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Statement of

Michael A. Friedman, M.D.
Lead Deputy Commissioner
Food and Drug Administration
Department of Health and Human Services


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.

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.


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.


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.


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.


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.


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.


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.