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An important consideration in this regard was the prevailing opinion of experts that the safety issues related to DES applied to estrogens in general. There was, therefore, no scientific basis for withdrawing DES per se from medical usage unless we were prepared to do so for all estrogens;

3. Contraindicate the use of DES for emergency postcoital contraception. We were, and remain, prepared to exercise this option whenever the scientific facts justify it. However, after careful review of available data, we regard the use of DES for this indication as effective and as safe under the conditions of approval;

4. Approve the use of DES for emergency use, for example, after rape, with specific limitations and conditions which would bring this use of DES under proper regulatory control. We believe the scientific evidence on the safety and effectiveness of DES that supports this option meets the statutory standards of safety and effectiveness. The requirements provided by regulation will allow reasonable control of this use of the drug, as I will outline shortly.

The final order, which became effective on March 8, 1975, permits marketing of DES for postcoital contraceptive use by any applicant who obtains approval of an abbreviated new drug application (ANDA) and who complies with the labeling and packaging requirements described in the regulation. I am submitting copies of the proposal and final order for the record (see p. 22). An ANDA is an application used for generic drugs when no additional data on clinical safety and effectiveness are necessary and only questions related to manufacturing and bioavailability exist.

The conditions for marketing DES as an emergency postcoital contraceptive set forth in the regulation include the following:

A patient leaflet is provided which assures that the essential information describing the risks of the treatment is available to the user so that she can reach, with the help of her physician, an informed decision about whether to use it. The leaflet also describes how DES must be used if it is to be effective.

Special packaging is required which assures that only the number of tablets necessary for a single patient are dispensed with the patient leaflet in a single package.

All other 25-milligram tablets of DES, that is, not in a special package and with appropriate patient labeling, have been eliminated, thereby assuring that no other source of tablets for this indication is readily available.

A warning is provided on all other dosage forms of DES to deter their prescription for this use, which I think is a very important point.

The limitation of DES dosage forms for postcoital contraceptive use to a single dosage form in a special package will, for the first time, permit the FDA to estimate the number of women being treated with DES for postcoital use, so that the national prescribing trend can be followed.

In summary, we consider our approval of DES as an emergency postcoital contraceptive, under the conditions outlined, to be a responsible solution to a complex problem. Our regulatory approach is in

accord with statutory standards and good medical practice, and offers certain women in emergency situations a safe and effective alternative to abortion. The risks of treatment are candidly expressed in the patient brochure. To date, no manufacturer has obtained an approved ANDA for this purpose, but we are prepared to approve one whenever an acceptable application is submitted.

Mr. Chairman. I will skip over to pages 12 and 13, and turn to the provisions of title I of S. 963.

In brief, the Department does not object to section 101 relating to the use of DES in animal feeds, but does oppose enactment of section 102 relating to the use of DES as a human drug.

Section 102 would amend the Federal Food, Drug, and Cosmetic Act to make any human drug containing DES misbranded unless its label bears a prescribed warning statement, and unless certain other specified requirements are met. These labeling requirements would apply to all uses and dosage forms of DES. The proposed labeling warning requires a statement ("Warning: This drug may cause cancer") which, without further explanation, is scientifically misleading and may unduly alarm patients. To be properly informed, a patient should receive a brief candid statement, such as that required by FDA in patient labeling of DES products intended for use as postcoital contraceptives, of what is known of attendant risks of developing cancer. There seems no valid reason for including either a short warning or a patient labeling about postcoital use with products intended for use, for example, in treating prostatic cancer.

Moreover, warnings and labeling for specific products should reflect what is known about the product. There is no evidence to date which has indicated any detectable risk of cancer to humans resulting from the use of postcoidal contraceptives, although, as the FDA labeling points out, DES is an animal carcinogen, and there is no way to be certain that evidence of human carcinogenicity will not be discovered in the future.

Labeling must also be flexible and subject to modification when new data become available. Thus, any legislated DES labeling is already outmoded because of recent new information regarding cancer from use of postmenopausal products estrogens (not DES) which will require labeling changes for all estrogen products.

The bill would impose an additional requirement that the label on all DES products, whether or not the drug was intended for use in postcoital contraception, state that, "This drug may not be used as a contraceptive after sexual intercourse except in cases of rape or incest or a comparable medical emergency." If this statement had any effect at all it would be to encourage the use of dosage forms of DES other than the one specifically intended for postcoital use for this purpose, impeding FDA's ability to monitor use of DES for postcoital contraception and assure that only the special package containing the patient leaflet is used. Such a statement, if added by a private firm (instead of by Congress) to labeling for these products would be a violation of the Federal Food. Drug and Cosmetic Act. FDA at present requires that these other dosage forms be labeled as not for postcoital use.

S. 963 requires that whenever DES is used, an informed consent form must be signed by the physician and submitted to FDA—the

Secretary. The bill makes no distinction based on what the DES is used for: it appears that DES use in treatment of prostatic cancer, for example, would require such a consent form. This costly and burdensome monitoring system would require that the Food and Drug Administration receive, in addition to the consent form, a copy of every prescription filled for DES (again for any use) in the United States. The system would not, however, contribute to FDA's ability to monitor postcoital use of DES because S. 963 fails to distinguish among the various dosage forms and uses of DES and requires that data be sent to FDA regarding all of them.

As noted, the required label reference to postcoital use of DES on all dosage forms would break down FDA's intended distinction between the various dosage forms and their appropriate use.

Finally, S. 963 forbids, quite properly, FDA's identification of the patients receiving the drug. We would thus be unable to determine what the DES was used for or whether it was used properly. It should be noted that while FDA regulations do not require written informed consent, they do require a patient package insert, which we believe is fully informative.

Unlike section 101 which parallels ongoing FDA efforts, section 102 would impair FDA's current authority to adequately regulate the use of DES as a human drug. Because we believe strongly that our regulations provide a greater degree of safety to patients who must use DES than would the procedures prescribed in the bill, because we believe that the requirements in the bill reflect rulemaking issues and are inappropriate for legislation, and because we generally do not favor such piecemeal approaches to broader regulatory issues, we oppose enactment of section 102.

In conclusion, I would like to mention some of the latest developments in this general area. Recently, FDA received new information in several separate reports indicating a possible relationship between estrogen therapy in postmenopausal women and cancer of the uterus. A meeting of our Obstetrics and Gynecology Advisory Committee and the authors of the reports started yesterday, and is continuing today, to consider labeling changes and any other necessary actions.

This call by the Agency for review of all estrogen labeling highlights the inadequacy of dealing with essentially rulemaking-type problems through legislation. Statutory language does not provide a flexible format in a subject area where new scientific evidence can have broad sweeping effects requiring quick action. We object to setting specific requirements for a drug or even a class of drug in the concrete of statutory language. Such substances are more appropriately controlled through the administrative rulemaking procedures which provide all interested parties the continued right to petition the Commissioner to review and change regulations, based on new

information.

It is clear that our regulatory decisions must be part of a system of review which is flexible and which allows us to make appropriate changes as new scientific evidence is available.

I urge the members of this subcommittee to keep this principle in mind when they consider the merits of section 101 and 102.

This concludes my giving parts of my prepared statement. My colleagues and I would be happy to respond to any questions the subcommittee might have.

65-596 0-76-3

[Dr. Schmidt's statement and attachments follow:]

STATEMENT BY ALEXANDER M. SCHMIDT, M.D., COMMISSIONER, FOOD AND DRUG ADMINISTRATION, PUBLIC HEAlth Service, Department of HEALTH, EDUCATION, AND WELFARE

MR. CHAIRMAN: It is our privilege to appear before your Subcommittee today to discuss our views on Title I of S. 963 which would prohibit administering the drug diethylstilbestrol (DES) to any animal intended for use as human food unless the Department determines, based on scientific evidence, that the drug is safe. Title I would also impose labeling requirements for DES as a postcoital contraceptive.

INTRODUCTION

As you know, DES is a synthetic female hormone, one of the class known as estrogens. It was originally synthesized in 1938, and has been widely used in medicine and in animal husbandry because it was the first available inexpensive estrogenic compound that remained active after oral administration.

Diethylstilbestrol has properties common to all estrogens. It is a feminizing hormone and is used in medicine as replacement therapy in estrogen-deficient states, for treating cancer of the breast in certain patients, and for treating prostate cancer in men. Although DES is not used in oral contraceptives, other estrogens are essential ingredients in the standard oral contraceptives commonly referred to as the "pill." Diethylstilbestrol has two additional characteristics which are of particular interest today. It prevents pregnancy if administered shortly after intercourse, even if the woman is at her most fertile period midway in the menstrual cycle.

DES is also known to produce cancer in several animal species and has been linked to a certain type of cancer in humans. As a result of these two properties of DES, its continued use as a human drug and as a growth promotant in animal feeds has been the subject of considerable public controversy during the past several years. The concern regarding the safety of DES is, of course, understandable. However, the provisions of S. 963 dealing with the use of DES address two distinct issues which, in our opinion, involve quite dissimilar considerations. Before commenting specifically on Title I of S. 963, I would like briefly to trace the use of DES in human drugs and livestock feed and explain the regulatory actions regarding DES which we have taken and propose to take.

THE USE OF DES AS A HUMAN DRUG

DES has a long history of effective use in human medicine. It is now approved for the following conditions:

Replacement therapy of estrogen deficiency associated with menopausal syndrome, female hypogonadism, amenorrhea, castration, or primary ovarian failure;

Control of functional uterine bleeding in the absence of organic pathology; Relief or prevention of engorgement of the breasts in the postpartum period; and

Palliative therapy in the treatment of carcinoma of the prostate in the male and carcinoma of the breast in post menopausal women.

DES has had another important use in the past. It was widely used in women during the 1950's and 1960's in an attempt to prevent spontaneous abortion, a purpose for which it is not effective. In 1971, Herbst and co-workers reported that the female children who had been exposed in utero to DES had a far greater than normal tendency to develop cancer of the vagina. This finding has been the basis of FDA's requirement that use of DES during pregnancy be contraindicated. It has also, quite properly, focussed attention on the potential harmful long-term effects of estrogen use, particularly DES use. At the present time, however, there is no evidence that the mothers treated for threatened abortion had an increased likelihood of developing cancer.

APPROVAL OF DES AS A POSTCOITAL CONTRACEPTIVE

In the mid-sixties, several reports, including those by Morris and van Wagenen and by Kuchera, indicated that DES prevented pregnancy when administered in large doses immediately following intercourse. It subsequently became apparent that widespread use of DES as a postcoital contraceptive followed the publication of these reports.

DES is a generic drug and is made by many manufacturers, none of whom came forward with data to support the use of DES as a postcoital contraceptive. FDA recognized that widespread use of DES for this purpose without assurance that the use was effective and, even if it was effective, without labeling providing adequate directions for use could pose safety problems for patients. Therefore, on its own initiative, that is without any application for marketing approval before us, the FDA addressed this problem. Medical and scientific journals over the past decade had carried reports on the safety and effectiveness of DES as a postcoital contraceptive and described significant use of the drug for this purpose. We, therefore, determined to consider the published data without an industry application through established procedures for public decisions, namely, public discussion before our Obstetrics and Gynecology Advisory Committee and the publication of regulations in the Federal Register.

The basic published information relating to the safety and effectiveness of DES for this use was reviewed and presented to the advisory committee by representatives of the National Institute of Child Health and Human Development. The action eventually agreed upon was developed in collaboration with the advisory committee, was published for comment in the Federal Register on September 26, 1973, and was later modified on the basis of these comments. În deciding to address the problem of DES for emergency postcoital contraception, an important example of widespread use of a drug for an unapproved use, we had four options:

Do nothing. i.e., ignore the use of DES as a postcoital contraceptive on the grounds that no application was presented to us. We considered this option as irresponsible in view of the widespread use and the safety issues involved;

Withdraw approval of DES as a drug. While some persons favor this position, no convincing case was ever developed by the responsible FDA staff or the advisory committee, and this option was not exercised. An important consideration in this regard was the prevailing opinion of experts that the safety issues related to DES applied to estrogens in general. There was, therefore, no scientific basis for withdrawing DES per se from medical usage unless we were prepared to do so for all estrogens;

Contraindicate the use of DES for emergency postcoital contraception. We were, and remain, prepared to exercise this option whenever the scientific facts justify it. However, after careful review of available data, we regard the use of DES for this indication as effective and as safe under the conditions of approval;

Approve the use of DES for emergency use, for example after rape, with specific limitations and conditions which would bring this use of DES under proper regulatory control. We believe the scientific evidence on the safety and effectiveness of DES that supports this option meets the statutory standards of safety and effectiveness. The requirements provided by regulation will allow reasonable control of this use of the drug as outlined below. The final order, which became effective on March 8, 1975, permits marketing of DES for postcoital contraceptive use by any applicant who obtains approval of an abbreviated new drug application (ANDA) and who complies with the labeling and packaging requirements described in the regulation. I am submitting copies of the proposal and final order for the record. An ANDA is an application used for generic drugs when no additional data on clinical safety and effectiveness are necessary and only questions related to manufacturing and bioavailability exist.

The conditions for marketing DES as an emergency postcoital contraceptive set forth in the regulation include the following:

A patient leaflet is provided which assures that the essential information describing the risks of the treatment is available to the user so that she can reach, with the help of her physician, an informed decision about whether to use it. The leaflet also describes how DES must be used if it is to be effective.

Special packaging is required which assures that only the number of tablets necessary for a single patient are dispensed with the patient leaflet in a single package;

All other 25 mg. tablets of DES (i.e., not in a special package and with appropriate patient labeling) have been eliminated, thereby assuring that no other source of tablets for this indication is readily available;

A warning is provided on all other dosage forms of DES to deter their prescription for this use; and

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