Mr. Cummings. Some of these provisions provide for an
accelerated approval of drugs for life-threatening conditions.
But a different part of Subpart H guides not expedited approval
but the restricted distribution of certain products. Why was
Subpart H used in the case of Mifeprex?
Dr. Woodcock. For Mifeprex, it was felt important that the
distribution be limited to qualified practitioners, because
although the intervention was found to be safe and effective,
it was in the hands of individuals in the clinical trials who
were able to diagnose pregnancy and date it properly, who were
able to rule out ectopic pregnancy with a high degree of
accuracy, and who were able to deal with the complications of
medical abortion, including incomplete abortion. The drug would
not be safe in the hands of practitioners who did not routinely
take care of pregnant women, for example. So that is why these
restrictions were put into place.
Mr. Cummings. So this had nothing to do with accelerating
approval?
Dr. Woodcock. Nothing to do with it. The evidence on
effectiveness for Mifeprex was submitted in three trials that
FDA found to be adequate and well-controlled trials for the
purpose of demonstrating termination of pregnancy.
Mr. Cummings. Well, the marketing application was submitted
in March 1996, is that correct?
Dr. Woodcock. Yes.
Mr. Cummings. But the drug wasn't approved until September
2000. That is like 4\1/2\ years later. The average time for
approval is about 18 months, is that correct?
Dr. Woodcock. Yes.
Mr. Cummings. So why did the approval process take so long?
Dr. Woodcock. FDA asked many questions and subjected this
application, everything from the manufacturing of the drug, the
pharmacology, the distribution of the drug, and the safety and
efficacy to a very thorough review, such as we would for any
drug, and in this case, it took that long.
Mr. Cummings. I mean, what is the record, do you know,
length of time?
Dr. Woodcock. Longer.
Mr. Cummings. All right. I see my time is about up so I
will submit questions.
Mr. Souder. Let me ask Congresswoman Schmidt and
Congressman Shays, did you want to ask questions of this
witness?
Mrs. Schmidt. I do.
Mr. Souder. Do you have questions, as well, Mr. Shays?
Mr. Shays. I don't want to ask her to have to stay after an
hour of hearings after our votes.
Mr. Souder. We are going to have about an hour's worth of
votes, so Mrs. Schmidt, why don't you ask some of your
questions here.
Will you answer any written questions that we give you from
the different Members, because it is going to be a long voting
stretch, probably at least an hour here.
Dr. Woodcock. Certainly.
Mr. Souder. Mrs. Schmidt.
Mrs. Schmidt. Thank you, Mr. Chairman. What I am
understanding is that there are seven deaths recorded from this
drug. As a woman, why aren't we pulling this drug from the
market?
Dr. Woodcock. You have to distinguish, first of all, and I
know it is very confusing, you have to distinguish reports to
the FDA, deaths that are actually occurred or related to
administration of the drug in some way, and then where there is
a causal relationship between administration of the drug and
the death.
FDA actually has nine reports of death related to medical
abortion in the United States. Three of those we find unrelated
to administration of the drug. In one case, we cannot--either
the patient is not documented to have taken the drug or other
reasons unrelated. One death was due to ruptured ectopic
pregnancy. Ruptured ectopic pregnancy, if the patient doesn't
seek medical care rapidly, can be fatal. The ectopic pregnancy
itself was a preexisting condition, was not caused by
administration of Mifepristone and Misoprostol.
There were five deaths were due to sepsis, to infection,
and what we don't know is whether or not medical abortion
increases the probability of getting this infection. This
infection has occurred after vaginal delivery, after Caesarian
section, and after spontaneous abortion or so-called
miscarriage, and there are documented cases in each of those
instances. So we do not know if in medical abortion there is an
increased rate of this infection or whether or not we are
simply seeing these because of our intense scrutiny of outcomes
after medical abortion due to the restricted distribution.
Mrs. Schmidt. May I have a followup, sir? I am having a
problem with your explanation and I will tell you why. The
ectopic pregnancy, the drug should never have been administered
if she had an ectopic pregnancy, period, case closed. I don't
care what the reason why the drug was administered. It was
administered wrongly. That woman died because of it. So there
is a problem.
But more importantly, the five of the infections, just
because you don't know how the infection occurred, we do know
they took the drug and they died. To me--I am from a farm
community--it sounds like you need to pull the drug until you
can be absolutely sure that there are no deaths related.
I have a whole list here of drugs that have been pulled
from the market either voluntarily or involuntarily. There has
just been a contact solution that has been pulled from the
market because of serious eye infection, including the loss of
sight. So we are real careful about other things about our
body, but when it comes to a woman's body, I am just finding a
problem that we are just not that careful.
I think this drug needs to be pulled from the market. It
needs to be pulled from the market now and it is time that the
FDA does something about it.
Mr. Souder. Thank you. We will send you some additional
questions. May I ask you quickly, the FDA reported 116 cases of
blood transfusion. Do you believe Mifeprex caused these
hemorrhage cases?
Dr. Woodcock. Hemorrhage is a common complication of
childbirth, spontaneous abortion, surgical abortion, and
medical abortion. So when a woman is pregnant, she faces a
possibility of experiencing hemorrhaging after childbirth and
so forth. Yes, we expected----
Mr. Souder. So you believe these were common hemorrhaging
cases, not extraordinary hemorrhaging cases?
Dr. Woodcock. It was expected and was observed in the
clinical trial. There was a case of needing transfusion, so it
was expected that some women after the medical abortion regimen
would have bleeding requiring transfusion. That is correct.
Mr. Souder. So you believe that 116 cases in 575,000 is
roughly similar to the population that would normally have it?
Dr. Woodcock. Yes. We feel that all the side effects except
the Sordellii are within what we would expect in this
population.
Mr. Souder. Thank you. We will submit----
Mr. Shays. Mr. Chairman.
Mr. Souder. Yes, Mr. Shays.
Mr. Shays. If I could submit questions in writing, because
I do have questions. I just don't want to hold her for an hour.
Mr. Souder. OK.
Mr. Shays. So I will have questions. I will submit them
through you.
Mr. Souder. Thank you.
Mr. Shays. Thank you.
Mr. Souder. The subcommittee stands recessed until we get
back from votes.
[Recess.]
Mr. Souder. The subcommittee is back in session.
If the second panel could come forward. The second panel is
Monty Patterson, father of Holly Patterson, who was 18 years
old when she died taking RU-486; Dr. Susan Wood, former FDA
Assistant Commissioner for Women's Health; Dr. Lisa Rarick, RAR
Consulting; Dr. Donna Harrison, a member of the Mifeprex
Subcommittee of the American Association of Prolife
Obstetricians and Gynecologists; and law professor O. Carter
Snead from the University of Notre Dame, former general counsel
for the President's Council on Bioethics.
As an oversight committee, it is our customary practice to
swear in each of the witnesses. Will you raise your right
hands.
[Witnesses sworn.]
Mr. Souder. Let the record show that each of the witnesses
responded in the affirmative.
We thank you each for coming. Thank you for your patience
of putting up with the congressional procedure of having
multiple amendments and bills. It makes for a long afternoon
but one that we can never predict when we schedule a hearing.
We will start with Mr. Patterson. Thank you for coming, and
once again, we express from all of us in the committee our
sympathies for the loss of your daughter.
STATEMENT OF MONTY L. PATTERSON, LIVERMORE, CA
Mr. Patterson. Thank you very much. First of all, I just
want to show you a picture of Holly so you know that we are
talking about my daughter and who she is.
Mr. Souder. Why don't you pull the mic closer to you.
Mr. Patterson. I said I wanted to show you a picture of my
daughter so at least you see what I have lost and actually what
she lost.
I owe and dedicate my presence here to those who have no
voice and particularly to my daughter, Holly, who died at 18,
and the other women who have died or have been seriously hurt
by taking the RU-486 medical abortion drug regimen as a
solution to their unplanned pregnancy.
I am here to testify about my personal experience as the
father of a victim of this drug and my consequent knowledge,
experiences, and views pertaining to RU-486, the drug. I want
to be clear that my views and testimony should be divorced from
any debate about abortion. I feel we must examine the dangers
associated with RU-486 for early medical pregnancy termination
that are separate and apart from any particular view about a
women's right to access and choice.
Twelve days after Holly's 18th birthday, on September 10,
2003, she walked into a Planned Parenthood clinic to be
administered an RU-486 medical abortion regimen. By the 4th
day, she was admitted to the emergency room of a local
hospital. She was examined. She was given pain killers. She
complained of bleeding, cramping, constipation, and pain, but
subsequently, she was sent home.
Seven days after taking RU-486, Holly returned to the same
emergency room hospital complaining of weakness, vomiting,
abdominal pain. Hours later, I was called to the hospital,
where I found her surrounded by doctors and nurses, barely
conscious and struggling to breathe. Holly was so weak she
could barely hold onto my hand. Feeling utter belief and
desperation, I watched Holly succumb to a massive bacterial
infection as a result of a drug-induced abortion with RU-486.
With the support of my family and friends, I have spent
thousands of hours researching medical and scientific journals,
talking to doctors, legislators, State and Federal agencies,
and to learn about the drug RU-486, otherwise known as
Mifepristone.
I believe that RU-486 is the substantial contributing
factor responsible for Holly's death. Currently, there have
been eight deaths reported by the FDA linked with the drug.
Furthermore, there are 900 or more serious health consequences
associated with RU-486.
One year after Holly's death, I met with FDA and White
House officials, in September 2004, to discuss concerns over
the drug's safety and health issues. Two months later, the FDA
announced additional black box warnings highlighting serious
infections and death.
On May 11, 2006, I attended the CDC-FDA-NIH scientific
conference in Atlanta whose main purpose was to discuss the
safety of the drug regimen RU-486 to terminate early
pregnancies. I presented a compilation of nearly 400 medical
and scientific publications as a result of my 2\1/2\ years of
extensive research. It is my hope this work will help to
facilitate the understanding and causal relationship of RU-486
and medical abortion infections. Medical experts, Dr. Esther
Sternberg, Dr. James McGregor, and Dr. Ralph Miech presented
their concurring studies that RU-486 has serious and lethal
medical implications as evidenced through animal models. I have
brought that disk here today for the subcommittee for their
review.
The FDA is responsible for protecting public health and,
therefore, must reconsider the use of RU-486 in early medical
pregnancy terminations. It should explore active epidemiology
and study animal models that show the alteration of the immune
response by its reaction with RU-486 as it relates to serious
and lethal infections. The FDA needs to provide the medical
community reliable means and methods to recognize cases of
serious adverse events associated with RU-486. Finally, the FDA
needs to implement a confident reporting apparatus of these
events so they can accurately evaluate the safety and health
consequences with the use of the drug.
Patients, families, and their physicians are entitled to
have all the information necessary to make informed choices.
The safety, health, and welfare of women considering medical
abortion with RU-486 is paramount and should not be jeopardized
with a drug that can seriously cause them harm or death. Women
have paid the ultimate price with their health and their lives.
How many must die needlessly before this drug is removed from
the market?
Women have been and are still relying upon what they think
is truthful information concerning the limited risk involved
with a medical abortion. Yet, does the average patient, a
teenager like Holly, understand she may be risking her life
taking RU-486 when she is repeatedly exposed to statements
like, ``It is what women have wanted for years. It is the first
FDA-approved pill providing women with a safe and effective
non-surgical option for ending early pregnancy.''
There are no quick fixes or magical pills to make an
unplanned pregnancy go away. My family, friends, and community
were deeply saddened and are forever marred by Holly's
preventable and tragic death. It is my vibrant memory of Holly
and her premature death that have inspired me to make the
public aware of the serious and lethal effects of the RU-486
regimen. Not a day goes by that I do not recall her brilliant
blue eyes, engaging smile, laughter, and sheer gentle beauty.
Holly's personal drive and unwavering determination
continue to inspire me and give me strength to pursue these
critical issues in her name. It is a natural instinct to
protect our loved ones and speak for those who cannot speak for
themselves. Thank you.
Mr. Souder. Thank you, and thank you for your willingness
to speak out.
[The prepared statement of Mr. Patterson follows:]
[GRAPHIC] [TIFF OMITTED] T1397.098
[GRAPHIC] [TIFF OMITTED] T1397.099
Mr. Souder. Dr. Wood.
STATEMENT OF SUSAN F. WOOD, FORMER ASSISTANT COMMISSIONER FOR
WOMEN'S HEALTH AND DIRECTOR OF THE OFFICE OF WOMEN'S HEALTH,
FOOD AND DRUG ADMINISTRATION
Ms. Wood. Thank you, Mr. Chairman, and thank you, members
of the subcommittee. My name is Susan Wood and for the last 15
years, I have worked in women's health policy within the
Federal Government. In each of my positions, I have advocated
for the promotion of women's health through increased research,
services, and prevention.
From November 2000 through August 2005, I was the Assistant
Commissioner for Women's Health and Director of the Office of
Women's Health at the U.S. Food and Drug Administration. Prior
to that, I was Director of Policy and Program Development at
the Department of Health and Human Services Office on Women's
Health.
But I began my work in women's health in 1990 as
congressional staffer for the bipartisan Congressional Caucus
for Women's Issues. My scientific training is as a Ph.D. in
biology and my research focused on basic cell biology and
biochemistry, carried out at Boston University and at Johns
Hopkins University School of Medicine.
Over the last 15 years, I have been proud to be part of the
following advances we have made in women's health: expanded
research at the NIH in areas such as breast and ovarian cancer,
osteoporosis, heart disease, HIV/AIDS, and menopause; more
inclusion of women in clinical research studies funded by NIH
and regulated by the FDA; increased screening of women for
cancer and for sexually transmitted diseases that lead to
infertility; better quality mammography; coverage for
preventive screenings by Medicare; and improved prevention and
services for victims of domestic violence.
While I was at FDA, the Office of Women's Health supported
groundbreaking research, including research on medications
taken during pregnancy, to help find out about the proper doses
of different medications that should be taken during the
different stages of pregnancy. We also funded important health
outreach programs in areas such as safe medication use,
diabetes, menopause, and hormone therapy. The office also
worked to implement and track the inclusion of women in
clinical studies reviewed by FDA and to ensure the analysis of
the data for important sex differences in safety and efficacy.
These advances and more were made through the concerted
efforts of Members of Congress, the various agencies of the
Department of Health and Human Services, the research and
clinical communities, and women's health advocates across the
country. One of the core principles that led to this progress
was and remains ensure that we move forward based on the best
available scientific and medical evidence, and when that
evidence is lacking, go out and do the studies necessary to get
it.
My commitment to women's health is founded on these
scientific principles, knowing that this is the best way to
expand our knowledge and improve the health of women and men
both here in the United States and abroad. My commitment to
women's health, particularly to drug safety, is also founded in
personal experience. I lost my much-loved sister to cancer at
age 34, caused directly by a drug given to our mother while she
was pregnant, the drug DES, also known as diethylstilbestrol. I
can assure you that my commitment to drug safety for women is
deeply felt and always at the forefront of my mind.
I appreciate your invitation to testify before this
subcommittee on the issue of Mifepristone and whether or not
FDA has held this drug to the best standard of review on safety
and efficacy.
Let me point out that Mifepristone is not Plan B emergency
contraception, which prevents unintended pregnancy and the need
for abortion, but Mifepristone, RU-486, is a medication that
causes abortion in the first few weeks of pregnancy.
Now, I was working at the Department of Health and Human
Services Office on Women's Health at the time of the
Mifepristone review. I, therefore, have no direct knowledge of
the evaluation and the review that was happening at FDA, and
that is exactly how it should be. The FDA was working
independently, reaching its conclusions and decisions based on
its usual processes and evaluation of the data. In fact, there
was curiosity among many of us at the Department level about
the subject, but we were given clear instruction by senior
management of the Department that we were not to inquire, even
informally, of our women's health colleagues at FDA about the
status of the Mifepristone application. This was to ensure that
there was not even a perception of Departmental influence on
this highly visible application.
Upon my arrival at FDA in the fall of 2000 as head of
women's health there, this independence of decisionmaking was
confirmed to me by the professional staff that was directly
involved in the review. The evidence presented to the FDA and
the subsequent experience with the marketed product in the
United States tells us that this is a safe and effective method
for early termination of pregnancy.
Now, the recent deaths due to Clostridium Sordellii in
women who have had a medical abortion are truly tragic and I do
offer my sincere condolences to Mr. Patterson, his family, and
the families of all the women. These deaths due to this
bacterial infection have put us on notice that health
professionals and women need to be aware of this potential
risk.
More importantly, the close surveillance of adverse events
associated with the use of Mifepristone have alerted us that
this bacterial infection is present and caused the death of
other women who have given birth or had a miscarriage--more, in
fact, than the number of women who underwent a medical
abortion. This pattern of infections and deaths after pregnancy
is indeed disturbing and tells us once again that we need to do
more to ensure safe pregnancy and safe motherhood. This is not
limited to women who have been exposed to Mifepristone, and to
focus solely on the women who have had a medical abortion is to
miss the real threat to the health of women.
Our surveillance systems for maternal mortality and
morbidity have been limited over the years due to limited
funding and lower priority. These systems need to be improved
and expanded to capture not only the impacts of Clostridium,
but also so that we can understand and prevent the other risks
that women face with pregnancy.
With Mifepristone, we can be confident that we have
identified all or most of the adverse events and deaths. We
cannot say the same for infections and deaths caused by C.
Sordellii in women who have given birth or had a miscarriage,
and those numbers may indeed be higher.
I applaud the CDC, FDA, and NIH for holding the scientific
meeting on May 11th to begin the process of examining the data
that we currently have on the nature of these infections,
potential strategies for prevention, early detection, and
effective treatment, and the research agenda that needs to be
undertaken to answer the critical questions that exist.
Although I did not attend, I understand that meeting
participants presented current information and discussed the
future needs to address this emerging infection.
Questions have been raised about whether Mifepristone is
involved through changes of the immune system. These are
serious questions that need to be studied, but at this point do
not seem to be the compelling mechanism. Experts at CDC, FDA,
and NIH reviewed the current information and appear to
recognize that the infections and death due to C. Sordellii are
not due to a simple drug effect. Rather, this is a complex
situation that involves multiple factors that are linked to
pregnancy. Getting to the bottom of what puts women at risk for
this infection and what can be done to prevent and treat it is
of the highest importance.
The experts at the meeting last week identified several
clear areas of research that are needed, including improved
surveillance of infection in women who have given birth or had
a miscarriage, improved diagnosis, the role of antibiotics, the
possible development of an antitoxin or other therapies, and
further research on the nature of the Clostridium bacterium
itself.
I strongly urge the subcommittee to support this research
and surveillance agenda to address this threat to women's
health. By doing so, we can improve the health outcome of all
pregnant women and also help ensure improved maternal outcomes.
Please do not allow politics to trump science once again when
the health of women is at stake. Thank you.
Mr. Souder. Thank you.
[The prepared statement of Ms. Wood follows:]
[GRAPHIC] [TIFF OMITTED] T1397.100
[GRAPHIC] [TIFF OMITTED] T1397.101
[GRAPHIC] [TIFF OMITTED] T1397.102
Mr. Souder. Dr. Rarick.
STATEMENT OF LISA D. RARICK, M.D., RAR CONSULTING, LLC
Dr. Rarick. Good afternoon, and thank you, Mr. Chairman and
members of the subcommittee, for the opportunity to provide
testimony in this important discussion of the use of
Mifepristone for medical abortion.
My name is Lisa Rarick. I am a medical doctor with training
and board certification in obstetrics and gynecology. I
received my medical degree from Loma Linda University School of
Medicine and my OB/GYN training at Georgetown University. After
my residency, I remained on the faculty of the Department of
OB/GYN at Georgetown and soon also began to work at the U.S.
Food and Drug Administration.
Although my work at the FDA began as a part-time position
in the Center for Drug Evaluation and Research looking into
fetal effects of drug exposure, I quickly grew interested in
CDER's broader mission of protecting and promoting public
health through pharmaceutical regulation.
I transitioned to full-time employment at the FDA by
September 1989. My work at CDER progressed from the review and
analysis of fetal exposure information to work as a primary
medical reviewer, also called medical officer, for new drugs in
the Division of Metabolic and Endocrine Drug Products. As a
medical officer, I had responsibility for the review of
investigational and approved drugs used in various conditions
for women's health.
In 1996, a new division, the Division of Reproductive and
Urologic Drug Products, was created. I was named as its first
Director. During that time, I was well acquainted with the
application for Mifepristone and participated in the review as
well as the Advisory Committee meeting discussions regarding
this product. I was actively involved in the regulatory actions
taken for this product during my tenure as Division Director.
By the year 2000, I continued to move up CDER's
organizational ladder in various positions and I spent my final
year at the FDA, July 2002 to July 2003, in FDA's Office of
Women's Health.
My conclusions after review of the available scientific
information regarding Mifepristone while at the agency, as well
as my subsequent review, are consistent with the FDA's
conclusions. The approval of Mifepristone in September 2000,
more than 4 years after its application was submitted, was
based on more than the necessary number of studies submitted
and reviewed by the division of which I was Director. As many
are aware, an application submitted to the FDA to support a new
drug approval must contain adequate and well-controlled studies
to confirm efficacy and safety. Generally, the word ``studies''
is interpreted as requiring two adequate studies. Although
there are some instances where one study is acceptable, most
applications contain the usual two confirmatory clinical
trials. In the case of Mifepristone, three studies were
submitted in order to establish efficacy and safety for early
intrauterine pregnancy termination.
The clinical review of this product included an analysis of
all human studies utilizing Mifepristone, including these three
large Phase 3 studies involving close to 2,500 women. The
Reproductive Health Drugs Advisory Committee was convened in
1996 and asked to discuss and provide recommendations during
the review of this application. The committee reviewed these
Phase 3 studies. They also heard from over 30 speakers during
the open public hearing portion of that meeting. They
recommended by a vote of six-to-nothing, with two abstentions,
that benefits exceeded risk.
The approval action taken by the agency in September 2000
utilized the regulatory option of Subpart H restrictions for
this product. Contrary to the assertion that Subpart H
designation was based on a desire for accelerated approval of
Mifepristone, this is clearly not the case. In this case, the
application of Subpart H regulations actually provided FDA with
more rigorous oversight and allowed for the formal imposition
of restricted distribution. In essence, a Subpart H approval is
meant to restrict the use of Mifepristone, not accelerate its
availability.
Clearly, since approval, the FDA has remained extremely
vigilant in its regulatory oversight of Mifepristone. The
labeling has been revised three times since its year 2000
approval. Each of these labeling change actions followed a
complete FDA review of the clinical studies and post-marketing
information available for Mifepristone and resulted in updated
presentations of scientific information for consideration by
prescribers and patients. Labeling revisions such as these are
an important and expected part of drug regulation and indicate
active and appropriate review of post-approval information.
As with any medication, when reports of serious adverse
events associated with Mifepristone use are received by FDA,
they are carefully analyzed and rigorous investigation is
employed to ascertain the relationship, if any, between the
drug and the event as well as to ascertain mechanisms to
prevent similar events in the future.
I applaud the FDA's efforts to better understand the recent
findings of serious bacterial infection reported in a small
number of women after Mifepristone use and in other pregnancy-
related conditions. In particular, as you have heard, the FDA,
CDC, and NIH held a joint meeting on May 11th of this year.
This meeting was an effort in which experts came together to
better understand reports of morbidity and mortality associated
with Clostridial infections. My understanding from those who
attended the meeting is that the rare cases of Clostridial
infection and death reported in Mifepristone users are, at this
time, not explained by a simple drug-based association. In
fact, the presentations and the discussion made it clear that
these infections are occurring in various pregnancy-related
conditions, not only post-abortion settings.
I say this not to dismiss the fact that some infections are
occurring in women who have chosen medical abortion but to
emphasize that the agencies must and are looking at the
infection trends more broadly. Further investigation and
understanding of these infections and various pregnancy-related
outcomes is essential.
In conclusion, I urge this subcommittee to allow the FDA to
continue to do its job. There is no evidence that FDA is shying
away from the difficult questions of risk and benefit for this
indication. Risks are being investigated. Adverse event
reporting for medical abortion is uncovering and forcing
investigation of previously unexplored risks related to
pregnancy and post-pregnancy events. Let us all continue to
support the FDA and others as they fulfill their mission to
protect and promote the public health.
The public can only have confidence in the FDA's conclusion
if it knows that it is impervious to political pressure. I urge
us to resist the temptation to interfere in this instance and
instead for Congress to allow the dedicated public health
professionals at the FDA to do their jobs, continue their
investigations, and take any actions that might be needed to
protect and promote women's health. Thank you.
Mr. Souder. Thank you.
[The prepared statement of Dr. Rarick follows:]
[GRAPHIC] [TIFF OMITTED] T1397.103
[GRAPHIC] [TIFF OMITTED] T1397.104
[GRAPHIC] [TIFF OMITTED] T1397.105
[GRAPHIC] [TIFF OMITTED] T1397.106
Mr. Souder. Dr. Harrison.
STATEMENT OF DONNA J. HARRISON, M.D., MEMBER, MIFEPREX
SUBCOMMITTEE OF AMERICAN ASSOCIATION OF PROLIFE OBSTETRICIANS
AND GYNECOLOGISTS
Dr. Harrison. Chairman Souder, Mr. Waxman, Ranking Member
Cummings, and distinguished members of the committee, I present
my testimony based on my observations and research as a board-
certified obstetrician-gynecologist who has personally examined
850 of the 950 adverse event cases reported to the FDA after
RU-486 abortions and also based on data from the CDC presented
at the CDC workshop in Atlanta last week, which I attended.
The FDA outlined areas of consideration prior to
withdrawing approval of RU-486 and these are as follows:
Examining the evidence that RU-486 caused the adverse events;
how soon these events occurred after RU-486; how severe these
events are; can these adverse events be predicted or avoided;
and how safe is the alternative treatment, surgical abortion?
I will speak first about the five Clostridium Sordellii
deaths. At the CDC-FDA workshop in Atlanta last week, Drs.
Sternberg, Miech, and McGregor detailed the evidence that RU-
486 interferes with the body's ability to fight infection by
blocking glucocorticoid receptors in the immune system. One of
the many studies demonstrated that mice injected with a certain
bacterial product die at a rate of 13 percent, but when these
mice are given even tiny doses of RU-486, 100 percent of the
mice die. The five women who died from infection with C.
Sordellii during their RU-486 abortions tragically illustrate
the same concept, as illustrated by data from the CDC presented
by Drs. Fischer and McGregor.
The statement has been made by some spokespeople from the
FDA that the C. Sordellii deaths may be due to a change in the
bacteria itself. This question was specifically addressed and
specifically refuted by CDC data presented by Dr. McDonald.
Some FDA spokespeople have implied that there are comparable
numbers of deaths from C. Sordellii in term pregnancy. This is
epidemiological nonsense. Dr. Fischer reported CDC data which
revealed 5 deaths from C. Sordellii in 550,000 RU-486
abortions. Dr. Fischer reported 8 deaths from C. Sordellii in
30 years out of well over 70 million deliveries. The risk of
death from C. Sordellii with RU-486 is well over 50 times
greater.
Dr. Fischer reported no deaths from C. Sordellii in 30
years of surgical abortion data. Dr. Greene reported 25 deaths
from other causes of infections in 13,161,608 surgical
abortions. The risk of death from Clostridium Sordellii with
RU-486 is 10 times greater than the risk of death from all
other kinds of infections in surgical abortion. Dr. Greene from
Harvard recently published this data. Remember also that the
women who died during their RU-486 abortions were all healthy.
They had no risk factors predisposing them to death, especially
from a bacteria that rarely causes death in humans with a
normal immune system. The CDC-FDA panelists were unable to
identify any risk factors to predict who is more likely to die
from C. Sordellii infection, nor could they identify any
treatment that would save a woman once she was diagnosed with
C. Sordellii infection. C. Sordellii infection during an RU-486
abortion is 100 percent fatal, despite any and all treatment.
These deaths are completely preventable.
But septic deaths are not the only health hazard posed by
RU-486 abortions. At least 116 women have been transfused from
massive bleeding, and at least 54 of them lost over one-half of
their blood volume. The medical literature states that 1 to 2
out of every 1,000 women will need to be transfused for massive
hemorrhage. Studies that compared surgical and RU-486 abortions
show much higher rates of blood loss in RU-486 abortions. These
are detailed in my written testimony. And there is no way to
predict who will hemorrhage.
The hazards to women's health from just the infections and
hemorrhages alone due to RU-486 clearly constitute ample cause
for the FDA to withdraw approval from RU-486. Thank you.
Mr. Souder. Thank you.
[The prepared statement of Dr. Harrison follows:]
[GRAPHIC] [TIFF OMITTED] T1397.107
[GRAPHIC] [TIFF OMITTED] T1397.108
[GRAPHIC] [TIFF OMITTED] T1397.109
[GRAPHIC] [TIFF OMITTED] T1397.110
[GRAPHIC] [TIFF OMITTED] T1397.111
[GRAPHIC] [TIFF OMITTED] T1397.112
[GRAPHIC] [TIFF OMITTED] T1397.113
[GRAPHIC] [TIFF OMITTED] T1397.114
[GRAPHIC] [TIFF OMITTED] T1397.115
[GRAPHIC] [TIFF OMITTED] T1397.116
[GRAPHIC] [TIFF OMITTED] T1397.117
[GRAPHIC] [TIFF OMITTED] T1397.118
[GRAPHIC] [TIFF OMITTED] T1397.119
[GRAPHIC] [TIFF OMITTED] T1397.120
[GRAPHIC] [TIFF OMITTED] T1397.121
[GRAPHIC] [TIFF OMITTED] T1397.122
[GRAPHIC] [TIFF OMITTED] T1397.123
[GRAPHIC] [TIFF OMITTED] T1397.124
[GRAPHIC] [TIFF OMITTED] T1397.125
[GRAPHIC] [TIFF OMITTED] T1397.126
[GRAPHIC] [TIFF OMITTED] T1397.127
[GRAPHIC] [TIFF OMITTED] T1397.128
[GRAPHIC] [TIFF OMITTED] T1397.129
[GRAPHIC] [TIFF OMITTED] T1397.130
[GRAPHIC] [TIFF OMITTED] T1397.131
[GRAPHIC] [TIFF OMITTED] T1397.132
[GRAPHIC] [TIFF OMITTED] T1397.133
[GRAPHIC] [TIFF OMITTED] T1397.134
[GRAPHIC] [TIFF OMITTED] T1397.135
[GRAPHIC] [TIFF OMITTED] T1397.136
[GRAPHIC] [TIFF OMITTED] T1397.137
[GRAPHIC] [TIFF OMITTED] T1397.138
[GRAPHIC] [TIFF OMITTED] T1397.139
[GRAPHIC] [TIFF OMITTED] T1397.140
[GRAPHIC] [TIFF OMITTED] T1397.141
[GRAPHIC] [TIFF OMITTED] T1397.142
[GRAPHIC] [TIFF OMITTED] T1397.143
[GRAPHIC] [TIFF OMITTED] T1397.144
[GRAPHIC] [TIFF OMITTED] T1397.145
[GRAPHIC] [TIFF OMITTED] T1397.146
[GRAPHIC] [TIFF OMITTED] T1397.147
[GRAPHIC] [TIFF OMITTED] T1397.148
[GRAPHIC] [TIFF OMITTED] T1397.149
[GRAPHIC] [TIFF OMITTED] T1397.150
[GRAPHIC] [TIFF OMITTED] T1397.151
[GRAPHIC] [TIFF OMITTED] T1397.152
[GRAPHIC] [TIFF OMITTED] T1397.153
[GRAPHIC] [TIFF OMITTED] T1397.154
[GRAPHIC] [TIFF OMITTED] T1397.155
[GRAPHIC] [TIFF OMITTED] T1397.156
[GRAPHIC] [TIFF OMITTED] T1397.157
[GRAPHIC] [TIFF OMITTED] T1397.158
[GRAPHIC] [TIFF OMITTED] T1397.159
[GRAPHIC] [TIFF OMITTED] T1397.160
[GRAPHIC] [TIFF OMITTED] T1397.161
[GRAPHIC] [TIFF OMITTED] T1397.162
[GRAPHIC] [TIFF OMITTED] T1397.163
[GRAPHIC] [TIFF OMITTED] T1397.164
[GRAPHIC] [TIFF OMITTED] T1397.165
[GRAPHIC] [TIFF OMITTED] T1397.166
[GRAPHIC] [TIFF OMITTED] T1397.167
[GRAPHIC] [TIFF OMITTED] T1397.168
[GRAPHIC] [TIFF OMITTED] T1397.169
[GRAPHIC] [TIFF OMITTED] T1397.170
[GRAPHIC] [TIFF OMITTED] T1397.171
[GRAPHIC] [TIFF OMITTED] T1397.172
[GRAPHIC] [TIFF OMITTED] T1397.173
[GRAPHIC] [TIFF OMITTED] T1397.174
[GRAPHIC] [TIFF OMITTED] T1397.175
[GRAPHIC] [TIFF OMITTED] T1397.176
[GRAPHIC] [TIFF OMITTED] T1397.177
[GRAPHIC] [TIFF OMITTED] T1397.178
[GRAPHIC] [TIFF OMITTED] T1397.179
[GRAPHIC] [TIFF OMITTED] T1397.180
[GRAPHIC] [TIFF OMITTED] T1397.181
[GRAPHIC] [TIFF OMITTED] T1397.182
[GRAPHIC] [TIFF OMITTED] T1397.183
[GRAPHIC] [TIFF OMITTED] T1397.184
[GRAPHIC] [TIFF OMITTED] T1397.185
[GRAPHIC] [TIFF OMITTED] T1397.186
[GRAPHIC] [TIFF OMITTED] T1397.187
[GRAPHIC] [TIFF OMITTED] T1397.188
[GRAPHIC] [TIFF OMITTED] T1397.189
[GRAPHIC] [TIFF OMITTED] T1397.190
[GRAPHIC] [TIFF OMITTED] T1397.191
[GRAPHIC] [TIFF OMITTED] T1397.192
[GRAPHIC] [TIFF OMITTED] T1397.193
[GRAPHIC] [TIFF OMITTED] T1397.194
[GRAPHIC] [TIFF OMITTED] T1397.195
[GRAPHIC] [TIFF OMITTED] T1397.196
[GRAPHIC] [TIFF OMITTED] T1397.197
[GRAPHIC] [TIFF OMITTED] T1397.198
[GRAPHIC] [TIFF OMITTED] T1397.199
[GRAPHIC] [TIFF OMITTED] T1397.200
[GRAPHIC] [TIFF OMITTED] T1397.201
[GRAPHIC] [TIFF OMITTED] T1397.202
[GRAPHIC] [TIFF OMITTED] T1397.203
[GRAPHIC] [TIFF OMITTED] T1397.204
[GRAPHIC] [TIFF OMITTED] T1397.205
[GRAPHIC] [TIFF OMITTED] T1397.206
[GRAPHIC] [TIFF OMITTED] T1397.207
[GRAPHIC] [TIFF OMITTED] T1397.208
[GRAPHIC] [TIFF OMITTED] T1397.209
[GRAPHIC] [TIFF OMITTED] T1397.210
[GRAPHIC] [TIFF OMITTED] T1397.211
[GRAPHIC] [TIFF OMITTED] T1397.212
[GRAPHIC] [TIFF OMITTED] T1397.213
[GRAPHIC] [TIFF OMITTED] T1397.214
[GRAPHIC] [TIFF OMITTED] T1397.215
[GRAPHIC] [TIFF OMITTED] T1397.216
[GRAPHIC] [TIFF OMITTED] T1397.217
[GRAPHIC] [TIFF OMITTED] T1397.218
[GRAPHIC] [TIFF OMITTED] T1397.219
[GRAPHIC] [TIFF OMITTED] T1397.220
[GRAPHIC] [TIFF OMITTED] T1397.221
[GRAPHIC] [TIFF OMITTED] T1397.222
[GRAPHIC] [TIFF OMITTED] T1397.223
[GRAPHIC] [TIFF OMITTED] T1397.224
[GRAPHIC] [TIFF OMITTED] T1397.225
[GRAPHIC] [TIFF OMITTED] T1397.226
[GRAPHIC] [TIFF OMITTED] T1397.227
[GRAPHIC] [TIFF OMITTED] T1397.228
[GRAPHIC] [TIFF OMITTED] T1397.229
[GRAPHIC] [TIFF OMITTED] T1397.230
[GRAPHIC] [TIFF OMITTED] T1397.231
[GRAPHIC] [TIFF OMITTED] T1397.232
[GRAPHIC] [TIFF OMITTED] T1397.233
[GRAPHIC] [TIFF OMITTED] T1397.234
[GRAPHIC] [TIFF OMITTED] T1397.235
[GRAPHIC] [TIFF OMITTED] T1397.236
[GRAPHIC] [TIFF OMITTED] T1397.237
[GRAPHIC] [TIFF OMITTED] T1397.238
[GRAPHIC] [TIFF OMITTED] T1397.239
[GRAPHIC] [TIFF OMITTED] T1397.240
[GRAPHIC] [TIFF OMITTED] T1397.241
[GRAPHIC] [TIFF OMITTED] T1397.242
[GRAPHIC] [TIFF OMITTED] T1397.243
[GRAPHIC] [TIFF OMITTED] T1397.244
[GRAPHIC] [TIFF OMITTED] T1397.245
[GRAPHIC] [TIFF OMITTED] T1397.246
[GRAPHIC] [TIFF OMITTED] T1397.247
[GRAPHIC] [TIFF OMITTED] T1397.248
[GRAPHIC] [TIFF OMITTED] T1397.249
[GRAPHIC] [TIFF OMITTED] T1397.250
[GRAPHIC] [TIFF OMITTED] T1397.251
[GRAPHIC] [TIFF OMITTED] T1397.252
[GRAPHIC] [TIFF OMITTED] T1397.253
[GRAPHIC] [TIFF OMITTED] T1397.254
[GRAPHIC] [TIFF OMITTED] T1397.255
[GRAPHIC] [TIFF OMITTED] T1397.256
[GRAPHIC] [TIFF OMITTED] T1397.257
[GRAPHIC] [TIFF OMITTED] T1397.258
[GRAPHIC] [TIFF OMITTED] T1397.259
[GRAPHIC] [TIFF OMITTED] T1397.260
[GRAPHIC] [TIFF OMITTED] T1397.261
[GRAPHIC] [TIFF OMITTED] T1397.262
[GRAPHIC] [TIFF OMITTED] T1397.263
[GRAPHIC] [TIFF OMITTED] T1397.264
[GRAPHIC] [TIFF OMITTED] T1397.265
[GRAPHIC] [TIFF OMITTED] T1397.266
[GRAPHIC] [TIFF OMITTED] T1397.267
[GRAPHIC] [TIFF OMITTED] T1397.268
[GRAPHIC] [TIFF OMITTED] T1397.269
[GRAPHIC] [TIFF OMITTED] T1397.270
[GRAPHIC] [TIFF OMITTED] T1397.271
[GRAPHIC] [TIFF OMITTED] T1397.272
[GRAPHIC] [TIFF OMITTED] T1397.273
[GRAPHIC] [TIFF OMITTED] T1397.274
[GRAPHIC] [TIFF OMITTED] T1397.275
[GRAPHIC] [TIFF OMITTED] T1397.276
[GRAPHIC] [TIFF OMITTED] T1397.277
[GRAPHIC] [TIFF OMITTED] T1397.278
[GRAPHIC] [TIFF OMITTED] T1397.279
[GRAPHIC] [TIFF OMITTED] T1397.280
[GRAPHIC] [TIFF OMITTED] T1397.281
[GRAPHIC] [TIFF OMITTED] T1397.282
[GRAPHIC] [TIFF OMITTED] T1397.283
[GRAPHIC] [TIFF OMITTED] T1397.284
[GRAPHIC] [TIFF OMITTED] T1397.285
[GRAPHIC] [TIFF OMITTED] T1397.286
[GRAPHIC] [TIFF OMITTED] T1397.287
[GRAPHIC] [TIFF OMITTED] T1397.288
[GRAPHIC] [TIFF OMITTED] T1397.289
[GRAPHIC] [TIFF OMITTED] T1397.290
[GRAPHIC] [TIFF OMITTED] T1397.291
[GRAPHIC] [TIFF OMITTED] T1397.292
[GRAPHIC] [TIFF OMITTED] T1397.293
[GRAPHIC] [TIFF OMITTED] T1397.294
[GRAPHIC] [TIFF OMITTED] T1397.295
[GRAPHIC] [TIFF OMITTED] T1397.296
[GRAPHIC] [TIFF OMITTED] T1397.297
[GRAPHIC] [TIFF OMITTED] T1397.298
[GRAPHIC] [TIFF OMITTED] T1397.299
[GRAPHIC] [TIFF OMITTED] T1397.300
[GRAPHIC] [TIFF OMITTED] T1397.301
[GRAPHIC] [TIFF OMITTED] T1397.302
[GRAPHIC] [TIFF OMITTED] T1397.303
[GRAPHIC] [TIFF OMITTED] T1397.304
[GRAPHIC] [TIFF OMITTED] T1397.305
[GRAPHIC] [TIFF OMITTED] T1397.306
[GRAPHIC] [TIFF OMITTED] T1397.307
Mr. Souder. Professor Snead.
STATEMENT OF O. CARTER SNEAD, ASSOCIATE PROFESSOR, UNIVERSITY
OF NOTRE DAME LAW SCHOOL, AND FORMER GENERAL COUNSEL FOR THE
PRESIDENT'S COUNCIL ON BIOETHICS
Mr. Snead. Thank you very much. Thank you, Chairman Souder,
Ranking Member Cummings, Ranking Member Waxman, Congresswoman
Schmidt. Thank you very much for inviting me today to discuss
the legal dimensions of this question, which I think are not
controversial and not contentious despite the contentious
nature of the underlying issue that we are discussing.
In my written comments, I lay out for the committee the
various regulatory options that the FDA would have and also
that the Secretary of Health and Human Services would have if
they were to decide that the circumstances warranted
intervention in this matter beyond the changing in labeling and
the public health advisories that have already been undertaken.
The central conclusion that I reach in my written testimony
is that the FDA is well equipped to respond forcefully to the
concerns raised by the co-panelists today regarding the safety
of Mifepristone should it decide that such a response is
warranted, and I focus on three principal mechanisms in my
written testimony that are available both to the FDA and to the
Secretary of Health and Human Services. In my oral testimony, I
am going to focus on the one mechanism that is unique to
Mifepristone given the circumstances of its approval, that is
to say under Subpart H, which has received some discussion
today already.
Subpart H was devised by the FDA to permit the approval of
drugs intended to treat serious or life-threatening illnesses
where such drugs imposed a greater-than-normal acceptable risk
to the patient. That is, Subpart H was designed in part as an
alternative means of approval for useful drugs that would
otherwise fail the traditional risk-benefit calculus required
for FDA approval. Subpart H facilitated approval of such drugs
by imposing additional post-marketing restrictions above and
beyond what was required in the normal mechanisms of approval,
as has been mentioned by numerous panelists.
These post-market restrictions are absolutely crucial both
in terms of their effectiveness and in terms of compliance with
those restrictions if the mechanism of Subpart H is to serve
its purpose. As the FDA has said in its own final rule, and I
am quoting from the final rule, ``For drugs approved under the
accelerated procedure regulations, the risk-benefit assessment
is dependent upon the likelihood that post-marketing
restrictions will enable safe use.''
Most important for present purposes, it is clear that
Subpart H provides a mechanism for expedited withdrawal of
approval upon a finding that the post-marketing restrictions
are either ineffective or are not being observed by the
manufacturer. As the FDA noted in its final rule also, if the
restrictions do not lead to safe use, the risk-benefit
assessment for these drugs changes significantly. FDA believes
that if that occurs, rapid withdrawal of approval as set forth
in this rule is important to the public health.
So this is a unique mechanism, and as the representatives
and former representatives of the FDA have noted already,
Subpart H is intended to facilitate the move to market of drugs
through the imposition of these additional post-market
restrictions. It is not difficult to see the implications of
Subpart H for the case of Mifepristone.
Danco Laboratories benefited from these unique approval
regulations, the cost of which was a promise to comply with the
post-market restrictions that the FDA thought appropriate under
the circumstances. Thus, if the FDA--and I formulate this as a
conditional because I am not privy to any facts that would go
to this conclusion, this is a judgment that would have to be
made based upon an evaluation of Danco's behavior--if, in fact,
the FDA were to conclude that Danco was not in compliance with
these post-market restrictions, or alternatively that the post-
market restrictions themselves were not effective to render the
drug safe for its approved use, then the FDA would be within
its authority to withdraw approval following notice and an
opportunity for hearing for the drug itself.
And, in fact, it would be difficult to imagine that if FDA
did come to that conclusion, that they would not regard it as
its duty to withdraw approval, because in the absence of
effective post-market restrictions, Mifepristone would
presumably not be able to satisfy the statutory criteria for
safety. If this were not the case, Mifepristone would have been
approved under the traditional provisions rather than under
Subpart H.
So essentially, among the mechanisms that I discuss in my
written testimony, Subpart H provides a unique opportunity for
the FDA to maintain control over the use of Mifepristone, and
if under its own inquiries the FDA finds that the post-
marketing restrictions are not effective or are not being
observed, then the truncated and expedited withdrawal
provisions would be activated and FDA would be fully authorized
to withdraw approval.
As has been suggested, I agree, I think FDA would have the
obligation to answer any open questions regarding the efficacy
of the post-market restrictions and also to answer--to inquire
about and answer any questions and respond appropriately to any
concerns regarding Danco's compliance with the post-marketing
restrictions.
Thank you very much.
Mr. Souder. Thank you.
[The prepared statement of Mr. Snead follows:]
[GRAPHIC] [TIFF OMITTED] T1397.308
[GRAPHIC] [TIFF OMITTED] T1397.309
[GRAPHIC] [TIFF OMITTED] T1397.310
[GRAPHIC] [TIFF OMITTED] T1397.311
[GRAPHIC] [TIFF OMITTED] T1397.312
[GRAPHIC] [TIFF OMITTED] T1397.313
Mr. Souder. I would like to start with a question for Dr.
Wood and Dr. Rarick. In your testimony, you pretty aggressively
said, both of you, that there was no evidence to support the
hypothesis that Mifeprex interferes with the immune response.
NIH researcher Esther Sternberg's studies directly conflict
with your assertion. Dr. Sternberg has conducted animal studies
that demonstrate that RU-486 can suppress natural immune
response. Dr. James McGregor of Los Angeles Women's and
Children's Hospital has published work hypothesizing the
pathway by which C. Sordellii causes multi-organ infection
after suppressing the immune response. Ralph Miech of Brown
University describes a mechanism whereby RU-486 suppresses the
immune system and causes shock.
Have either of you read in entirety any of these papers,
not just a summary, but have read those papers, and are you
aware of any research that calls into question Sternberg,
McGregor, and Miech's conclusion that Mifepristone may
interfere with the immune response? You made a flat assertion.
What about those studies?
Ms. Wood. I will say, no, I have not read those studies in
full. However, I spoke to Dr. Sternberg and discussed her
findings and I would agree with you that there are certain--
this is certainly a pathway that needs to be investigated. I
think the issues and the use of the questions that arise about
studies is that they are not questioning the studies themselves
or even the outcomes of their studies, but they are, in fact,
limited to particular species of rat and mouse and do not apply
across even the different species of rats and mice. There is
great variability in the level of the responses to different
things.
This is an extraordinarily complex issue of how the immune
system is regulated, either regulated up or regulated down by
various----
Mr. Souder. So let me ask you----
Ms. Wood. This is complex, and I agree with you, there
are----
Mr. Souder. Let me ask you this question. So I don't
misrepresent what you said, you said you have talked to Dr.
Sternberg and you think that it is inconclusive, but in fact,
in certain types of animals, the study shows that it
suppresses?
Ms. Wood. In her animal studies, it shows what it shows----
Mr. Souder. And----
Ms. Wood [continuing]. But it is very preliminary----
Mr. Souder [continuing]. You are not familiar with McGregor
or Miech's studies?
Ms. Wood. I have----
Mr. Souder. Then how in the world under oath could you make
an assertion like you did, under oath?
Ms. Wood. I asserted that this is a very worthwhile and
serious pathway to explore----
Mr. Souder. You said there was no evidence.
Ms. Wood [continuing]. But it does not look like----
Mr. Souder. Under oath, you said there was no evidence.
Ms. Wood. I did not say that.
Mr. Souder. OK.
Ms. Wood. I said there is not compelling evidence.
Mr. Souder. Dr. Rarick----
Ms. Wood. I said there needs to be further research.
Mr. Souder. Dr. Rarick, are you familiar with these
studies? Have you read them through and----
Dr. Rarick. No, and I did not attend the meeting at the
CDC. I similarly looked at some of the slides from the CDC
presentation. I think the last part of your question was the
most key word, which you said, don't you agree that they may
be--that there may be a mechanism. I don't think we are
disputing that there may be some mechanism of Mifepristone on
glucocorticoid receptor issues and that the science in animals
may have both sides of this story. Pregnancy, as you well know,
is a complicated hormonal milieu with all kinds of receptor
activations and inactivations of the various hormones that are
happening during a pregnancy and pregnancy.
I think the last part of your question, which was ``may,''
do we know that Mifepristone is causing an immune reaction in
women? No. Might they? Possibly.
Mr. Souder. Well, it is very important because I was
subjected to opening statement after opening statement with the
implication that we are inserting politics. You in your
statement said--it is really interesting, because if you want
to restore the faith of the American people, they have to feel
that there is actually an honest debate going on, and there is
an increasing feeling that certain people who get control of
the establishment research want to jam their views down
everybody else and not listen to alternative research. And the
assertion was made that there is no contradiction. There is a
debate going on. We need to make sure that debate goes through.
Now, I was blown off in a question, quite frankly, to the
Assistant Commissioner on the blood question. Dr. Harrison, my
understanding of what you--did you go through the different
cases on those who were reported? You seem to imply that these
were transfusion cases and fairly serious bleeding, whereas I
got the impression, oh, bleeding is common. This wasn't
extraordinary bleeding.
Dr. Harrison. I have had a chance, an opportunity to review
850 of the 950 cases, which we obtained by Freedom of
Information Act. Of those 950 cases, I reviewed 68 women who
were transfused. Of those 68 women who were transfused, we have
9 transfusion cases where the women received over four units of
blood. We have 10 cases where they received over three units of
blood and 38 cases where two units of blood were transfused.
And there were also 10 cases where the adverse event report to
the FDA did not document the number of cases transfused, and
this is in settings where the clinical picture in the adverse
event report was consistent with massive hemorrhage, which to
me is unconscionable if you are actively trying to give the
description of how much bleeding is there, to not even have a
hemoglobin concentration or not even have an amount of blood
transfused.
In addition to those that I reported in my paper, which is
what I just quoted, there were an additional 12 in the adverse
event cases from September 2004 to July 2005, and I would refer
you to my spreadsheets that I gave you. And of those cases, the
12 that I mentioned were life-threatening hemorrhages. So of
the life-threatening hemorrhages, it is basically 54 life-
threatening hemorrhages altogether as of July 2005.
When I use the CTCIE criteria for coding these, that is a
criteria that is used by the--developed by the National Cancer
Institute to grade adverse events and to determine how serious
they are so that you can compare them. What I used was a
criteria of a women with a documented hemoglobin of less than
7--remember, the normal hemoglobin is 13--and transfused at
least two units. So these are women who have lost over half of
their blood volume.
I have in that time, from September 2000 to July 2005, 54
cases. Now, if you look at that compared to the number that the
FDA reports, which is 119, that is almost half of the women who
were transfused were in life-threatening situations. That is
not the kind of bleeding that you normally expect from surgical
abortion. It is also not the kind of bleeding that you normally
expect from a spontaneous abortion. In fact, it is more
comparable to the kind of bleeding you see in major motor
vehicle accidents. So this bleeding that is being said as
normal and expected is a large amount of blood.
Mr. Souder. Thank you, and one question for Mr. Snead. Is
there a way that during additional research, and maybe Dr.
Rarick or Dr. Wood would be able to answer, under normal
research, that a drug cannot be taken--to me, taken off the
market implies it is not coming back on, but could be suspended
while additional research is done?
Mr. Snead. Sure. I take up three mechanisms in my
testimony, two of which are mechanisms that require notice and
an opportunity for a hearing before the actual approval is
withdrawn. But the third option that I take up is actually an
option that is exercisable only by the Secretary of Health and
Human Services. It is a non-delegatable authority vested in the
Secretary of Health and Human Services to declare a particular
an imminent hazard. If he does so, the effect of that is to
immediately suspend the approval of the drug and then the
manufacturer then provided an expedited sort of post facto
hearing to make their case for why it was improvidently
declared an imminent hazard.
Mr. Souder. What about if--that still puts the burden on--
because this is obviously a very explosive political question
because it is abortion. Whether I like it or not or whether
anybody likes it or not, it is a legal process and we don't
have a right to stop it. I personally have my views on RU-486.
Other members have their views on RU-486. The question is to
say that it is being stopped and then the manufacturer has to
make a case is different than saying additional research needs
to be done, because that would imply that the government has
determined that it is unsafe as opposed to additional research
needs to be done.
Mr. Snead. That is right. In order to effect the imminent
hazard privilege the Secretary enjoys, he would have to make a
determination that it does, in fact, present an imminent
threat, which is a judgment about the safety of the drug
itself. There is a provision in the regulations for an
administrative stay. The Secretary or the Commissioner has the
authority to stay the effective date of any decision at any
point in the process, which I think is more of what you are
talking about, which is sort of--it is the equivalent in civil
litigation to a temporary restraining order or a permanent
injunction which sort of holds in place--which freezes the
status quo and then tries to resolve whatever dispute or
questions that there might be.
Mr. Souder. Mr. Cummings.
Mr. Cummings. Thank you very much, Mr. Chairman.
Dr. Wood, I want to go back for a moment. I have always
been one to--I don't like to leave things hanging. It seems
like you were trying to say something and I want to give you an
opportunity. The chairman asked you some questions and implied
that you said something that you said you didn't say. I just
wanted to give you the opportunity to clear that up if you
would like. If you don't want to, that is fine.
Ms. Wood. I would just make the point that I actually agree
with the chairman and also with Mr. Patterson about the need
for answering all of these questions. Is the immune system
involved or compromised? What is it that causes this bacteria
to become so virulent in women? What is it about pregnancy,
either the ending of pregnancy either through termination or
through childbirth, that has led to these deaths and these
infections?
So I actually would agree that more research is necessary
and my statement in my written statement and I believe orally
was that I just don't--my reading of it at the point is that
the evidence is not compelling to be conclusive that is the
answer, but I certainly would urge any and all research to
address these questions.
Mr. Cummings. Thank you very much. Let me just go on from
there. Tell me, Dr. Wood, could you explain why some women
would prefer Mifeprex over a surgical abortion?
Ms. Wood. Mifeprex is available to women much earlier in
the course of pregnancies and so the termination of the
pregnancy can be done in a matter of days after the pregnancy
is established, of implantation in the womb, and up to several
weeks. This is much earlier than a regular surgical abortion,
which is required to wait a few more weeks. So this provides an
earlier option if the women is determined to end pregnancy. It
is also one that can be more private and also avoid surgery,
which certainly many people prefer in making a decision.
I would also agree that access to all information about any
known risks as they become known for any type of medical
procedure needs to be available to women, and in the case of
Mifeprex, because of the patient information that is required
under the distribution restrictions on Mifeprex, that, in fact,
we can work to assure that all women do get up-to-date
information on any risk of any medical abortion.
Mr. Cummings. It seems that as I listen to Mr. Snead and I
am listening to your testimony and others, it seems as if the
key question is where is the line drawn with regard to taking a
drug off the market and I am just trying to figure out, what is
taken into account when determining whether a drug should stay
on the market, like this, for example? It seems that Mr. Snead
has very eloquently stated all the options that could happen if
the line is crossed. The question, it seems to me, is where is
the line and when is it crossed.
Ms. Wood. That question is the type of question that FDA
has to deal with every day looking at every product when they
get in a report of adverse events or deaths. And it is not
simply the report of the deaths, but it is whether or not there
are causal links, the magnitude of the response, how many
people are affected in terms of the baseline use. There are
many factors in trying to determine when a product should come
off the market. It is not a simple question, but it is that
balance of risks and benefits, and that is something the
scientists and clinicians at FDA do every day and I would just
urge that they be allowed to continue what they are doing,
which is investigating this, evaluating it, and making their
determinations without intervention.
Mr. Cummings. Now, have you ever been in a position, you or
Dr. Rarick, where you are, say for example, any position and
certain evidence was presented to you and you were the person
who suggested that we, or had the power to suggest that FDA
take another look at a drug to determine whether or not it
stays on the market at all, either one of you?
Dr. Rarick. I think I can speak to that, thank you. FDA
does that kind of determination all the time. Every time you
see a new labeling come out on a product, that means the FDA
has relooked at the studies as well as the post-marketing
events to assess it. Maybe there is a new safety issue that
needs to be put on the label or not. When those discussions
happen, there is always the option of considering withdrawal of
the product if those risks outweigh benefits and that
calculation is done often for all the products that are
available.
Mr. Cummings. I see my time is up, but just one last
question. You heard Dr. Harrison.
Dr. Rarick. Yes.
Mr. Cummings. Is there anything that she said that would
make you all say, well, you know, maybe--I am just trying to be
fair here--make you all say, well, maybe this is something we
need to take another look at? I am just curious. Have you heard
something, anything here today that causes you any kind of
radar to go up?
Dr. Rarick. My perspective is what I have heard here today
is extremely important, but it is all information that the FDA
is well aware of.
Mr. Cummings. OK.
Dr. Rarick. The adverse event reporting that Dr. Harrison
is quoting is from the FDA.
Mr. Cummings. OK.
Dr. Rarick. They are looking at this every day. They were
involved in the CDC meeting last week. My impression from this
discussion is that, yes, FDA is on the case. It is looking into
this. These are really important questions and they should take
an action that is appropriate with the data.
Mr. Cummings. Thank you very much.
Mr. Souder. I want to make sure in the record that we are
clear. Dr. Wood stated, this is a question to be studied, and
to the degree I said there was--you said there was no evidence,
that was incorrect. But you did say, if the immune system were
suppressed, we would expect to see, and we didn't. We would
expect to have seen this, and we didn't. Somewhere, we would
expect to see this, and we didn't. Thus far, this pattern has
not emerged. Basically, what you said was there was no
evidence, and what I asked you was about three studies. Then
you said those studies need to be studied further.
And then on top of that, you had denied, in effect, what
was the consensus of the CDC panel, that there was, in fact,
evidence. Dr. Rarick said in her statement, to date, there is
no evidence that has emerged to support the hypothesis, which
did not refute either of the three studies or the fact that the
scientific community at a recent panel of which neither of you
were present concluded the opposite conclusion.
Now, more research needs to be done on it, I will grant
that, and I think that has been clear today. But it was not a
false assertion that I made about Dr. Rarick said specifically
in her testimony, no evidence, and Dr. Wood basically didn't
cite any evidence. But I think we all agree more study needs to
be done to see how common and how you disaggregate the two
types of things.
Mr. Cummings. Would the gentleman yield just for 1 second
for a clarification?
Mr. Souder. Yes.
Mr. Cummings. Mr. Chairman, all I was trying to do when I
asked the question is I don't like for witnesses--I think when
people are--these are professional people and I don't want them
to ever be in the position where they come before the committee
and for whatever reason they don't get a chance to explain
something that puts into question what they have said, their
credibility. I just think it is, as one human being to another,
bad to do that. That is all.
Mr. Souder. And I understand the gentleman's concern, but
you also know in a 5-minute rule that she had answered the
question and she was then off to another. I didn't mean to
cutoff her ability to respond, and that is why I want to grant
that you, in fact, said more study was needed and the direct
``there was no evidence'' quote was actually Dr. Rarick's, not
Dr. Wood's, but Dr. Wood had a series of things that suggested
it wasn't. I want to make sure the record reflects accurately,
as you did.
Mrs. Schmidt.
Mrs. Schmidt. Thank you, Mr. Chairman. I actually have
questions for Dr. Rarick, Dr. Harrison, and Mr. Patterson, if
that is all right.
Dr. Rarick, Dr. Wood stated that politics--she didn't want
to see politics triumphing science once again, and none of us
want to see that. My concern is how this product came to market
in 2000. Dr. Wood stated that controlled trials were performed
in support of the RU-486 FDA application. Could you tell us
what the control group was in those trials that made those
trials controlled? More specifically, was there a double-blind
study, and if so, how did it result?
Dr. Rarick. Certainly. In this area of pregnancy-related
conditions, including contraception or birth control,
oftentimes the FDA accepts clinical trial designs that are
appropriate and use historical controls. So, for example, you
can't have women who come in and want to contracept and suggest
that they should be blinded and randomized to placebo versus a
contraceptive that you expect to work and expect that to be an
ethical trial design.
Similarly, in medical abortion, when a woman comes in with
a request to terminate a pregnancy, you can't suggest to her,
well, we think this pill will terminate your pregnancy based on
all the science, but we want you to sign a consent form that
states you will be randomized to a pill that we know has no
effect--a sugar pill, a placebo pill--on your pregnancy and
then let us know if you abort or not. That is just simply not a
reasonable trial design.
In this setting, you know if you don't do anything, there
is almost a 100 percent chance that they will continue to be
pregnant, although there is a miscarriage rate, as you well
know. But in an early intrauterine pregnancy termination, you
can't expect placebo to have any potential effect. So you go
back to the sort of historical control concept, that if you
didn't give the woman anything, what would be the chances of
her aborting versus giving her something.
Mrs. Schmidt. Mr. Chairman, I have to comment on this
because I am troubled by this statement. In 1995, my father was
involved in a very critical car wreck and he almost died and
they put him on a clinical trial regarding getting him off of
oxygen, because the longer you stay on oxygen the harder it is
to get off the oxygen. It was a double-blind study. We didn't
know whether they were giving him the opportunity to wean off
quicker or not. The alternative obviously is more of an
opportunity to die.
So the argument that a double-blind study can't be used in
this case but it can be used in a life or death case of a man
in an ICU unit at University Hospital, that just doesn't fly in
my face and that is what makes me concerned with all of this,
is that I believe politics was there in 2000. I think that
while I was back home in another role in my life, I think that
there was a rush to judgment to get this drug to market and
what we are seeing now are some problems that are arising from
it.
My concern is we don't have adequate knowledge one way or
another whether RU-486 has a direct or an indirect cause for
death. We do know that there is a relationship between the
death and the taking of the drug. We don't know whether it is
direct or indirect. But we do know that there is a
relationship. And my concern is that politics, once again, is
playing out.
But my next question is actually for Dr. Harrison. Your
colleagues say that if the theory were true that Mifeprex
comprised the immune system, then we would see a higher rate of
other kinds of infections. Your colleagues say this. What is
your response to that?
Dr. Harrison. Well, I think the focus of the CDC meeting
and most of our discussion today has been on the infectious
deaths, but there were actually at least 7 other life-
threatening infections to date in the 850 severe adverse event
reports that I reviewed, 1 of them being a 15-year-old who
spent several weeks in the intensive care unit but lived.
So there is an issue of critically looking at those
infection-related complications and there is a secondary issue
in even identifying those infection-related complications,
because if Mifepristone suppresses the immune system, the
infection may not be pelvic, and if it is not pelvic, it may
not be recognized as being related to the Mifepristone abortion
and, therefore, never reported. So we have a number of women
walking around potentially with a decreased immune system or
decreased ability to fight off infection whose connection with
their Mifepristone abortion will not be known, and that is a
big concern.
Mrs. Schmidt. Thank you, and my final question is for you,
Mr. Patterson. I am so glad that you are brave enough to bring
this to our attention and I know that your daughter is smiling
down on you. You are a very brave person.
What do you have to say about the assertion that the
benefits for RU-486 weigh the risks associated with it and what
do you think should be done to protect other families from the
same tragic fate that your family continues to experience?
Mr. Patterson. I think if you were to ask Holly here today,
had she lived, if the benefit outweighed the risk, I think she
would disagree. I have spent many, many hours researching this
drug and I can tell you that I feel very strongly about the
link that this drug does impair the innate immune system and
predisposes women to these--and can predispose these women to
serious and lethal infections. There has been a lot of
discussion of that at the CDC, FDA, and NIH conference.
I think the research is absolutely necessary. I think we
have information that has come out from very well renown and
respected doctors. It is very compelling that we need to pursue
this research to answer these questions.
Had Holly been given all the information in the very
beginning, you know, talking about the risk-benefit profile and
weighing those options, I think that had she been given all the
information she needed, she certainly would not have chosen an
RU-486 abortion because Holly was not the kind of young lady
that would risk her life for any reason whatsoever. Being the
pinnacle of fitness and the type of healthy individual that she
was, she would have chosen an alternate method and I can't say
enough that it is all about having all the information to make
an informed choice that is in the best interest of that
particular individual and the family that are making those
decisions.
Mr. Souder. Mr. Waxman.
Mr. Waxman. Thank you, Mr. Chairman.
I am trying to sort out these different positions and I
guess the first thing we are talking about is an infection that
has proved to be fatal in some cases and this infection is
called C. Sordellii. The first question is, is this infection
caused by this drug? People who didn't use this drug have had
this infection, is that accurate, Dr. Rarick?
Dr. Rarick. Yes.
Mr. Waxman. So it is not related exclusively to this drug.
Now, we know that some people who used this drug had the
infection. We don't know whether it caused the infection, is
that accurate?
Dr. Rarick. Correct.
Mr. Waxman. So we need to get an answer to that. If the
theory is that the immune system is suppressed because of the
RU-486, wouldn't we have a lot of evidence more of other
infections besides this one, because this is a fairly rare kind
of infection, isn't it?
Dr. Rarick. It is a very rare infection and I think this
situation is that it seems to be cropping up in pregnancy-
related events, not just medical abortion, but deliveries,
vaginal and Caesarian, and other conditions of post-pregnancy
conditions. I think the FDA is actively looking at whether they
agree or not that Mifepristone has any component of making it a
higher risk in women who are using it for medical abortion
versus other kinds of miscarriages or pregnancy termination.
Mr. Waxman. Well, this is not an issue that Congressmen
should decide. This is a very clear scientific issue. Evidence
ought to be reviewed very carefully. The Food and Drug
Administration, the Centers for Disease Control, the National
Institutes of Health all met on this issue this last week, is
that correct, Dr. Wood?
Ms. Wood. Yes.
Mr. Waxman. So they are looking at it. Dr. Harrison, do you
have any information that the FDA does not have?
Dr. Harrison. No. I have less information than the FDA
does. My information on the adverse event reports were obtained
by FOIA----
Mr. Waxman. From the FDA?
Dr. Harrison [continuing]. From the FDA, and my information
that I presented on the risk of C. Sordellii was directly from
the notes that I took from the meeting in Atlanta on----
Mr. Waxman. Were you able to share----
Dr. Harrison [continuing]. Dr. Fischer and Dr. McGregor's
testimony, who both are from the CDC.
Mr. Waxman. Were you able to share your views with people
at the FDA and perhaps at that meeting last week?
Dr. Harrison. I was not a participant and the panelists,
the speakers and those who were in research, were segregated
from the rest of the observers. I was in an observer spot and
not allowed to talk with the speakers until after.
Mr. Waxman. Are you able to submit your views to them in
writing?
Dr. Harrison. Someone from the FDA has requested a reprint
of my adverse event analysis that was printed in January and I
think that was the last request that I had or contact with the
FDA.
Mr. Waxman. You are listed on our list of witnesses today
as a member of the Mifeprex Subcommittee of the American
Association of Prolife Obstetricians and Gynecologists. In
January 2001, your organization issued a statement--this was
several months after the FDA's approval of Mifepristone. The
statement said, ``The American Association of Prolife
Obstetricians and Gynecologists opposes the destruction of an
unborn human being at any stage of development. Therefore, we
oppose pharmaceutical abortion with the same vigor that we
oppose surgical abortion.'' Would your organization hold the
same position on Mifepristone no matter what the safety data
said?
Dr. Harrison. I did not write that statement, although I am
a member of the American Association of Prolife Obstetricians
and Gynecologists. We characterize ourselves as pro-woman and
prolife and this is a women's health issue. When it becomes
clear that a method of abortion is 10 to 50 times more risky
than its alternative, then this takes it out of the realm of
the abortion debate and puts it into the realm of the women's
health debate----
Mr. Waxman. No doubt about it, but your organization--
excuse me, your organization----
Dr. Harrison. I would like to finish, please.
Mr. Waxman. No, no, let me, because I only have a very
limited time. Your organization's position is that you oppose
destruction of an unborn human being at any stage of
development, whether it is a pharmaceutical abortion or a
surgical abortion. So if that is your organization's position,
it is really unrelated to how safe or unsafe this may be. I
gather what you are saying is in addition to that, you feel it
is unsafe, but your organization started off with the position
that you don't want any abortions under any circumstances. Do
you subscribe to that view?
Dr. Harrison. I wouldn't agree with the way you said it,
no. What I would say is that in this particular----
Mr. Souder. Dr. Harrison.
Dr. Harrison. Yes, sir?
Mr. Souder. You do not have to state your position on
abortion or I am going to ask all the witnesses their position
on abortion.
Mr. Waxman. Well, Mr. Chairman----
Mr. Souder. The question is what the----
Mr. Waxman. Mr. Chairman----
Mr. Souder [continuing]. Issue at hand is, not what her
personal position on abortion is.
Mr. Waxman. Mr. Chairman, she is here representing an
organization and that organization has taken a position against
abortion under any circumstances. And they took that position
when RU-486 was approved without any of these other
complications or possible causations or connections ever came
about. And so my question of her is since they took that
position, no matter what the safety data said, how I should
view that as a representative from that organization. Did you
agree with the organization's position even if the safety data
didn't convince you further that this is a possible problem
with this drug?
Dr. Harrison. If the issue were whether or not there is a
human being being destroyed during the RU-486 abortion process,
that is a separate and completely different issue than the
issue this committee is authorized and mandated to look at,
which is oversight of the FDA process by which this drug was
approved, and are they doing their job to take an unsafe drug
off the market.
Mr. Waxman. Well, I appreciate that. I appreciate that, and
our job is to make sure that the FDA is doing its job. But FDA
is a scientifically based organization. They have to follow the
science. It may lead to a conclusion one way or it may lead to
a conclusion another way, but I want them to follow the
science, not some preconceived notion, and I think that is the
important point that I would make.
I see my time is up and I will conclude on that note.
Dr. Harrison. May I respond to that?
Mr. Waxman. Well, no, because we are not going to argue
that issue. The position, it seems to me, is there may be a
problem that is related to this drug. There may be a problem
that has no relationship to this drug. Let us get the truth.
Let us get to the scientific evidence and let the scientists
decide it, not politicians, no matter what our views may be on
the abortion question, because this is strictly, to me, a
scientific question.
Thank you, Mr. Chairman.
Mr. Souder. Mr. Waxman and I fence a lot in the media, even
though we have tremendous personal respect for each other and
get along real well, and it is awkward when we have deeply held
views of he believes that I and others are trying to impose our
political views and I and others believe the political views
have been imposed on the system already.
But what I really find disconcerting, and I understand
where you were headed here, because there are two issues. We
can't undo whatever abortion rights are in America. This is a
question about this drug. But you cannot possibly hold the
position that prolife people who oppose abortion can't
participate in a debate----
Mr. Waxman. And I wouldn't take that position.
Mr. Souder. Then what----
Mr. Waxman. I certainly wouldn't take that position.
Mr. Souder. What is the relevance of her position on RU-
486, because if you are asking her, can she be neutral on the
research, that is the question, not what her position is.
Mr. Waxman. My question related to the fact that if she is
representing an organization that took the position, we don't
care about safety data, we are just against the drug
accomplishing the purpose for which it is intended, which was
to terminate a pregnancy, if that is your position--let us put
it the other way. If you had somebody who said, I want to
terminate all pregnancies whether anybody wants to do it, which
is not my position, by the way. I don't want to see abortions,
but I don't want the decision made by you or Mr. Cummings or
myself. It ought to be made by the individual with the
consultation with a physician and an ethicist and others. It is
a personal decision, not one to be decided in Washington.
But if somebody takes the position that they are from an
organization that is against RU-486 under any circumstances,
even if it were safe, then you sort of wonder, well, if they
come in and say, well, we don't want this drug because it is
unsafe, I think their views ought to be submitted to the FDA
and they ought to evaluate them.
Mr. Souder. I don't think that is a--I think that, in
effect, that is why so many conservatives have a deep distrust
of our current research structure when we hear that it is
nonpolitical, because, in fact, what you just outlined was
something--a position that somebody who deeply believes that
all babies are human cannot detach that view or should be
somehow demeaned if they belong to any organization that is
pro-life as if we are under extra scrutiny as a doctor, as a
researcher, as a politician, that somehow, then, we are not
allowed to have a scientific discussion without wondering
whether our motives are impure.
Mr. Waxman. Well, she is not here as a well-known doctor,
as I understand it. She is listed as here representing that
organization. Now, if she happened to be somebody from NIH or a
researcher very well known in the field and she is here for her
expertise alone, that is one thing. But she is here
representing an organization.
Mr. Souder. It is really interesting, because she gave very
compelling testimony, very detailed testimony on the individual
cases, more than we got by far on blood transfusion actually
from FDA, and that rather than debate about her testimony, you
choose to attack the witness.
Mr. Waxman. No, I am not attacking her, but Mr. Patterson's
daughter didn't die from hemorrhaging. She died from this
particular infection and this infection is a very dangerous
infection and we need to know if it is connected to this drug.
If it is, even though I am pro-choice, I would be the first,
along with you, to say it ought to be taken off the market, or
it ought to be labeled as such. But if it is not a safety
threat, then I don't think it ought to be accused of being a
problem just because it shouldn't have been approved in the
first place by the people who want to take it off the market.
Mr. Souder. Furthermore, she is a published author in
research documents. I----
Mrs. Schmidt. Mr. Chairman, I think in fairness, I want to
know where everybody stands on the issue of abortion----
Mr. Souder. I don't think----
Mr. Waxman. Do you want to start off with yourself?
Mrs. Schmidt. Sure. I would be more than happy to.
Mr. Souder. Reclaiming, I think the line of questioning was
inappropriate. I made my statement. Mr. Waxman is the senior
ranking member of the full committee. He is free to do that. I
think the public can judge whether that was a fair approach,
but it certainly will reinforce people across the country who
are watching, a feeling that there is a discrimination against
people who are pro-life from being able to participate in
research, and that is some of why there is so much questioning
about this whole science debate.
Mr. Waxman. Would you yield to me just for me to make one
comment? I appreciate your views. I don't agree with you. But
the only comment I would make is that the Government
Accountability Office did an evaluation of FDA's action on the
Plan B contraceptive drug, and even though the scientific
committee appointed to review it said it should be approved,
even though the researchers at NIH said it should be approved,
it appeared that a political judgment was made because of the
Bush administration that it shouldn't be approved and its
approval is now in limbo. Many of us look at that as clear
politics when the science points in a different direction.
I want to know what the science says about this issue. You
say it is compelling. It is not compelling if scientists are
still evaluating the matter. I want them to see whether it is
compelling, whether there is a clear case made, and I don't
want politics interfering with science.
Mr. Souder. You can keep repeating that, but the funny
thing is, I have been a staffer here, I have been a member
here. We all know who requested the GAO study, who has picked
on the GAO study, which is heavily steered. GAO will do a study
on either side depending on who basically pushes it and what
mixes are. We have gone into this.
Mr. Waxman. Well, now you are attacking the GAO's
credibility just because it came up with a study that you
disagreed with.
Mr. Souder. No, I am questioning----
Mr. Waxman. That is more of an attack than I ever did with
Dr. Harrison.
Mr. Souder. As the GAO----
Mr. Waxman. And I didn't mean--I attacked the research----
Mr. Souder. As I have said, when you get into controversial
political subjects, the GAO, how you phrase the question, who
does it, in any honest--forget here for a second that the TV is
on--you know full well that we have problems in the GAO as far
as what kind of study you get back, and to act like it is a
pure scientific study out of the GAO--they do good research,
they research it, but they are going to have a bias based on
who is put on a given study and who is requesting the different
study. And if I request it with Republicans, you are going to
get a slightly different study back than you do.
There are subjects where they aren't that kind of laden
with the political overlay on this and the GAO will be very
forthright. You can go through the researchers they contracted.
You can look at the footnotes. You can look at the previously
published records of it. I am saying the GAO is transparent on
it, but when you go through the evaluation, you will see who
they hired as a contractor will determine what research they
get back.
Mr. Waxman. We have another Member who wants to ask
questions----
Mr. Souder. Yes, I----
Mr. Waxman [continuing]. But I just want to defend GAO.
Requesting a study by GAO doesn't mean that they have to come
out with your preferred conclusion. I think they have a lot
more integrity and honesty than you are suggesting. They can
decide who they are going to do the investigation. I think they
are a reputable source of information. Sometimes they come up
with conclusions I like, sometimes not, but they come up with
the facts and then we can draw the conclusions. I want the
science reviewed and then we can let the appropriate
policymakers reach the conclusion, but----
Mr. Souder. Ms. Watson----
Mr. Waxman [continuing]. Ms. Watson has been very nice
here.
Ms. Watson. I came in late and I am sorry about that. I
would like to know what we are investigating and looking at in
this particular meeting. Now, reading from the information that
was given to us, it says ``RU-486: Demonstrating a Low Standard
for Women's Health?'' May I ask, I would maybe ask Dr. Rarick
or Dr. Harrison, the question. Let me start with Dr. Rarick.
Are we talking about a low standard for women's health, and
if so, what is that? And are you agreeing that we have seen
more women die after using this drug than women who die after
having abortions? I just want to focus this discussion. I think
we have gotten off the track. So can you respond to that,
because we are looking at a low standard for women's health. At
least, that is what I thought this meeting was about and not
our beliefs and what sides we are taking. So can you answer
that question, the low standard question?
Dr. Rarick. Certainly. I will start with that. Mifepristone
in its review at the FDA was held to the highest standards,
similar to any drug product that is reviewed in the Center for
Drugs. It was reviewed in a rigorous way. It took over 4 years
from its submission to its approval. It was appropriately
labeled. It was held to the highest standards for women's or
men's health at the FDA and I believe they are still treating
it that way. They are looking at the issues that you are asking
about.
Are there more deaths reported with Mifepristone than with
surgical abortion? Some would say that there is tenfold more
deaths. I think we just heard that reported. But again, we have
to think about how they are looking at this data. Is there a
way to get more accurate data on surgical abortions, etc.? Is
there a way to understand the Mifepristone-associated deaths so
that they can be prevented? The issue is risk and benefit. They
are looking at that very seriously and I think it is being held
to the appropriate and high standards.
Ms. Watson. As the department of government that looks at
drugs and their usage and results, what would be the next step
if you then conclude that there appears to be a higher number
of deaths associated with the approval and the use of this
particular drug? What is the next step?
Dr. Rarick. Well, the next steps would be to look into
those types of deaths in all pregnancy-related events to try to
understand those better, make providers aware of those
infections and that potential, understand how to prevent it,
understand how to treat it, do women the service of
understanding pregnancy-related deaths in the broader sense,
not just related to Mifepristone. Many more women die from
childbirth than die from using Mifepristone for medical
abortion. Putting money into those questions, surveillance into
maternal mortality, appropriate money to explore maternal
mortality in its broadest sense, those would be the next steps.
Should the FDA look at all this information? Absolutely. As
was said before, they have all the information and more than
Dr. Harrison has referred to. They are looking at it very
seriously. If they believe that--they come to the conclusion
that the risks do not outweigh the benefits, they will take
appropriate action.
Ms. Watson. OK. And do you feel that we are demonstrating a
lower standard for women's health?
Dr. Rarick. Not at all.
Ms. Watson. All right. I would hope that this committee
would provide the oversight as FDA moves along and we would
then look at the empirical evidence that would emanate from
your studies to address this question. If we are demonstrating
a lower standard, then provide the scientific evidence. I would
beg that we don't discuss the ``A'' word in terms of looking at
this particular drug. It gets us off track, as it did just
about a minute ago. What I want to be presented with as a
decisionmaker is what evidence we might have that we have
approved a drug that lowers the standards for women. Thank you.
Mr. Waxman. Will the gentlelady yield to me?
Ms. Watson. Yes, I will, certainly.
Mr. Waxman. I wasn't even aware of it until you just
pointed it out. The chairman said it depends on how you ask the
question, but the hearing is titled for today, ``RU-486:
Demonstrating a Low Standard for Women's Health?'' so that is
the way we are asking the question. I think we need to see
whether there is a--and you answered that question and I was
pleased with your answer, but I think the question should be,
is there a connection between Mr. Patterson's daughter and the
five people that have died from this particular infection and
the use of RU-486? That seems to me the key to it, because if
there is a connection with the use of this drug and getting
something as deadly as this infection, that is a serious
matter. So we need to explore it, but evidently it is not so
clear when we find people have had the infection who didn't
have the drug. So I agree with you. Let us get the science. Let
us get the facts.
Mr. Souder. Dr. Rarick, I was a little confused by your
response. You said that if, in fact, there were deaths, you
would work for or believe there should be further notification
to doctors. I inserted this earlier, but Palladone, Purdue
Pharma agreed to voluntarily suspend, and they said, to date,
FDA is not aware of any patients who had life-threatening side
effects from drinking alcohol while taking Palladone, but they
took it off the market.
Tysabri Biogen voluntarily suspended marketing of the drug
as well as its use in clinical trials until more detailed
information could be gathered on one death and one other
adverse effect.
In NeutroSpec, Palatin Technologies voluntarily suspended
sales and marketing of NeutroSpec. No determination was made
regarding the relationship between that and reported adverse
effects.
In Cylert, Abbott chose to stop sales and marketing based
on 13 reports of liver failure, but they did not grant--and RU-
486 had 10 to 14 times more than surgical abortion, even though
in this case liver failure was 10 to 25 greater in the general
population.
Bextra, Pfizer voluntarily withdrew Bextra from the market
even though it concluded that the overall risk versus benefit
was unfavorable.
In Baycol, they withdrew after reports of 31 deaths. In
Roplin, it was 5 deaths.
In Lontronex, it was a total of 70 cases of adverse effects
of which 34 required hospitalization without surgery and it was
pulled off.
In Orlaam, it was discontinued after a report of severe
cardiac-related events among opiate-addicted patients. They
pulled it off the market, not just warnings.
So is your position that FDA should treat this drug unlike
other drugs, because when there are adverse effects with deaths
and so on, at the very least, you think it would be suspended.
That has been the whole pattern. The problem here is you have a
drug company that only has one drug. It is in the Cayman
Islands. There is no incentive to do what all these other
companies did which went off the market. And so what is the
responsibility of the Federal Government when the private
sector won't act responsibly like the others.
Now, I happen to believe, even though I don't want RU-486
on the market, that there may be some debate here as to whether
it is the primary, and that is why I was asking questions of
can it be suspended while we find that out. But I see no
pattern of FDA that we leave something on the market while we
are doing that study, because it is clear that it was toxic in
a disproportionate amount if you are using RU-486, that the
blood transfusions were certainly disproportionate, and under
any standard of the past, you would at least suspend, hence the
question of the hearing.
Dr. Rarick. I would simply disagree with you. You can list
all the ones that have been suspended, but you have to think of
the thousands of drugs that are on the market that have post-
marketing reports of deaths. The easiest example is Viagra,
where we had at least several hundred deaths during its first
year of prescription, the same company, Pfizer, that you
mentioned there for Bextra. There are all kinds of examples of
post-marketing death adverse event reports and other serious
adverse event reports where the majority are certainly not
suspended from marketing.
Mr. Souder. Even if it was directly related to that
product, the FDA does--then what standard would you have FDA
intervene?
Dr. Rarick. The standard that they use, which is a risk-
benefit analysis for each particular case.
Mr. Souder. Mr. Snead, what is your response to that?
Mr. Snead. I think, essentially, that is exactly right,
namely that you need a risk-benefit analysis that is undertaken
to determine whether or not a drug is initially approved. But I
would like to add something that I think would be informative
to the Members. What we are talking about here as a legal
matter is a drug that has been approved under Subpart H, and
what that means is that creates an inference that the FDA in
approving Mifepristone had a concern, safety concern, that
required additional safeguards beyond the normal safeguards
that attend a normal risk-benefit analysis.
In the passage that I read before from the FDA's final
rule, they said the risk-benefit analysis that yields the
conclusion that this should be approved assumes that these
post-marketing requirements will, A) be effective, and B) be
observed. So there has been much discussion about the safety
piece of that particular question. But what seems to be getting
lost among the discussion is there is a second question, a
second grounds under Subpart H, which is a factual question
about the compliance with the post-marketing restrictions by
Danco Corp.
So I would just draw the committee's attention back to the
fact that, of course, safety is a principal concern as laid out
in the withdrawal approvals of Subpart H as well as with the
other withdrawal approvals that I take up in my written
testimony, but the question of compliance is equally important
of a question, because without meaningful compliance by Danco,
the risk-benefit analysis is not what the FDA intended it to
be. The risk-benefit analysis depends on the assumption that
there is compliance, and if there is no compliance, then the
risk-benefit analysis is substantially different.
Mr. Waxman. Mr. Chairman, could you yield to me?
Mr. Souder. Yes.
Mr. Waxman. Do you have evidence of noncompliance?
Mr. Souder. I have no evidence of any kind. I am just
simply describing to you what the considerations are.
Mr. Waxman. So you are saying if there hadn't been
compliance with the limitations----
Mr. Souder [continuing]. I am making a conditional
statement. If the FDA were to determine that there was no
compliance, then they would have additional grounds to withdraw
approval under Subpart H.
Mr. Waxman. But I hadn't heard anybody assert that there
hadn't been compliance of the approval itself under the Subpart
H. Of course, this is unusual, because most drugs are just
approved and once they are approved, they can be used for any
purpose. This one was approved for limited purposes under
limited circumstances so that there would be extra care taken.
I guess I should ask that question of Dr. Rarick. Am I correct
in that? It wasn't----
Dr. Rarick. Correct----
Mr. Waxman [continuing]. Approved like most other drugs, go
ahead and use it----
Dr. Rarick. There was a determination that it shouldn't be
released through pharmacies, that it had to be provided by
specific types of prescribers.
Mr. Souder. And I should say for the record that we did
invite Danco so we could address that question and they
withdraw 2 days before the hearing and we didn't have a chance
to get somebody else to directly address the question, but it
is a fair question.
Mr. Waxman. It is not a fair question unless you know there
has been some non-compliance.
Mr. Souder. No, your question is a fair question, because
we don't know for sure about compliance. I tried to address
that with FDA. I don't think, personally, that what was tested
has been followed through the way it was tested, but the
Assistant Commissioner explained why she thought that was still
allowable, but we don't have Danco here and we don't have a
substitute for Danco to follow through that question, but it is
a question we need to followup in our written questions and we
said at the beginning that I was going to do that with Danco.
Dr. Harrison, could you talk about the proportionate use
effect, too? Viagra is used over and over. RU-486 would not be.
And any comments you had on Dr. Rarick saying, look, there are
other drugs we allow on the market, because that is a fair
point. If there are lots of drugs on the market that have
adverse effects, why should this be treated differently than
those?
Dr. Harrison. The issue is not the absolute number of
adverse events. The issue is, as is stated in the FDA letter to
this committee, the evidence whether or not RU-486 was causally
related to the adverse events, the timing of the event--
remember that these RU-486 septic deaths happened within 7
days. There is no issue of confounding factors here. These
women were healthy. They didn't have other medical conditions
that could explain why they would suddenly get an extremely
rare bacterial infection that doesn't usually kill normally
immuno-competent people. How severe these events are--the death
is the ultimate severe adverse event.
And I would have to add that transfusions are also a
significant severe adverse event, and to minimize the
significance of having a blood transfusion is to underestimate
the care that goes into clinically judging whether or not this
person needs a transfusion. Transfusions aren't done lightly.
They are done when there is a significant risk to the person's
life.
Can the adverse events be predicted or avoided? The CDC
meeting was absolutely clear that at this point in time, there
is no way to predict who is going to get--who is going to die
from C. Sordellii. Because we can't predict who and we can't
identify risk factors, we also can't avoid C. Sordellii in
Mifepristone abortions. There has been a consistent
spontaneous--a consistent rate, excuse me, of about 1 death for
every 100,000 Mifepristone uses. So if that continues unabated
while we debate these questions of how much research and who
gets the grant money and all that stuff, that means that for
every 1,000 uses of Mifepristone, one more American woman is
going to die, and I think that is something that has to be put
into perspective. These are human beings that are being
subjected to a completely unnecessary risk.
Surgical abortion is available and legal and safer, and how
safe is the alternative treatment, and that is the other issue.
Surgical abortion is available. It is legal. And to say that
Mifepristone is being used in cases where surgical abortion
isn't available, think about what would have happened to these
transfusion deaths if there hadn't been surgical abortion
available. Any place that has the capability to--excuse me. Any
place that doesn't have the capability to have an abortion
clinic also doesn't have the capability to do transfusion. We
are talking pretty sophisticated medical facilities. So the
person you absolutely do not want to use Mifepristone is the
one who has no access to surgical facilities to complete this
under an emergency circumstance, so I think that is kind of a
spurious argument.
So that would be my response. Thanks.
Mr. Cummings. Mr. Chairman, may I please----
Mr. Souder. Yes.
Mr. Cummings. Thank you.
Mr. Souder. Mr. Cummings.
Mr. Cummings. I have sat here and I have listened to all of
this and I was sitting here saying to myself, I am so glad that
there are women making these arguments. I would hate to see a
group of men. They would probably say that we were not as
sensitive as we need to be, and I say that to say this, that I
think we are all concerned about women's health. As a matter of
fact, I know that we are.
I don't think that in this country we are talking about low
standards. Let us not kid ourselves. This is the United States
of America. There is no way that I think any member of this
panel would in any way accept a low standard or even a mediocre
standard. The witnesses, I know you feel the same way. We may
differ on your opinions and what have you.
The key is, Mr. Patterson, is we want to make sure that we
do everything in our power, as I know you want us to do, to
make sure this does not happen to anyone else. That is what
this is all about.
And I would hope and I would think that you, Dr. Rarick,
when I asked you the question a little earlier, because I
really wanted to get a sense of exactly--obviously, there is a
procedure that you have there at FDA, and obviously, and you
can tell me if I am wrong, you try to keep the politics out of
it because you are talking about people living and dying, I
guess. I trust that you do.
But you have heard the testimony of Dr. Harrison and I
would assume that you would be, as we all are, as sensitive to
women's health. Is there anything that you have heard that you
would question whether you all have a low standard? I know that
may be a sort of self-serving question and I am not trying to
do that, but I am trying to get to the bottom of this, because
sometimes we can get so caught up in our politics that we
forget where we are trying to get to and we get sort of off-
track. The key is that we want to make sure, all of us, that
FDA has a standard which will protect every woman with regard
to her health choices.
So that leads me to this. Somebody said a few minutes ago,
I think it was you, Mr. Patterson--it was you--when you were
talking about your daughter, you said if there was information,
if she had access to all the information, she probably would
not have made that choice.
Now, I am asking you, based upon all that you know, Dr.
Rarick, is there anything that you could have or the FDA could
have put on the label or put on the little description of the
drug's side effects, whatever, that should have been there,
just based on what you know to this date? I am not talking
about--I know there is still research to be done and all that
kind of stuff--that should have been on there?
Dr. Rarick. Well, I would stand behind the FDA's labeling
at each point when they revised their labeling, and if you look
at the current labeling, it does describe that there has been
some unusual and severe bacterial infections and deaths. It
describes some of the way the regimen was given in those cases.
It provides that information.
I agree with you that the FDA has to look at this very
seriously and always decide, do the benefits remain to outweigh
the risks?
If you ask me about high standards, I would say the FDA
holds this to a very high standard. I believe if you are
looking for low standards in women's health, it would be that
we don't have very much information about maternal mortality in
general, not just post-abortal or post-medical abortion
mortality, but just infections and pregnancy outcomes, any
events in general.
But in terms of Mifepristone being held to a particularly
low standard, absolutely not. It is held to the highest
standards. I think the FDA is considered the most rigorous
regulatory body in the world and it, of course, meets those
needs.
I agree with you that these things are incredibly serious.
Nobody is trying to minimalize any of these events. I believe
the FDA is looking at this from their scientific viewpoint.
They at the meeting last week I think were quoted as saying
they initially saw this as probably a simple drug-based
association and they realized when they looked into it that
simply wasn't true, that it was much more complicated than just
Mifepristone and infection and they are looking at it.
Mr. Cummings. Now, you said the labeling has changed. I am
going to get back to you, Mr. Patterson, in 1 second. I see you
shaking your head. But you said the labeling has changed, is
that right?
Dr. Rarick. Yes. The labeling has been updated, I think at
least three times since its original approval.
Mr. Cummings. And I take it that when Mr. Patterson's
daughter took the--there have been changes since Mr.
Patterson's daughter used this medication?
Dr. Rarick. Yes.
Mr. Cummings. Maybe one of you all could tell us, were
those the changes that you just authorized? You said something.
I am just trying to figure out, have we made much progress with
regard to going back to what you said, Mr. Patterson, putting
it out there, as much information as possible that we feel
comfortable is accurate?
Mr. Patterson. Well, first of all, I would like to say
again that if Holly had all the information to make an informed
choice, she wouldn't have chosen Mifepristone or an RU-486
medical abortion.
There is evidence that a death did occur in Canada with an
infection and she, in fact, did die from C. Sordellii, and that
was what I uncovered in my medical research that was not very
well known or very well published. As a matter of fact, the
author of the paper of the woman who died in Canada was Dr.
Christian Sinave. It just so happens that at the time, my wife
and I, when we called Dr. Sinave, we were the very first person
or concerned people to call about that particular infection as
it is associated with RU-486. He said in his own words that he
had been discouraged to write the paper and that we were like
the only ones that had ever showed any interest, and since
then, there has been a considerable interest over this
infection and its relationship with the drug.
To say that this drug, there is no causal relationship, I
think is ridiculous. My daughter took the drug and she died. I
mean, it is that simple. So the medical community was aware of
it. Danco was aware of it. The Population Council was aware of
it and there were studies showing that there were infections as
a result of medical abortion. However, Holly was not indicated
in the label and Holly was not given that information.
Since my daughter died, I have been to Washington. I have
discussed my concerns with the FDA over these safety and health
concerns. There have been--consequently, there have been four
more women died after Holly and some very shortly, within
months, after Holly. As a matter of fact, with the reporting,
it took one of the deaths right after Holly, it took almost a
year and a half to get reported. That is why today I have
discussed there needs to be some very accurate mechanisms to be
able to evaluate from the FDA's level what is really going on
out there. I am very concerned that women are dying and these
events are not getting reported so that the FDA can actually do
their job.
Mr. Cummings. All right. So there have been--and thank you
very much. Just a last question. There have been some updates
with regard to the warnings, is that right?
Dr. Rarick. Correct.
Mr. Cummings. I think in November 2004, the black box
warning was revised and strengthened to add new information on
the risk of serious bacterial infections, sepsis, bleeding, and
death that may occur following any termination of pregnancy,
including Mifeprex. In July 2005, apparently the FDA approved a
labeling supplement to again strengthen the black box warning
on the product, but noting that atypical presentations of
serious infection can occur without fever, bacteria, or
significant findings on pelvic exam, etc. Is that accurate?
Dr. Rarick. My review of the label, I believe would agree
with that. I have the label here if you want to see the whole
label.
Mr. Cummings. No problem. I just wanted to make sure that
it is being updated.
Mr. Souder. Anything else, Mr. Waxman?
Mr. Waxman. This issue of death associated with a drug,
when FDA approves drugs, they look at the safety and they look
at the efficacy, whether the drug accomplishes what it is
intended to accomplish. Aren't there risks associated with a
lot of drugs, Dr. Rarick?
Dr. Rarick. Oh, every drug has risks associated with it,
yes.
Mr. Waxman. Viagra could cause death. Penicillin could
cause death. They are on the market. But I assume they are on
the market because there is a risk-benefit analysis that even
though there may be a rare case of death, it is not so out of
control that it diminishes the fact that there is a benefit
from those drugs. Is that what we mean by a risk-benefit
analysis?
Dr. Rarick. Correct, that you look at those risks, those
death reports and rates in contrast to the benefits.
Mr. Waxman. There is a question in my mind about deaths or
harm associated with a drug as opposed to death or harm caused
by the drug. Can you clarify what that means in terms of FDA
regulation?
Dr. Rarick. It sounds like a legal term, but I will try.
When you think of cause and causation, you think, you know, if
I tell my kid, don't touch the hot stove, you are going to get
burned, and he touches the hot stove and gets burned, to me,
that is cause and effect. When you look at drugs and the risks
associated with them, it is very rare that you can actually say
X drug causes Y, because, as you know, many, many people take
the drugs that don't get that effect. The majority of people
who take a particular drug won't have the side effects that are
described in the label, but there are going to be side effects
in many people, and there, you would call that a side effect
that is associated with the use of that product.
Mr. Waxman. Well, Mr. Patterson has pointed out, I think
appropriately, that he wished his daughter would have known
that there was this potential side effect. Now, FDA has issued
public health advisories in connection with safety concerns
related to Mifepristone in 2004, 2005, and most recently, in
March 2006. The FDA has consistently highlighted the fact that
the cases of severe infection occurred with regimens of
Mifepristone and Misoprostol that were not in approved
labeling, although the relationship of the infections to such
use remains unknown. What does that mean? Could you tell us
more about this, if you know?
Dr. Rarick. That means even though the products are being
used outside of their labeled instructions, the FDA wants to
make sure that providers and patients are aware that it has
been associated with these infections. Whether it would be
associated with those infections if it had been used as per
label, they are not stating. They are simply saying--they could
just say, well, that wasn't used by the label. We don't even
need to put it on the label. But instead, they are saying, no,
we need to make sure providers and patients are aware that in
certain circumstances, we have had these reports. They are not
suggesting that it is absolutely that circumstance that caused
the increased risk, but they want to make sure that information
is available.
Mr. Waxman. Well, I thank you for that clarification and I
will conclude by saying I just hope the FDA will continue to
reevaluate all the evidence, advise people of information that
is pertinent, and if they see there is a real threat to this
drug, or any other drug, they need to take actions, including
taking the drug off the market. But I don't think they ought to
act until they look at the science and reach some conclusions
on this drug or any other drug.
Thank you, Mr. Chairman.
Mr. Souder. Thank you. Rather than ask Dr. Harrison the
question again, I think we will insert in the record your
earlier response on the causal link, that there were multiple
things, including alternatives such as surgical abortions and
so on, because you gave a complex answer to that question early
on. Did you have anything you want to add?
Dr. Harrison. No, that is fine.
Mr. Souder. Ms. Watson.
Ms. Watson. I just hope that we can have, Mr. Chairman, a
followup hearing as FDA proceeds along its track to assess the
risks of this drug, that we will do the oversight that we are
responsible for here in Congress, and I would hope that we
would base our debate on the results of your studies so that we
can come from a scientific base as we discuss this.
So I want to thank the chair for this hearing. I think it
has opened up a debate on the efficacy of this drug that has
been approved and we need to see what the effects actually are.
So thank you so much for the hearing and thanks to the panel.
Mr. Souder. Thank you, and I want to thank each of the
witnesses and I want to say this directly to Dr. Wood and Dr.
Rarick. Whether we agree on the nuances here, or maybe we do
long-term or not, that your work long-term, Dr. Wood
particularly but also Dr. Rarick, on women's health issues,
because certainly it was an area that was underrepresented in
the research, and without aggressive advocacy, we wouldn't be
where we are on breast cancer, on the whole range of women's
health issues. So regardless of where we stand on this issue, I
appreciate your lengthy career working with that, Dr. Rarick,
as well.
I thank Mr. Patterson for speaking out, Dr. Harrison for
giving us that detailed analysis of each of the type of cases
and your rigorous analysis of that, and Mr. Snead for bringing
the legal aspects in and we will find out, particularly if
Danco responds, how to address some of their questions legally
on whether they have been following through on the guidelines
of FDA.
With that, the subcommittee stands adjourned.
[Whereupon, at 6 p.m., the subcommittee was adjourned.]
[Additional information submitted for the hearing record
follows:]
[GRAPHIC] [TIFF OMITTED] T1397.314
[GRAPHIC] [TIFF OMITTED] T1397.315
[GRAPHIC] [TIFF OMITTED] T1397.316
[GRAPHIC] [TIFF OMITTED] T1397.317
[GRAPHIC] [TIFF OMITTED] T1397.318
[GRAPHIC] [TIFF OMITTED] T1397.319
[GRAPHIC] [TIFF OMITTED] T1397.320
[GRAPHIC] [TIFF OMITTED] T1397.321
[GRAPHIC] [TIFF OMITTED] T1397.322
[GRAPHIC] [TIFF OMITTED] T1397.323
[GRAPHIC] [TIFF OMITTED] T1397.324
[GRAPHIC] [TIFF OMITTED] T1397.325
[GRAPHIC] [TIFF OMITTED] T1397.326
[GRAPHIC] [TIFF OMITTED] T1397.327
[GRAPHIC] [TIFF OMITTED] T1397.328
[GRAPHIC] [TIFF OMITTED] T1397.329
[GRAPHIC] [TIFF OMITTED] T1397.330
[GRAPHIC] [TIFF OMITTED] T1397.331
[GRAPHIC] [TIFF OMITTED] T1397.332
[GRAPHIC] [TIFF OMITTED] T1397.333
[GRAPHIC] [TIFF OMITTED] T1397.334
[GRAPHIC] [TIFF OMITTED] T1397.335
[GRAPHIC] [TIFF OMITTED] T1397.336
[GRAPHIC] [TIFF OMITTED] T1397.337
[GRAPHIC] [TIFF OMITTED] T1397.338
[GRAPHIC] [TIFF OMITTED] T1397.339
[GRAPHIC] [TIFF OMITTED] T1397.340
[GRAPHIC] [TIFF OMITTED] T1397.341
[GRAPHIC] [TIFF OMITTED] T1397.342
[GRAPHIC] [TIFF OMITTED] T1397.343
[GRAPHIC] [TIFF OMITTED] T1397.344
[GRAPHIC] [TIFF OMITTED] T1397.345
[GRAPHIC] [TIFF OMITTED] T1397.346
[GRAPHIC] [TIFF OMITTED] T1397.347
[GRAPHIC] [TIFF OMITTED] T1397.348
[GRAPHIC] [TIFF OMITTED] T1397.349
[GRAPHIC] [TIFF OMITTED] T1397.350
[GRAPHIC] [TIFF OMITTED] T1397.351
[GRAPHIC] [TIFF OMITTED] T1397.352
[GRAPHIC] [TIFF OMITTED] T1397.353
[GRAPHIC] [TIFF OMITTED] T1397.354
[GRAPHIC] [TIFF OMITTED] T1397.355
[GRAPHIC] [TIFF OMITTED] T1397.356
[GRAPHIC] [TIFF OMITTED] T1397.357
[GRAPHIC] [TIFF OMITTED] T1397.358
[GRAPHIC] [TIFF OMITTED] T1397.359
[GRAPHIC] [TIFF OMITTED] T1397.360
[GRAPHIC] [TIFF OMITTED] T1397.361
[GRAPHIC] [TIFF OMITTED] T1397.362
[GRAPHIC] [TIFF OMITTED] T1397.363
[GRAPHIC] [TIFF OMITTED] T1397.364
[GRAPHIC] [TIFF OMITTED] T1397.365
[GRAPHIC] [TIFF OMITTED] T1397.366
[GRAPHIC] [TIFF OMITTED] T1397.367
[GRAPHIC] [TIFF OMITTED] T1397.368
[GRAPHIC] [TIFF OMITTED] T1397.369
[GRAPHIC] [TIFF OMITTED] T1397.370
[GRAPHIC] [TIFF OMITTED] T1397.371
[GRAPHIC] [TIFF OMITTED] T1397.372
[GRAPHIC] [TIFF OMITTED] T1397.373
[GRAPHIC] [TIFF OMITTED] T1397.374
[GRAPHIC] [TIFF OMITTED] T1397.375
[GRAPHIC] [TIFF OMITTED] T1397.376
[GRAPHIC] [TIFF OMITTED] T1397.377
[GRAPHIC] [TIFF OMITTED] T1397.378
[GRAPHIC] [TIFF OMITTED] T1397.379
[GRAPHIC] [TIFF OMITTED] T1397.380
[GRAPHIC] [TIFF OMITTED] T1397.381
[GRAPHIC] [TIFF OMITTED] T1397.382
[GRAPHIC] [TIFF OMITTED] T1397.383
[GRAPHIC] [TIFF OMITTED] T1397.384
[GRAPHIC] [TIFF OMITTED] T1397.385
[GRAPHIC] [TIFF OMITTED] T1397.386
[GRAPHIC] [TIFF OMITTED] T1397.387
[GRAPHIC] [TIFF OMITTED] T1397.388
[GRAPHIC] [TIFF OMITTED] T1397.389
[GRAPHIC] [TIFF OMITTED] T1397.390
[GRAPHIC] [TIFF OMITTED] T1397.391
[GRAPHIC] [TIFF OMITTED] T1397.392
[GRAPHIC] [TIFF OMITTED] T1397.393
[GRAPHIC] [TIFF OMITTED] T1397.394
[GRAPHIC] [TIFF OMITTED] T1397.395
[GRAPHIC] [TIFF OMITTED] T1397.396
[GRAPHIC] [TIFF OMITTED] T1397.397
[GRAPHIC] [TIFF OMITTED] T1397.398
[GRAPHIC] [TIFF OMITTED] T1397.399
[GRAPHIC] [TIFF OMITTED] T1397.400
[GRAPHIC] [TIFF OMITTED] T1397.401
[GRAPHIC] [TIFF OMITTED] T1397.402
[GRAPHIC] [TIFF OMITTED] T1397.403
[GRAPHIC] [TIFF OMITTED] T1397.404
[GRAPHIC] [TIFF OMITTED] T1397.405
[GRAPHIC] [TIFF OMITTED] T1397.406
[GRAPHIC] [TIFF OMITTED] T1397.407
[GRAPHIC] [TIFF OMITTED] T1397.408
[GRAPHIC] [TIFF OMITTED] T1397.409
[GRAPHIC] [TIFF OMITTED] T1397.410
[GRAPHIC] [TIFF OMITTED] T1397.411
[GRAPHIC] [TIFF OMITTED] T1397.412
[GRAPHIC] [TIFF OMITTED] T1397.413
[GRAPHIC] [TIFF OMITTED] T1397.414
[GRAPHIC] [TIFF OMITTED] T1397.415
[GRAPHIC] [TIFF OMITTED] T1397.416
[GRAPHIC] [TIFF OMITTED] T1397.417
[GRAPHIC] [TIFF OMITTED] T1397.418
[GRAPHIC] [TIFF OMITTED] T1397.419
[GRAPHIC] [TIFF OMITTED] T1397.420
[GRAPHIC] [TIFF OMITTED] T1397.421
[GRAPHIC] [TIFF OMITTED] T1397.422
[GRAPHIC] [TIFF OMITTED] T1397.423
[GRAPHIC] [TIFF OMITTED] T1397.424
[GRAPHIC] [TIFF OMITTED] T1397.425
[GRAPHIC] [TIFF OMITTED] T1397.426
[GRAPHIC] [TIFF OMITTED] T1397.427
[GRAPHIC] [TIFF OMITTED] T1397.428
[GRAPHIC] [TIFF OMITTED] T1397.429
[GRAPHIC] [TIFF OMITTED] T1397.430
[GRAPHIC] [TIFF OMITTED] T1397.431
[GRAPHIC] [TIFF OMITTED] T1397.432
[GRAPHIC] [TIFF OMITTED] T1397.433
[GRAPHIC] [TIFF OMITTED] T1397.434
[GRAPHIC] [TIFF OMITTED] T1397.435
[GRAPHIC] [TIFF OMITTED] T1397.436
[GRAPHIC] [TIFF OMITTED] T1397.437
[GRAPHIC] [TIFF OMITTED] T1397.438
[GRAPHIC] [TIFF OMITTED] T1397.439
[GRAPHIC] [TIFF OMITTED] T1397.440
[GRAPHIC] [TIFF OMITTED] T1397.441
[GRAPHIC] [TIFF OMITTED] T1397.442
[GRAPHIC] [TIFF OMITTED] T1397.443
[GRAPHIC] [TIFF OMITTED] T1397.444
[GRAPHIC] [TIFF OMITTED] T1397.445
[GRAPHIC] [TIFF OMITTED] T1397.446
[GRAPHIC] [TIFF OMITTED] T1397.447
[GRAPHIC] [TIFF OMITTED] T1397.448
[GRAPHIC] [TIFF OMITTED] T1397.449
[GRAPHIC] [TIFF OMITTED] T1397.450
[GRAPHIC] [TIFF OMITTED] T1397.451
[GRAPHIC] [TIFF OMITTED] T1397.452
[GRAPHIC] [TIFF OMITTED] T1397.453
[GRAPHIC] [TIFF OMITTED] T1397.454
[GRAPHIC] [TIFF OMITTED] T1397.455
[GRAPHIC] [TIFF OMITTED] T1397.456
[GRAPHIC] [TIFF OMITTED] T1397.457
[GRAPHIC] [TIFF OMITTED] T1397.458
[GRAPHIC] [TIFF OMITTED] T1397.459
[GRAPHIC] [TIFF OMITTED] T1397.460
[GRAPHIC] [TIFF OMITTED] T1397.461
[GRAPHIC] [TIFF OMITTED] T1397.462
[GRAPHIC] [TIFF OMITTED] T1397.463
[GRAPHIC] [TIFF OMITTED] T1397.464
[GRAPHIC] [TIFF OMITTED] T1397.465
[GRAPHIC] [TIFF OMITTED] T1397.466
[GRAPHIC] [TIFF OMITTED] T1397.467
[GRAPHIC] [TIFF OMITTED] T1397.468
[GRAPHIC] [TIFF OMITTED] T1397.469
[GRAPHIC] [TIFF OMITTED] T1397.470
[GRAPHIC] [TIFF OMITTED] T1397.471
[GRAPHIC] [TIFF OMITTED] T1397.472
[GRAPHIC] [TIFF OMITTED] T1397.473
[GRAPHIC] [TIFF OMITTED] T1397.474
[GRAPHIC] [TIFF OMITTED] T1397.475
[GRAPHIC] [TIFF OMITTED] T1397.476
[GRAPHIC] [TIFF OMITTED] T1397.477
[GRAPHIC] [TIFF OMITTED] T1397.478
[GRAPHIC] [TIFF OMITTED] T1397.479
[GRAPHIC] [TIFF OMITTED] T1397.480
[GRAPHIC] [TIFF OMITTED] T1397.481
[GRAPHIC] [TIFF OMITTED] T1397.482
[GRAPHIC] [TIFF OMITTED] T1397.483
[GRAPHIC] [TIFF OMITTED] T1397.484
[GRAPHIC] [TIFF OMITTED] T1397.485
[GRAPHIC] [TIFF OMITTED] T1397.486
[GRAPHIC] [TIFF OMITTED] T1397.487
[GRAPHIC] [TIFF OMITTED] T1397.488
[GRAPHIC] [TIFF OMITTED] T1397.489
[GRAPHIC] [TIFF OMITTED] T1397.490
[GRAPHIC] [TIFF OMITTED] T1397.491
[GRAPHIC] [TIFF OMITTED] T1397.492
[GRAPHIC] [TIFF OMITTED] T1397.493
[GRAPHIC] [TIFF OMITTED] T1397.494
[GRAPHIC] [TIFF OMITTED] T1397.495
[GRAPHIC] [TIFF OMITTED] T1397.496
[GRAPHIC] [TIFF OMITTED] T1397.497
[GRAPHIC] [TIFF OMITTED] T1397.498
[GRAPHIC] [TIFF OMITTED] T1397.499
[GRAPHIC] [TIFF OMITTED] T1397.500
[GRAPHIC] [TIFF OMITTED] T1397.501
[GRAPHIC] [TIFF OMITTED] T1397.502
[GRAPHIC] [TIFF OMITTED] T1397.503
[GRAPHIC] [TIFF OMITTED] T1397.504
[GRAPHIC] [TIFF OMITTED] T1397.505
[GRAPHIC] [TIFF OMITTED] T1397.506
[GRAPHIC] [TIFF OMITTED] T1397.507
[GRAPHIC] [TIFF OMITTED] T1397.508
[GRAPHIC] [TIFF OMITTED] T1397.509
[GRAPHIC] [TIFF OMITTED] T1397.510
[GRAPHIC] [TIFF OMITTED] T1397.511
[GRAPHIC] [TIFF OMITTED] T1397.512
[GRAPHIC] [TIFF OMITTED] T1397.513
[GRAPHIC] [TIFF OMITTED] T1397.514
[GRAPHIC] [TIFF OMITTED] T1397.515
[GRAPHIC] [TIFF OMITTED] T1397.516
[GRAPHIC] [TIFF OMITTED] T1397.517
[GRAPHIC] [TIFF OMITTED] T1397.518
[GRAPHIC] [TIFF OMITTED] T1397.519
[GRAPHIC] [TIFF OMITTED] T1397.520
[GRAPHIC] [TIFF OMITTED] T1397.521
[GRAPHIC] [TIFF OMITTED] T1397.522
[GRAPHIC] [TIFF OMITTED] T1397.523
[GRAPHIC] [TIFF OMITTED] T1397.524
[GRAPHIC] [TIFF OMITTED] T1397.525
[GRAPHIC] [TIFF OMITTED] T1397.526
[GRAPHIC] [TIFF OMITTED] T1397.527
[GRAPHIC] [TIFF OMITTED] T1397.528
[GRAPHIC] [TIFF OMITTED] T1397.529
[GRAPHIC] [TIFF OMITTED] T1397.530
[GRAPHIC] [TIFF OMITTED] T1397.531
[GRAPHIC] [TIFF OMITTED] T1397.532
[GRAPHIC] [TIFF OMITTED] T1397.533
[GRAPHIC] [TIFF OMITTED] T1397.534
[GRAPHIC] [TIFF OMITTED] T1397.535
[GRAPHIC] [TIFF OMITTED] T1397.536
[GRAPHIC] [TIFF OMITTED] T1397.537
[GRAPHIC] [TIFF OMITTED] T1397.538
[GRAPHIC] [TIFF OMITTED] T1397.539
[GRAPHIC] [TIFF OMITTED] T1397.540
[GRAPHIC] [TIFF OMITTED] T1397.541
[GRAPHIC] [TIFF OMITTED] T1397.542
[GRAPHIC] [TIFF OMITTED] T1397.543
[GRAPHIC] [TIFF OMITTED] T1397.544
[GRAPHIC] [TIFF OMITTED] T1397.545
[GRAPHIC] [TIFF OMITTED] T1397.546
[GRAPHIC] [TIFF OMITTED] T1397.547
[GRAPHIC] [TIFF OMITTED] T1397.548
[GRAPHIC] [TIFF OMITTED] T1397.549
[GRAPHIC] [TIFF OMITTED] T1397.550
[GRAPHIC] [TIFF OMITTED] T1397.551
[GRAPHIC] [TIFF OMITTED] T1397.552
[GRAPHIC] [TIFF OMITTED] T1397.553
[GRAPHIC] [TIFF OMITTED] T1397.554
[GRAPHIC] [TIFF OMITTED] T1397.555
[GRAPHIC] [TIFF OMITTED] T1397.556
[GRAPHIC] [TIFF OMITTED] T1397.557
[GRAPHIC] [TIFF OMITTED] T1397.558
[GRAPHIC] [TIFF OMITTED] T1397.559
[GRAPHIC] [TIFF OMITTED] T1397.560
[GRAPHIC] [TIFF OMITTED] T1397.561
[GRAPHIC] [TIFF OMITTED] T1397.562
[GRAPHIC] [TIFF OMITTED] T1397.563
[GRAPHIC] [TIFF OMITTED] T1397.564
[GRAPHIC] [TIFF OMITTED] T1397.565
[GRAPHIC] [TIFF OMITTED] T1397.566
[GRAPHIC] [TIFF OMITTED] T1397.567
[GRAPHIC] [TIFF OMITTED] T1397.568
[GRAPHIC] [TIFF OMITTED] T1397.569
[GRAPHIC] [TIFF OMITTED] T1397.570
[GRAPHIC] [TIFF OMITTED] T1397.571
[GRAPHIC] [TIFF OMITTED] T1397.572
[GRAPHIC] [TIFF OMITTED] T1397.573
[GRAPHIC] [TIFF OMITTED] T1397.574
[GRAPHIC] [TIFF OMITTED] T1397.575
[GRAPHIC] [TIFF OMITTED] T1397.576
[GRAPHIC] [TIFF OMITTED] T1397.577
[GRAPHIC] [TIFF OMITTED] T1397.578