APRIL 30, 1998
STATEMENT BY
MICHAEL A. FRIEDMAN, M.D.
LEAD DEPUTY COMMISSIONER
FOOD AND DRUG ADMINISTRATION
DEPARTMENT OF HEALTH AND HUMAN SERVICES
BEFORE THE
CONGRESSIONAL CAUCUS FOR WOMEN'S ISSUES
APRIL 30, 1998
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.
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