Followup is essential when DES is given to the patient. However, followup of rape victims is virtually impossible for many reasons. After the rape, the victim may move out of town or move to another part of town; get an unlisted phone; change jobs; live with relatives. Some rape victims initially give false names and addresses because they are afraid of harassment.

Many rape victims are brought to a county hospital, sometimes by the sheriff, from outlying parts of the county, and they will not travel that distance for a followup.

The rape victim wants to forget. The last thing in the world she wants to do is to return to the hospital.

When the rape victim comes to the emergency room, she may be disoriented or in a state of shock; she may not realize she needs to come back for a followup.

But the greatest deterrent to followup is the cost involved. Most victims simply cannot afford to pay another $30 or $40 for a hospital visit.

Finally, followup is not considered the responsibility of the emergency room personnel. According to Dr. George Fin, of St. Joseph Hospital in Ann Arbor, Mich., "Our policy is to refer rape cases as well as other emergency cases to follow up with their own family physician or at local medical facilities. Followup is not within our capacity. We do not have the setup, and we do not do it."

In reviewing the 1974 rape cases seen at Wayne County Hospital in Detroit, one doctor estimated that only about 25 percent of all rape victims come back for any kind of followup, even VD testing.

Senator KENNEDY. I want to put the rest of the statement in the record. I think the matter that we are primarily interested in and concerned about is the use of DES as a morning after.

With regard to rape and the implications of that, in terms of followup, which we have all heard about, is extremely important, but I would like to get back to this major point of consequence to us, and that is the use of the morning-after pill and your particular experience.

I understand this is a copy of the form which the University of Michigan uses [indicating]. On that form it says, it has "DES Initial Visit Form," the age, and a number of other items and questions on it.

And No. 14 on this says, "I understand that the use of diethystilbestrol as a morning-after pill is an FDA-approved use of the drug and that it should not be taken if there are any chances of pregnancy from previous exposure this month."

Then it continues, "It might cause cancer years later in the offspring. I have been advised this is only emergency-type therapy for unprotected intercourse. No guarantee or promises have been made to me as a result of taking these pills."

I imagine those words in the early part of this statement that "I understand the use of the morning-after pill is an FDA-approved use of the drug" would at least create a climate and atmosphere in the mind of the student that it is going to cover the purpose and does not really present significant danger.

Ms. COWAN. I am acquainted with that form. I would like to say that words on a form are one thing, but doctors' prescribing habits are another.

The person signs that form. I think the form was drawn up for legal reasons rather than health services' interests in completely informing the students; despite the fact that students must now sign that form, they can still readily obtain the morning-after pill.

It is given to them more than once.

Senator KENNEDY. Well, there are a number of points.

One is that when the order went out almost 2 years ago, May 1973, it was a mistake because it was never approved. But, nevertheless, it was continued. As we will hear later on, there was no important effort to try to curb the possibility of abuse by the Food and Drug Administration.

Then, beyond that, it certainly seems to me to suggest to the students that the fact that it has been approved by the FDA would give it sort of a premature safety and efficacy which, obviously, is a dangerous situation.

Ms. COWAN. Continuing, in my statement, on emergency room procedures

Senator KENNEDY. I think if you want to summarize just that aspect of it, this is of great importance and interest generally, but is it not to the point here, with regard to rape victims that may take DES because of the control situation, there is little followup for the reason you have outlined here, even in emergency situations?

Ms. COWAN [continuing]. I am recommending DES not be given to rape victims by emergency room personnel because the emergency situation associated with rape is because of trauma, both physical and psychological of the rape, and the emergency situation does not constitute the possibility of pregnancies and is really secondary to the

emergency.

And I feel that even in rape cases DES should not be given out by the emergency rooms.

Senator KENNEDY. Can you see any use for it then?

It should not be used in an emergency and should not be used in other situations.

Is there any use for it?

Ms. COWAN. I believe it should not be used as a morning-after pill, and I think Dr. Greenwald has pointed out its legitimate uses.

Senator SCHWEIKER. One statistic I do not think you got to in your prepared statement, and I think it does have some relevancy; you say, "We know that statistically less than 5 out of every 100 single unprotected sexual encounters result in pregnancy. Therefore, we are subjecting 95 percent of women given DES to an unnecessary drug."

I think that is a very important point because we are exposing 95 percent of women needlessly to something where we are probably really only really concerned about 5 out of 100. So we have to get the problem in perspective.

Ms. CoWAN. That is correct, which then leads into the final issue, which is the possible legal liability on the part of doctors who prescribe DES.

Recently, even the AMA has conceded that the doctrine of informed consent includes disclosure by the doctor of risks to the patient, including risk of failure of the drug, as well as disclosure of alternative treatments.

As far as I could tell, few doctors are suggesting any alternatives to DES. They could suggest menstrual aspiration or early abortion. In conclusion, DES must be given only under the following conditions:

1. A thorough personal and family history must be taken.

2. Warnings as to risks to the patient and possible offspring must be discussed.

3. FDA must provide adequate information in a patient insert. 4. A pregnancy test must be given prior to and after DES therapy. 5. There must be followup.

6. The patient must be informed of alternatives, including menstrual aspiration and early abortion.

Unless all of these steps are taken, DES should not be prescribed to anyone.

Senator KENNEDY. Thank you very much.

Senator SCHWEIKER. I have one question for Dr. Greenwald.

Doctor, I am not clear on one point, and maybe you can clear it up. If a woman had been taking DES preceding the time when she became pregnant, is there a connection, or must the administration of DES occur at the time of or immediately following to the actual pregnancy?

Dr. GREENWALD. As far as we know, DES is not not retained very long in the body, and it would have to be taken after the pregnancy started. That is our best information.

Senator SCHWEIKER. It must occur sometime during the pregnancy period?

Dr. GREENWALD. Yes; because it does not stay around in the body very long.

Senator SCHWEIKER. That is all I have.

Senator KENNEDY. Thank you very much.

Dr. GREENWALD. Thank you.

Senator KENNEDY. Our next panel of witnesses consists of two employees of the Food and Drug Administration who are testifying before us pursuant to subpenas.

Dr. Marvin Seife is Director of the Generic Drug Division of FDA's Bureau of Drugs. He has been with FDA since 1965.

Dr. Vincent Karusaitis, an obstetrician and gynecologist, is a medical officer in the Generic Drug Division.

Dr. Seife, what is your position in the FDA, and when did you get involved with the morning-after drug?

STATEMENT OF DR. MARVIN SEIFE, DIRECTOR OF THE GENERIC DRUG DIVISION, BUREAU OF DRUGS, FOOD AND DRUG ADMINISTRATION, ACCOMPANIED BY DR. VINCENT KARUSAITIS, OBSTETRICIAN AND GYNECOLOGIST, MEDICAL OFFICER IN THE GENERIC DRUG DIVISION, FOOD AND DRUG ADMINISTRATION Dr. SEIFE. At the present time I am Director of the Division of Generic Drug Monographs in the Office of Drug Monographs.

I have held many positions since I have been with the FDA, for the past, approximately 10 years, many supervisory positions. At the present time we are involved with generic drugs from the years 1938 to 1962.

In other words, we are implementing the Kefauver-Harris amendments as to safety and efficiency.

Prior to the Kefauver-Harris amendments drugs were passed only for safety. As a result of the 1962 amendments, efficacy had to be shown. The huge task of showing efficacy for all drugs from 1932 through the third week of October 1962, had to be undertaken after a 2-year period, that is the end of 1964, by FDA to show efficacy.

All the drugs we handle have been published in the Federal Register, and are declared effective, and the indications listed.

In some instances the actual labeling is given.

In this instance, for diethystilbestrol, for 1971 the first publication in the Federal Register gave the usual indications for diethystilbestrol. The indication for postcoital use was not listed.

In August of 1973 we received a submission from a small firm inv New Jersey, August 6, 1973, asking for 25 milligram tablet of diethystilbestrol for purpose of postcoital use.

We assigned it abbreviated new drug application number. On September 17, 1973, I sent them a letter stating that we could not accept it for this use since the Federal Register had not indicated it to be effective for this use.

Senator KENNEDY. Why did you do ANDA abbreviated instead of NDA?

Dr. SEIFE. At this point the previous diethylstilbestrol which was a generic drug used for many, many years was considered to be abbreviated, and listed accordingly in the Federal Register of November 10, 1971.

Now,

the company, for some reason

Senator KENNEDY. Is that true for postcoital use?

Dr. SEIFE. No; only for usual uses.
Senator KENNEDY. Is this procedure

Dr. SEIFE. This is not procedure.

In all my years with the FDA, this is unique, this is the first time in my experience that a drug has been published for a new use in the Federal Register without any study, without any investigative new drug application for a totally new indication.

Senator KENNEDY. Was that the correct thing to do?

Dr. SEIFE. No.

Senator KENNEDY. Who made the decision to do it?

Dr. SEIFE. I have no idea.

Senator KENNEDY. Who told you to do it?

Dr. SEIFE. The Federal Register.

Senator KENNEDY. Who puts that out? Who put it in the Federal Register?

Dr. SEIFE. This goes up to the chain of command.

Senator KENNEDY. Give us the next one up.

Dr. SEIFE. Probably on the first document, the November 10, 1971, document, I was probably Acting Director of the Office of Scientific Evaluation, and I probably had my signature on the document, which declared it to be an abbreviated new drug application for the usual

uses.

But later in the game

Senator KENNEDY. Let me go back. Did your division approve or disapprove this?

Dr. SEIFE. No.

Senator KENNEDY. No, what?

Dr. SEIFE. We have never approved it, we never saw the document. Senator KENNEDY. Did you protest this procedure?

Dr. SEIFE. Our group was unanimous in protesting this particular

use.

Senator KENNEDY. Who was trying to get it approved, was it the drug companies, was it FDA, you?

Dr. SEIFE. No; FDA published-apparently the Division of Metabolic Endocrine Drug Products handled this application. Our unit had nothing to do with it.

And on September 26, 1973, a Federal Register statement came out stating that the 25-milligram tablet could be used for postcoital use. Now, based on that, we resurrected this application, which came to us in August 1973. Now in December 1973, Dr. Karusaitis and Dr. Carroll, who represented me, attended a meeting, an in-house meeting at which many subjects were discussed, among which diethylstilbestrol for postcoital use..

I think Dr. Karusaitis can relate what happened.
Senator KENNEDY. Can you relate what happened?

Dr. KARUSAITIS. We were given a period of time which was sufficient to have our say, and the gist

Senator KENNEDY. Tell us what your position is.

Dr. KARUSAITIS. My position, I am a practicing physician in New York State, work for FDA for the past 512 years. My specialty is

OBGYN.

The first submission that we received, I made this notation, the indication was new, the dosage was new, therefore this application was not acceptable, and would have to pursue a full NDA.

And I said it was a "no-go" period.

Senator KENNEDY. What happened to that?

Dr. KARUSAITIS. That went through channels, to Dr. Seife.

Dr. SEIFE. We sent them a letter on September 17, 1973, to the firm, saying that we cannot review their application since there was no appropriate Federal Register statement.

Now, September 26, almost 10 days later, a Federal Register statement appears calling for the use of the drug as a morning-after pill, and calling for abbreviated new-drug application, which means no studies.

Senator KENNEDY. Means no studies?

Dr. SEIFE. Which circumvents the usual procedures.

Senator KENNEDY. Quite clearly the usual procedures were not followed?

Dr. SEIFE. Right.

Senator KENNEDY. And the procedures which were outlined were objected to by those such as yourselves who have primary responsibility in these areas, and for some reason-the decision was made further up the line about these unusual procedures, and we will get back to the Commissioner a little later, for the reasons for it.

Can you tell me, at any time, did any of you feel there was a pressure for speeding up the application?

Dr. KARUSAITIS. Since the original was a proposal-therefore we would have finalization of that proposal, and we would have to have input, comment was invited, and people were asked to appear, and to give their viewpoints.