Madam Chairwoman, Members of the Congressional Caucus for Women's Issues, I
am Michael A. Friedman, M.D., Lead Deputy Commissioner for the Food and
Drug Administration (FDA or the Agency). Accompanying me is Sharon Smith
Holston, Deputy Commissioner for External Affairs. We are pleased to be
here today to discuss the Agency's role in the review and approval process
for a new indication or use for the drug tamoxifen (trade name Nolvadex),
which already is approved for the treatment of breast cancer patients. We
expect that the Agency shortly will receive a supplemental application for
the new use of this important cancer therapy for "prevention" of breast
cancer. We also will discuss the process the Agency will use to review the
anticipated supplement, our cancer initiative, and some of the Agency's
activities related to women's health, such as women in clinical trials and
our Take Time To Care initiative.
I. INTRODUCTION
First and foremost, I would like to recognize the generous and even
courageous women who participated in this prevention trial, without whom we
could have learned nothing. The National Cancer Institute (NCI) at the
National Institutes of Health, the clinical investigators, and Zeneca also
should be recognized for their efforts in this landmark study, which
appears to have yielded extremely promising results.
My interest in participating in this forum is manyfold. In my role as Lead
Deputy Commissioner for Food and Drugs, I am committed to improving the
public's health. I am also an oncologist who, during the course of my
career, has treated far too many breast cancer patients. As a husband,
father of four daughters, brother, and citizen, I have a personal interest
in seeing such a preventative treatment become available, lessening the
incidence of this serious disease.
The Breast Cancer Prevention Trial (BCPT) was a clinical trial designed to
see whether taking the drug tamoxifen (Nolvadex) can prevent breast cancer
in women who are at an increased risk of developing the disease. The BCPT
also was designed to assess whether taking tamoxifen decreases the number
of heart attacks and reduces the number of bone fractures in these women.
The study investigators began recruiting participants in April 1992 and
closed enrollment in September 1997; 13,388 women ages 35 and older were
enrolled. Researchers with the National Surgical Adjuvant Breast and Bowel
Project (NSABP) were conducting the study in more than 300 centers across
the United States and Canada. The study was funded by NCI.
We at FDA share the anxious concerns of all women who are believed to be at
increased risk for breast cancer, and we want to assure you that we are
committed to approving effective new preventions as expeditiously as
possible. FDA has adopted a common sense approach to approving promising
new cancer therapies, and we are eliminating unnecessary and burdensome
regulations while still maintaining critical public health protections. As
the law requires, however, FDA must approve drugs on the basis of
scientific data showing them to be "safe and effective" for the
indication(s) for which they are being considered.
II. CURRENT STATUS OF TAMOXIFEN
Since its original approval in 1977 for patients with advanced breast
cancer, tamoxifen has been tested and found to be describably safe and
effective in several additional breast cancer patient populations and has
been used widely in the treatment of women with breast cancer. In June
1990, FDA approved the use of tamoxifen for a major additional use to help
prevent the recurrence of cancer in "node-negative" patients. A
node-negative patient is one in whom the cancerous cells have not spread
from the breast area to the lymph nodes under the arm.
With these demonstrable benefits are also associated risks. In April 1994,
FDA required a warning on the package insert to provide a stronger caution
than previously stated to patients and doctors that tamoxifen poses an
increased risk of cancer of the uterus. Studies showed that women taking
tamoxifen faced a risk of uterine cancer about two to three times higher
than the risk for women who did not take tamoxifen in the general
population. Despite this increased risk, study results at that time
reaffirmed that tamoxifen could delay or prevent relapse in patients who
had undergone surgery for breast cancer. The results of NCI's prevention
study with respect to this drug bring very encouraging news, especially to
the tens of thousands of women who are at risk for breast cancer each year.
The caution for increased toxicity, however, remains.
The question which will now be presented to FDA is whether tamoxifen should
be approved for the "prevention" of breast cancer. Since NCI was a sponsor
of this study, and since the study was (properly) terminated earlier than
originally planned, the manufacturer of tamoxifen still must finish its
examination of the data and then prepare a Supplemental New Drug
Application (SNDA) filing to revise the prescribing information for
tamoxifen to include this new use.
When the Agency was contacted by NCI regarding the preliminary results, we
took a proactive approach and began reaching out to the leadership of NSABP
and Zeneca. FDA has spoken to both groups on multiple occasions, indicating
our interest in expediting the process. As previously announced in an April
6, 1998 FDA press release, in our contacts with NCI and the sponsors of the
breast cancer prevention clinical trial, we have expressed our interest in
reviewing the data from their study as quickly as possible. We anticipate
that Zeneca and NSABP can work together to provide an adequate SNDA filing,
based on data and reports that already are available at NSABP, in a matter
of days. Once an SNDA is received from the sponsor, we will perform a
priority review. Under the Agency's review procedures, consistent with the
Cancer Initiative and the Prescription Drug User Fee Act, such a review is
to be completed in no more than 6 months. Actually, we expect it to be
completed more quickly. We have reviewed multiple prior applications based
on NCI and NSABP studies, and we are familiar with their research practices
and the generally high quality of their research results. FDA will act as
expeditiously as possible but also must take the time required to address
important questions, such as any increased risks of uterine cancer, or
serious episodes of thrombophlebitis, and to examine the data on the deaths
that occurred. The data on thousands of patients collected in the study
must be thoroughly and carefully reviewed.
It should be noted that since tamoxifen already has been approved for other
indications, and based upon the well publicized, albeit preliminary, NCI
report of potential utility of tamoxifen in preventing breast cancer,
medical practitioners can presently prescribe tamoxifen for prevention as
an "off-label" use. The physicians and patients choosing to do so would
make the determination that they have sufficient confidence that the
benefits for an individual patient would outweigh not only those known
risks already stated on the package insert, but also those unknown
potential risks that may result. While physicians frequently use drugs for
indications not included on the label in general, all patients are best
served when the data supporting such uses are reviewed by the Agency. Uses
found safe and effective then can be included on the drug's label, with
information about side-effects and contraindications, for use by all
physicians, insurance providers, and, most importantly, consumers.
III. NEW USAGE
Product labeling is intended to provide full prescribing information for a
product and should include all clinical indications for which adequate data
are available to establish the product's safety and effectiveness. In order
for a new indication to be added to the label of an already approved drug,
the sponsor, usually the manufacturer, must file an SNDA with FDA. An SNDA
is reviewed in much the same manner as any New Drug Application.
FDA recently published a guidance for industry entitled, "A New Use
Initiative - FDA Approval of New Cancer Treatment Uses for Marketed Drug
and Biological Products," to explore the steps the Agency can take to
improve the process for approving promising new uses for drug and
biological products. Even though it has not been fully implemented, the
Agency already is utilizing the procedures in many instances. This new
initiative is based on FDA's belief that when products approved for one use
are shown to be safe and effective for treating other conditions, those new
uses should be added to product labeling as simply and quickly as possible.
In the past, some sponsors or manufacturers have been reluctant to submit
applications for supplemental new uses for their drug or biological
products. There was a perception that revising product labeling to add new
uses (which requires submission and FDA approval of a supplemental
marketing application) is difficult, costly, and time-consuming.
Recognizing the value of proper labeling, FDA has sought to simplify and
improve its supplemental approval process in order, hopefully, to increase
the number of safe and effective new uses being added to drug labeling. The
recently issued guidance clarifies what evidence should be provided for
primary, as well as supplemental, applications.
For example, if a product already has been shown to be safe and effective
in the treatment of patients with a given type of cancer, a single,
adequate and well-controlled, multicenter study demonstrating acceptable
safety and effectiveness in another biologically similar form of cancer
that is known to have a generally similar pattern of responsiveness to
chemotherapy may support labeling for that additional form of cancer.
Many newer uses of anticancer products that are common in clinical practice
and appear to be supported by published data from clinical studies,
however, are not included in product labeling, despite the incentives
sponsors have to keep their product labeling updated with information about
new uses. The guidance document describes several other steps FDA is taking
to foster continued updating of labeling for anticancer products.
Once an SNDA is submitted to the Agency, members of the FDA review team
simultaneously apply their special technical expertise to the review of the
SNDA. Physicians and statisticians each review, and chemists,
pharmacologists, and pharmacokineticists may review, the relevant
information as it pertains to the indication under consideration. FDA also
reviews samples of the new labeling changes. The human studies generate
information that will be in the drug's professional labeling, the guidance
approved by FDA on how to use the drug. This is the package insert that
accompanies a drug in all shipments to physicians and pharmacies and which
pharmacists can make available to The public.
IV. EXPEDITING REVIEW: THE CANCER INITIATIVE
In March 1996, building on FDA's accelerated approval program, President
Clinton and Vice-President Gore announced a new FDA initiative to improve
patient access to promising new cancer therapies. Under this initiative,
FDA has taken four steps to speed the approval of promising therapies for
treating cancer. These include:
-
shortening approval times for cancer treatments by recognizing that tumor
shrinkage often is a reasonable surrogate endpoint of a treatment's
effectiveness in patients with otherwise untreatable cancer. Basing
approval on evidence of tumor shrinkage--which can be demonstrated more
easily and quickly--can speed up access to promising new therapies
(compared with waiting for evidence of improvement in survival time);
- encouraging pharmaceutical companies to submit expanded access protocols in
the United States for cancer therapies that have been approved by
recognized foreign regulatory authorities, thus helping to make promising
cancer therapies approved by foreign countries available to cancer patients
before the products are approved in the United States;
- improving the product review process by ensuring that all FDA cancer
therapy advisory committee meetings include an ad hoc member who has
personal experience with the illness for which a new product is being
considered; and
making it easier for investigators to test new uses for cancer therapies
already on the market by reducing the number of Investigational New Drug
applications filed for additional studies of already approved therapies.
FDA undertook these initiatives after careful consideration of suggestions
and advice offered by cancer patients and their advocates, pharmaceutical
industry representatives, and physicians and researchers about how to speed
access to cancer therapies. FDA's goal is to improve significantly patient
access to promising cancer treatments without compromising patient safety
or the requirement that marketed drugs be proven safe and effective before
they are sold.
FDA's Office of Special Health Issues has been designated specifically to
work with patients who currently are being treated for various diseases,
including cancer. Patients are counseled regarding the options available to
them, including participation in authorized clinical trials. Patients may
call OSHI directly at (301) 827-4460.
V. WOMEN'S HEALTH INITIATIVES
The Office of Women's Health (OWH) was created by FDA in 1994. Its
establishment began a new chapter in the Agency's dedication to promoting
women's health issues. In less than 4 years, OWH has established itself as
an effective voice for women's health concerns. Major activities and
accomplishments of the office include sponsoring mission-related research
and education/outreach programs, initiating a national public awareness
campaign on safe medication use, providing leadership on the issue of women
in clinical trials, acting as an advocate for women's health in Agency
actions, and working with external constituencies.
Sponsoring Intramural Projects Related To Women's Health OWH funds
intramural research and education programs on pressing women's health
issues related to FDA's mission. It utilizes a competitive peer review
process for selection of the highest quality projects, with an emphasis on
outcomes with the greatest potential for significantly contributing to
knowledge of women's health in a brief time frame. In 4 years, OWH has
funded over 50 scientific projects totaling over $6 million in grants for
these projects to date. A few examples of projects producing important
results include the development of an estrogen knowledge base for research,
regulation, and prediction of estrogenicity of new compounds; and the
development of a software program designed to estimate the reproductive
toxicity of pharmaceuticals. OWH also has funded educational programs about
pressing women's health issues. For example, "Before Time Runs Out," an
educational play followed by a panel discussion to address myths about
breast cancer and encourage mammography by minority women, was presented in
Houston, Texas, and Washington, D.C. In addition, OWH sponsored a series of
Minority Women's Health Empowerment Workshops which focused on health
promotion and disease prevention for inner city minority women in the
Mid-Atlantic states and Washington, D.C.
Gender Effects
One of the core missions of OWH is looking at gender effects, which
involves the inclusion of women in clinical trials, and the analysis of
data by gender to see how FDA-regulated products impact both men and women.
Through their intramural funding program, OWH has funded a pilot project to
examine the number of women in clinical trials reviewed by four divisions.
This project determined that, after publication of FDA's 1993 Gender
Guideline, the number of women excluded from protocols started to decrease.
Other OWH-funded projects have had important outcomes for women's health,
for example women appear to have prolonged cardiac depolarization as a
result of some drugs (quinidine) and drug-drug interactions (seldane and
erythromycin). With another FDA-regulated product, an OWH-funded study
found that women and men have the same beneficial outcomes with a cardiac
stent. Just recently, another project successfully developed a technique to
determine if adverse events from drugs occur in different rates in women
than in men.
Drugs and Pregnancy
For women with child bearing potential, the Agency has reexamined the way
drugs are labeled for use in pregnant women and is proposing a new system
to bring better information to pregnant women and their health care
providers. OWH has funded a study that collected information on all drugs
taken by pregnant women in a managed care setting. This study will help us
prioritize our goals in collecting information on drug exposure during
pregnancy that can then be incorporated into labeling of drugs. FDA's
Center for Food Safety and Applied Nutrition (CFSAN) has issued regulations
for the supplementation of grains and cereals with folic acid aimed to
prevent neural tube defects such as spina bifida in newborns. This has been
accompanied by a public outreach program in English and Spanish. CFSAN also
did a study on infant feeding practices and substantiated the benefits of
breast milk to infants.
Contraception
In the United States, 43 percent of all pregnancies are unintended, and the
prevalence of HIV and other sexually transmitted diseases (STDs) has
reached epidemic proportions. FDA has worked with industry to improve the
safety, efficacy, and availability of contraceptive choices. OWH has funded
the development of a contraceptive efficacy table for uniform labeling
which is included on all contraceptive labeling to simplify drug and
barrier method comparisons for consumers. Additional labeling changes, such
as expiration dates on condoms and a statement addressing the product's
ability to prevent the spread of STDs, recently have been instituted by the
Agency. OWH also has funded research to determine if certain drugs impact
the effectiveness of oral contraceptives.
Menopausal Women's Health
With the aging of the population and increasing life span, the number of
women in the post-menopausal age group will continue to expand for several
decades. Hormone Replacement Therapy has been a mainstay of the prevention
and treatment of post-menopausal problems for many years. Reflecting the
industry's understanding of the potential of such a large market, more
products are being developed. FDA has worked to ensure that only safe and
effective treatment options are available for women. In 1997, FDA did not
approve applications for a generic formulation of conjugated estrogens due
to a concern about the lack of certain active ingredients, which precluded
a determination of equivalency between the innovator and generic. FDA has
been dealing with potential new indications for hormone replacement
therapy, such as prevention of breast cancer, cardiovascular disease, and
osteoporosis. The Agency recently approved Raloxifene, a new class of drug
called a selective estrogen receptor modulator, for osteoporosis
prevention. In addition to treatments for perimenopausal and postmenopausal
conditions, FDA also works with device manufacturers to ensure that safe
and effective diagnostic devices are available for assisting in the
diagnosis of these diseases. For example, the Agency regulates Bone Density
Measurement devices which aid in diagnosing osteoporosis in at-risk
individuals.
Women's Health: Take Time To Care
As recently reported in an article published in the Journal of the American
Medical Association, researchers estimate that adverse drug reactions from
correctly prescribed and used medication in hospitals in the United States
may cause more than 100,000 deaths per year, making it one of the top ten
causes of death in this country. OWH has initiated a major public awareness
program, "Women's Health: Take Time To Care," to bring important health
promotion messages to mid-life and older women, with an emphasis on the
underserved. The message is "Use Medicines Wisely," in order to raise
awareness about better health practices, encourage consumers to become in
involved in their health care, reduce health risks, and reduce the annual
cost of $75 billion in doctors' visits, hospitalizations, and lost wages
resulting from improper use of medication.
Women and Cancer
The Agency has been working on several initiatives to improve cancer
outcomes in women. OWH funded a pilot study to see if there was one place
that women could find information on all breast cancer clinical trials
throughout the country. This effort has been expanded, and FDA has been
working with manufacturers to encourage them to list their trials on the
NCI Physician Data Query system. FDA has been responsible for
implementation of the Mammography Quality Standards Act, and now all 10,000
mammography facilities in this country meet these quality standards. FDA
had a tremendous outreach effort to facilities, states, and accreditation
bodies to put these initiatives in place in a relatively short period of
time. OWH funded a service so that any woman can find an FDA-certified
mammography facility in her area by calling 1-800-4-CANCER.
While formal clinical studies are being conducted, the Agency has allowed
silicone gel breast implants to be available under special circumstances to
those women who have had breast cancer and seek reconstruction with this
type of implant. FDA's Office of Consumer Affairs has an 800 number to take
calls on breast implants and has produced a Breast Implant Update packet.
We have sponsored a study on the rupture rate of breast implants, with
results due by the end of the year.
Working With External Constituencies
OWH staff provides information on women's health issues to Congress, the
press, health professionals, women's health advocates, and the lay public
in a multitude of ways. OWH publishes articles in scientific journals to
update the medical community about FDA actions relating to women's health.
Consumer publications, such as an FDA Consumer Special Report entitled,
"Your Guide to Women's Health," provide educational material on a range of
women's health issues. The Office maintains a website containing FDA
publications of useful women's health information and delivers speeches to
the full-range of audiences and constituencies interested in women's
health.
VI. CONCLUSION
FDA is committed to making promising new treatments and the proper
accompanying information available to the public in a timely manner. We
have tried to be responsive and compassionate to requests for new products
and for new uses for previously approved drug products by continually
evaluating and improving our review and approval processes. In meeting our
mission of promoting and protecting the public health, we must constantly
strike a balance between providing access with ensuring that new treatments
are describably safe and effective. It is what the public deserves and the
law requires.
Thank you for the opportunity to testify.
