Mr. PILLARELLA. We were prepared to evaluate that requirement. Senator KENNEDY. I have no further questions.

Senator SCHWEIKER. I have no questions.

Senator KENNEDY. Thank you very much.

Mr. PILLARELLA. Thank you.

Senator KENNEDY. Finally, we will hear from two old friends of the Senate Health Subcommittee.

Frank J. Rauscher, Ph. D., is Director of the National Cancer Institute of the National Institutes of Health.

Alexander Schmidt, M.D., is Commissioner of the Food and Drug Administration.

I want to welcome you gentlemen back to the Senate Health Subcommittee.

Dr. Rauscher, do you want to start?

STATEMENT OF FRANK RAUSCHER, PH. D., DIRECTOR, NATIONAL CANCER INSTITUTE, NATIONAL INSTITUTES OF HEALTH, ACCOMPANIED BY ALEXANDER M. SCHMIDT, M.D., COMMISSIONER, FOOD AND DRUG ADMINISTRATION; J. RICHARD CROUT, M.D., DIRECTOR, BUREAU OF DRUGS; PETER BARTON HUTT, GENERAL COUNSEL; AND ROBERT C. WETHERELL, JR., DIRECTOR, OFFICE OF LEGISLATIVE SERVICES

Dr. RAUSCHER. Thank you, Mr. Chairman.

Mr. Chairman and members of the subcommittees, I am pleased to appear before you today to present findings concerning the use of diethylstilbestrol, DES, as an "emergency" postcoital contraceptive and to provide information on the use of DES as an animal feed additive. I will address the latter use first and point out that the National Cancer Institute remains fully supportive of legislation, regulation, and activities which serve to reduce or eliminate environmental exposures to chemical carcinogens.

Specifically, if DES were used as an animal feed additive and if residues of the drug were left in edible portions of animals, the result would be long-term exposures to virtually the entire population of the United States.

It should be recognized that there is no health advantage to the exposed individual as is the intent when the drug is used therapeutically. The law prescribes that substances like DES which have been shown to be carcinogenic can be used as feed additives providing no residues appear in any of the edible portions of the animal at the time of slaughter.

The NCI remains fully supportive of these requirements.
Senator KENNEDY. Residues are now appearing.

Dr. RAUSCHER. That is correct.

Senator KENNEDY. You want to end that?

Dr. RAUSCHER. Indeed.

Senator KENNEDY. You want DES out of beef?

Dr. RAUSCHER. That is our recommendation.

Senator KENNEDY. All right.

Dr. RAUSCHER. Concern that the newly approved use of DES as a postcoital pill for emergency situations may cause cancer in treated

patients is to be viewed in light of present-day knowledge and information on human subjects.

Since the intended use of DES is, as a postcoital contraceptive for emergency use, following unprotected intercourse, the primary concern over dangerous side effects, assuming the treatment is effective, would be for the patient.

Secondarily, however, concern for the embryo must be addressed since treatment might be ineffective and a child might be born despite these efforts.

First, I will speak to the concern for the treated patient.

Among the women treated with DES for threatened abortion, no increase in the incidence of cancer at any organ site has been detected to date. The dosage of DES and the duration of treatment varied widely from 2.5 to 150 milligrams per day and from 3 to 212 days.

Most of these women were treated with as much as 50 milligrams per day for 150 days or longer. These observations date back to the late 1940's. They show no evidence that such use may be cancer causing.

It should be pointed out, however, that such observations are in contrast to those attendant to the use of DES for treatment of what is term "gonadal dysgenesis." Gonadal dysgenesis in the female implies defective and incomplete development of the ovaries, and DES has been used in an attempt to correct that condition.

Among those patients who have been treated for 5 or more years with an average treatment time of 12 years, evidence exists which suggests an increased risk of an unusual type of cancer. In fact, in a recent study performed by Bruce S. Cutler in 1972, 3 cases of cancer of this unusual type were discovered among a group of 24 females who had been treated for gonadal dysgenesis over a period of 5 or more years.

Because this form of cancer is so rare, it has been assumed that such treatment puts the patient at increased risk as regards this disease.

The contrast between the cancer experience of women treated for threatened abortion and those treated for defective development of the ovaries can reasonably be assumed to be the result of differences in total dosage and duration of treatment.

As indicated earlier, the risk associated with the use of DES as treatment for threatened abortion was so low that it could not be demonstrated. Only at the higher exposure levels to the drug does evidence exist which suggests an increased cancer risk.

On this basis it can reasonably be assumed that the postcoital use which involves 50 milligrams per day for a period of only 5 days would represent far less risk to the patient than did treatment for threatened abortion where, indeed, no increase in risk could be demonstrated.

Senator KENNEDY. Could I ask you why you are so interested in banning it in animal feed, and yet you do not mind the additional amounts being taken under these controlled conditions-——

Dr. RAUSCHER. As you mentioned earlier in the hearing, Senator, it is a matter of risk-benefit. We feel that under a very limited circumstance the American woman should have an option in her treatment for threatened pregnancy with respect to this particular drug.

I continue to be very concerned, as you know, about its use in animals because American women who may be pregnant at the time may eat

DES-contaminated meat products, leading to the possible increased. cancer risk to their female offspring.

That is why I would be very concerned about its continued use in animal feed.

Senator KENNEDY. What are these extreme cases?

Dr. RAUSCHER. Rape, incest, and any disease that could be life threatening following pregnancy. Severe juvenile diabetes is one example in which pregnancy could constitute a definite risk to life.

Senator KENNEDY. What is your reaction to the testimony we have heard today about the widespread use of DES? Does this present a health hazard of important consequences?

Dr. RAUSCHER. I think it is very important. If widespread use were to continue, I would recommend to you, in the strongest terms possible, that its use be discontinued.

Senator KENNEDY. Why?

Dr. RAUSCHER. Because of the potential danger to the fetus, where DES did not work as a postcoital drug.

Senator KENNEDY. But the bulletin that went out, even the 1973 bulletin that went out, indicated that it only should be used for emergency purposes, along the lines, I think, that you have outlined here. for incest, rape; so is that going to provide sufficient protection to the American woman, or does something more have to be done?

Dr. RAUSCHER. I believe Dr. Schmidt will describe new procedures ( that he thinks will control the indiscriminate use of DES. I would agree with him that if proper monitoring, proper restriction of a drug cannot be assured as being applied only to these emergency situations, I would recommend very strongly that it not be used at all.

SENATOR KENNEDY. Given the kind of general testimony about the widespread use, are we going to wait another year, 2 years, while we develop some kind of procedures? And who are the people that are going to be at risk in the meantime?

Dr. RAUSCHER. In March the new procedures will go into effect. May I comment on that after we hear what procedures will be introduced?

Senator KENNEDY. All right. That would be fine. But let me gather, at least from what you have stated here, that over the period of the last 2 years, even with the statement in the FDA Bulletin, that it only be used and restricted for emergency puropses, would not the reality of the situation, in terms of the wider distribution, as we have heard this morning, that this is the case-can we afford to go any longer period of time without getting a real handle and control on this?

Dr. RAUSCHER. I would agree with you. We cannot afford to go any longer. if we cannot agree, ourselves, that safeguards can be introduced immediately.

Senator KENNEDY. The safeguards we have heard are not adequate. Dr. RAUSCHER. Evidently that is correct.

Senator KENNEDY. So we will hear from Commissioner Schmidt on what he thinks would be adequate safeguards. But would you proceed?

Dr. RAUSCHER. Thank you.

Concern for the daughters exposed immediately following conception also needs to be addressed, since the effectiveness of treatment

is unlikely to be 100 percent, and the possibility exists that some daughters may be born to treated mothers.

Since 1971 there have been extensive studies which document that the daughters of women treated with DES for threatened abortion during the first 17 weeks of pregnancy have a low but demonstrably increased risk for cancer of the vagina and cervix. These cancers appear around the time of puberty but in some case do not come to clinical attention until several years after puberty. Currently, the incidence is estimated to be no greater than three to four per thousand daughters at the 95 percent confidence level; but the incidence may very well increase as the daughters grow older.

It should be pointed out, however, that all of these exposures occurred in mothers who were demonstrably pregnant at the time of treatment. This, then, differs markedly from postcoital treatment which is recommended to begin within 24 to 72 hours following unprotected intercourse.

The significance of this statement lies in the fact that it is considered unlikely that treatment at such an early time and for such a short period would create risks comparable to those associated with treatment for threatened abortion. The period during which the drug is administered precedes the critical stages of tissue and organ development and differentiation.

It therefore seems improbable that the effects of DES administered at such an early time would produce effects similar to those induced by treatment for threatened abortion. One can only speculate as to what the former effect might be, if any, and how such effects would translate into human risks such as congenital diseases or cancer.

In summary, Mr. Chairman, I believe that current evidence suggests that the risk of causing cancer in the treated patient, the adult female, is extremely small.

Considered against the emotional trauma experienced by a rape victim, including the fears and anguish over the possibility of pregnancy or of intervention procedures such as uterine scraping and frank abortion, the benefit would appear to greatly outweigh the minimal risks involved.

It is my feeling that physicians who have responsibility for treating emergency pregnancies should not be deprived of what may be a useful medical tool, particularly so since there is a considerable accumulation of evidence which indicates the risks to the patient are small and, to date undetected despite the long and wide use of DES.

And, finally, Mr. Chairman, if I may just comment in synopsis, I recommend and the National Cancer Institute recommends that DES not be used in animal feed if residues result, that DES not be used routinely as post coital drug, and that its use be confined to victims of rape, incest, or illnesses which could be life-threatening following pregnancy.

Finally, that its use for this purpose be withdrawn if it continues to be used for nonemergency purposes.

Thank you, Mr. Chairman.

Senator KENNEDY. Well, you have heard the testimony about the use of nonemergency purposes, where there are incidences where roommates were picking up these pills for their friends, and very little follow-up procedures. This is the kind of abuse that would be of great concern to you?

Dr. RAUSCHER. Of much concern, yes.

Senator KENNEDY. As I understand from your testimony, unless you are given absolute assurances that that kind of use was to be terminated and ended, and ended now, that you would be for banning the use of the drug?

Dr. RAUSCHER. I agree. That is correct.

Senator SCHWEIKER. Dr. Rauscher, one thing that I am concerned about is, how often our Government makes a decision based on theoretically what should happen, or what might happen, because of the guidelines it publishes, whether in the Federal Register or through instructions to the pharmaceutical manufacturers. If everybody followed such instructions to the letter, there is no question that the safeguards would be there.

But I do not think the witnesses here, who we heard this morning, are really untypical or atypical. I think in the field it is a different world than we envision down here, whether it is in the Senate, in the executive department, on the regulatory agencies.

I wonder how realistic it is to presume that these instructions are going to be followed to the letter.

My question, I guess, is: If the reality of the "field" is really somewhat different from what we hope it would be, or wish it would be, or regulated it to be, then do we not have a responsibility to maybe not prescribe or not issue the drug approval, particularly we in fact know that we can never obtain the theoretical control? It is so important in a drug like this, to prevent people from getting cancer.

Dr. RAUSCHER. I agree with what you said. I do not think we can presume that out in the field we are going to be able to control the situation. It must be monitored. If the FDA cannot set up adequate means for effective monitoring, then we would not know to what extent use has been controlled. Under those circumstances, I would again recommend that its use be withdrawn.

Senator SCHWEIKER. I think your summary is a fair summary. You were talking about weighing the risks. You suggest the risk of causing cancer is extremely small, and perhaps four people in a thousand may well be in that category. It may be less because you are talking about a different usage of it. I realize it may be less than that. But I ask the basic question: Is not 1 in 1,000 too many?

Dr. RAUSCHER. One in 1,000 is a very high risk. You are talking now about mothers treated with DES.

Senator SCHWEIKER. What figures can you give me, do you have, or did you base your statement on, then, that I do not have concerning the risk being extremely small? What do we say the risks are?

Dr. RAUSCHER. Here I was talking about mothers who were treated, not the daughters. We have been following the daughters, and most of these are NCI-supported studies you heard about this morning. We have also been following the mothers that were exposed. There is no increased risk to these. Cancers are virtually nonexistent in the adult female following exposure during their first trimester pregnancy to DES. I am talking about mothers here, not the daughters. Senator SCHWEIKER. Let us talk about the daughters.

Dr. RAUSCHER. The risk 4 per 1,000 is a very high risk. It could never be tolerated. That is 400 per 100,000.

Senator SCHWEIKER. I understand you were talking about mothers, but I do not understand why we are not talking about daughters.