With this in mind, I would go down to the hearing clerk, look at the proposal sent in, the comments, and in June we sent a letter to Paul Bryan, Dr. Finkel, and Dr. Ortiz, with the question: What finalization, if ever, if when, would be made on the proposal which was the original proposal, September 26, 1973.

We felt that since it was a proposal, until you got a finalization, it was open.

Senator KENNEDY. What happened at the December 1973 meeting? Dr. KARUSAITIS. I cannot say about the December meeting. I can say that there was a meeting in which I presented the fact that I did not understand the pregnancy bit, how would you determine the pregnancy of a woman who had just been raped, or was an emergency, what type of test would be taken.

I could not understand that we would approve this in a simplistic matter without a full NDA, which we asked for a year ago.

Senator KENNEDY. And was that advice heeded, or was it overruled? Dr. KARUSAITIS. It was overruled. It stayed in our bailiwick, we were told we would keep the submission.

Senator KENNEDY. Would it be fair to say you were forced to approve it? Dr. KARUSAITIS. No, sir.

Senator KENNEDY. It would not?

Dr. KARUSAITIS. My feeling was always the same. I would not approve it.

Senator KENNEDY. You would not approve it?
Dr. KARUSAITIS. No, sir.

Senator KENNEDY. What about you Dr. Seife?

Dr. SEIFE. I would not sign the letter. In fact, Dr. Crout called me recently and said he would sign the final approval letter if it were approved. The drug has not been approved for this use, and will not be until March 7, 1975. That is the date of the final order, the date of the effectiveness of the final order.

Senator KENNEDY. You mean as of today it is not approved?

Dr. SEIFE. That is right.

Senator KENNEDY. Even though the bulletin went out in May 1973? Dr. SEIFE. Right.

Senator KENNEDY. As of today it is not approved?

Dr. SEIFE. Correct.

Senator KENNEDY. But on March 7 it will be?

Dr. SEIFE. Yes, sir.

Senator KENNEDY. For emergency purposes?

Dr. SEIFE. Postcoital use; yes.

Senator SCHWEIKER. I am trying to determine the sequence of

events.

The first thing, which was an abnormal departure from pattern, was the letter to you which, as I understand it, was a variance from what the Federal Register said, is that correct?

Dr. SEIFE. Yes.

Senator SCHWEIKER. A letter of application which did not coincide with the Federal Register, abnormal situation, number one.

The second abnormal situation was the application submitted in abbreviated form, and since there was a new indicated use, this was also a departure from precedence, is that correct?

Dr. SEIFE. Yes.

55-647 O-75 - 3

Senator SCHWEIKER. Third, and I am not sure I have the sequence right, but third, a letter of approval was erroneously sent out.

Dr. SEIFE. No, no letter of approval has ever been issued for this use ever. I would be the one to sign it, until Dr. Crout relieved me of this burden.

Senator SCHWEIKER. The letter was sent out, I guess, a couple of years ago, what did it say then?

Dr. SEIFE. That was a bulletin to physicians, saying that this was an indication for the drug.

Senator SCHWEIKER. Now, explain to me what the Bulletin said. Did it approve the drug?

Dr. SEIFE. No, it just stated that 25 milligrams, taken twice a day for 5 days, 5 consecutive days, the morning after, or as soon after coitus as possible, would be effective in preventing pregnancy.

Senator SCHWEIKER. It did not approve the drug. But it said it would be effective, and it was an FDA bulletin?

Dr. SEIFE. Yes.

Senator SCHWEIKER. I have trouble comprehending exactly what you are telling me.

Senator KENNEDY. If the Senator would yield

Senator SCHWEIKER. I will be glad to yield, because it is a very key issue.

Senator KENNEDY. This is the FDA Drug Bulletin, May 1973, and it says:

"In agreement with the ***" FDA has approved under restrictive conditions postcoital use of diethystilbestrol.

So even though it was in error, it was sent out?

Dr. SEIFE. Yes. I imagine that is how the company that filed the ANDA received their information

Senator KENNEDY. You did not approve it?

Dr. SEIFE. No.

Senator SCHWEIKER. It said FDA did approve it, and that is the question I asked, which you denied.

Dr. KARUSAITIS. He is not denying it. He is telling you he did not sign the approval, it goes through him.

Senator SCHWEIKER. You are saying you did not approve it, but it is pretty obvious that the Bulletin said FDA approved.

Dr. SEIFE. That is correct.

Senator SCHWEIKER. That was abnormality No. 3.

Dr. SEIFE. Yes.

Senator SCHWEIKER. Then just a few weeks ago the new indication for postcoital usage was approved in an abbreviated form procedure. Dr. SEIFE. No.

Dr. KARUSAITIS. To be effective, Senator, the 7th of March.

Senator SCHWEIKER. What occurred then?

Dr. KARUSAITIS. It is coming, the 7th of March, to be.

Dr. SEIFE. Next month.

Senator SCHWEIKER. Under abbreviated procedure.

Dr. SEIFE. Yes.

Senator SCHWEIKER. This also, as you said earlier, is a departure from normal procedure?

Dr. SEIFE. Yes.

Senator SCHWEIKER. So we really have four abnormal occurrences here that differed from normal practice and pattern, that is all I tried to establish.

Thank you.

Dr. SEIFE. Yes.

Senator KENNEDY. On a drug that causes cancer.

Dr. SEIFE. Yes, that is true. That is why we felt very strongly about having this as an abbreviated new drug application.

Senator KENNEDY. I want to thank the both of you for your appearance here.

Let me just say that I think you have performed nobly in trying to do what I think the Congress had intended the Food and Drug Administration to do, and that is to pursue the public interest on this.

I think you deserve a great deal of credit. There have been times before this committee we have had our differences, and it has not been really with the employees in the Food and Drug Administration, who have been performing, I think, nobly. I think that ought to give the American people a great sense of confidence.

It is these other administrative decisions which I think we are questioning. That is a matter of great concern to us.

We want to commend you. I do. We want to thank you for performing the job.

Senator SCHWEIKER. I share those sentiments.

I have one more question.

Even though the fourth abnormality I cited indicated that some approval for March 7

Dr. KARUSAITIS. Approval will be effective the 7th of March, 1975. Senator SCHWEIKER. OK. Your Department has still not approved that?

Dr. SEIFE. Correct.

Senator SCHWEIKER. It is normal for your Department to approve procedures such as that?

Dr. SEIFE. That is right.

Senator SCHWEIKER. You are telling us, even though this future approval date has gone out, it still has not cleared your Department, is that right?

Dr. SEIFE. Right.

Senator SCHWEIKER. So that is abnormality No. 5.

Dr. SEIFF. We have to receive draft labeling, final printing labeling, we have to review the whole application before approval. This might take several months.

Senator KENNEDY. Well, the bottom line is you have been overruled, that is the way I read it.

Dr. SEIFF. On the abbreviated part.

Senator SCHWEIKER. About five times the way I count them.

Senator KENNEDY. Thank you very much. You have been very frank and very responsive to our questions, and very helpful, and we want to thank you.

Dr. SEIFF. Thank you.

Dr. KARUSAITIS. Thank you.

Senator KENNEDY. Our next panel of witnesses appear here as representatives of companies which have marketed or still market a product with a 25-milligram dosage of DES.

Robert H. Furman, M.D., is vice president of Lilly Research Laboratories, Eli Lilly & Co. In late 1973, Lilly deleted the 25-milligram dosage forms of DES from its product line.

Robert L. Pillarella is president of Tablicaps, Inc., of Franklinville, N.J. Tablicaps is presently marketing a 25-milligram dosage form of DES, in accordance with FDA regulations regarding the emergency usage of this drug.

Mr. Pillarella, I want to indicate that Mr. Williams wanted me to extend a word of welcome to you and regret that he is unable to be here.

He wanted me to indicate to you that he looks forward to reading your testimony and wanted to thank you for coming.

Dr. Furman, please proceed.

STATEMENT OF ROBERT H. FURMAN, M.D., VICE PRESIDENT, LILLY RESEARCH LABORATORIES, ELI LILLY, INC., ACCOMPANIED BY ROBERT L. PILLARELLA, PRESIDENT, TABLICAPS, INC., FRANKLINVILLE, N.J.

Dr. FURMAN. Mr. Chairman, I am Robert Furman, a physician, vice president, Eli Lilly Research Laboratories.

Eli Lilly & Co. is pleased to respond to the invitation of the chairman to appear today. As requested, our statement will include comments on Lilly's decision not to market a 25-milligram dosage form of diethylstilbestrol for postcoital contraception. It also will discuss Lilly's suggestions for the proper use of prescription pharmaceuticals. Diethylstilbestrol, DES, is a synthetic compound capable of producing feminizing effects similar to those of the naturally occurring feminizing hormones-estrogen.

It was synthesized by Dodds in 1938. DES was added to the Lilly product line in 1941 "at a time when the natural products were scarce and expensive." It was regarded as a milestone in the development of effective hormone therapy, and it is used today in the treatment of a number of conditions.

The four principal conditions in which DES is most often employed are the following:

(A) As replacement therapy in states of estrogen deficiency, for example, the menopause or the absence of ovaries.

(b) For the prevention of post partum breast engorgement.

(c) Cancer of the prostate.

(d) Breast cancer in postmenopausal women.

Since 1951, studies in animals and humans have indicated that high doses of estrogen, administered after the ovum (egg) had been released from the ovary-determined by body temperature rise-prevent pregnancy.

In 1966, and subsequently, reports by Morris and Van Wagenen and by Kuchera demonstrated that DES prevented pregnancy when administered in large doses-25 milligrams twice daily for 5 daysbeginning no later than 72 hours after sexual contact.

Precisely how DES acts to prevent pregnancy when administered after sexual contact is not known. It probably interferes with the attachment of the fertilized ovum to the lining of the uterus (implantation).

The term "interceptives" has been suggested for agents which interfere with implantation. We are not aware of any evidence that DES will interrupt an already implanted ovum.

Lilly had provided a 25-milligram dosage form of DES for use in patients with carcinoma. In February of 1973, a spokesman for the FDA indicated to the Senate Subcommittee on Health that DES had been approved as a postcoital contraceptive. In the May 1973 FDÄ Drug Bulletin, the provisions of the newly approved indication were. delineated.

Senator KENNEDY. That was the bulletin referred to and was not approved until for this coming March?

Dr. FURMAN. Yes, sir.

with draw at

In the Federal Register for September 26, 1973, the FDA gave notice to the effect that it was proposing to withdraw its approval of 25 milligram dosage forms of DES for all indications except postcoital contraception. Industry was invited to submit abbreviated new drug applications for the use of the 25-milligram DES dosage for this indication.

Senator KENNEDY. Do you think it would have been appropriate for new drug application, ANDA, an abbreviated new drug application

Dr. FURMAN. I will point out a little bit later in my testimony, Mr. Chairman, it is our feeling that under circumstances such as this that the company has the responsibility to carry out studies of its own or support studies which demonstrate not only efficacy but safety as well. Senator KENNEDY. Well, then, I guess your answer would be, no, you think not abbreviated application, but ought to be new drug application, is that correct?

Dr. FURMAN. Yes, sir.

In the Federal Register for February 5, 1975, the final labeling, patient package information and package size are set forth. The notice indicates that only one abbreviated new drug application has X

been received.

After the Federal Register notice of September 26, 1973, Eli Lilly & Co. deleted the 25-milligram dosage forms from its product line. These items had been made available to physicians for other uses, such as carcinoma.

We elected not to submit an abbreviated NDA for the use of DES as a postcoital conrtaceptive. This decision was arrived at after careful review and evaluation of the medical and scientific aspects of the situation.

After prior review by FDA, a letter was mailed to over 230,000 physicians and approximately 55,000 pharmacists in March of 1974, discussing the use of DES, including its use as a postcoital contraceptive. The letter informed them as follows:

Although postcoital contraception is recognized by some authorities as an indication for diethylstilbestrol, Eli Lilly and Company has neither conducted nor supported laboratory or clinical investigations to establish efficacy and safety of its product for this indication. Therefore, diethylstilbestrol supplied by Eli Lilly and Company is not recommended for postcoital contraception, and we are deleting from our product line the 25 milligram dosage forms. We continue to endorse diethylstilbestrol for the indications included in our current literature. Although diethylstilbestrol is supplied by many manufacturers, Eli Lilly and Company believes it important to acquaint the medical profession with this information.