which were copies of FDA interoffice memorandums concerning a report of a field investigation by our New York district into a case of alleged toxic hepatitis in a patient who had taken Flexin.

I have had our files reviewed and they show the memorandums that you introduced from our New York district office included a report of interview with the patient's physician and as well as rather complete copies of the pertinent medical records.

This report, together with the medical records, was sent to our Bureau of Field Administration, by the New York district, on October 6, 1959, in the regular course of business. It was then sent to the Division of New Drugs.

Dr. Irwin Siegal reviewed the report and wrote a summary of his conclusions. He then sent the investigative report and attachments, together with his comments, to two other branches of the Bureau of Medicine, where they were likewise reviewed. The reviewing officers concurred in his decision that the report and the records on their face did not demonstrate that Flexin was the cause of the injury.

This is all contained in the memorandums dated at the top October 6, 1959, which you as chairman entered as an exhibit near the close of yesterday's meeting.

The other two medical officers, who were not then in the New Drug Branch, judged the investigational report of this patient on its merits. They came to the same conclusion as did Dr. Siegal. Food and Drug Administration's Bureau of Field Operations then sent a memorandum to our New York district including Dr. Siegal's comments and suggesting reinterview of the physicians who reported the injury to determine the patient's course and current diagnosis. As a result of this communication, on December 2, 1959, New York district did reinterview the attending physician and a second physician, who by that time had been called in on the case.

The two physicians told the inspector they believed that the patient did not have a toxic hepatitis, but possibly had a secondary viral hepatitis. This report then was made by the district office, sent to the Bureau of Field Administration by the New York district on December 7, 1959.

The final entry which we find in our file on this matter is another FDA interoffice memorandum from Dr. Siegal to our then Bureau of Field Operations in which he noted that New York district's report of December 7, 1959, confirmed his earlier decision that this injury was probably not drug induced and that he did not believe further followup was indicated. This is the other exhibit which you have already introduced into the record at the end of yesterday's hearing, Mr. Chairman.

You will recall that during your questions yesterday I was asked who participated in the institutional decision to permit the original Flexin NDA to become effective. I have rereviewed the files overnight to check on my answer to that question.

As we stated, Dr. Barbara Moulton was the new drug officer, and Dr. Geoffrey Woodard was the pharmacologist. The letter from FDA to McNeil Laboratories, making the application effective, shows that the chemist who reviewed the application was Dr. Claudia Prickett, who was not a physician, but who is a Ph. D. chemist and that, as we mentioned, Dr. Ernest Q. King, who is an M.D. and a Ph. D., also

participated in this decision. I would, with your permission to complete the record, like to introduce a copy of this letter, if I may.

Mr. FOUNTAIN. Thank you, Mr. Larrick. I think your information is helpful. However, I am not quite sure that you answered the question I asked. My question was, How do you account for the fact that three of your medical officers were not aware in October 1959 of the company's statements in the supplemental new drug applications of June 1958 and September 1959 concerning hepatitis reports in association with Flexin? The quote I gave from one medical officer is a direct quote. In other words, one officer made the statement, “I am not aware of Flexin causing a toxic hepatitis," and two other medical officers agreed with those remarks; at least the memorandum says that. Mr. LARRICK. My understanding is, and I would ask the other gentlemen perhaps to supplement this, that the information which was submitted late in September 1959 to the new drug branch that did suggest strongly the relationship between drug-induced hepatitis and the drug, came to the new drug branch and had not been reviewed. The officer had a great pile of mail on his desk, involving a great many other matters, and my understanding is that at the time Dr. Siegal and these others made this statement that you quoted from, that neither he nor the new drug officers, who had handled the file, were aware of what was in the material that McNeil had reported at that time. Is that correct?

Dr. SMITH. I am not sure; I don't know; I would have to check the dates on that.

Mr. LARRICK. Mr. Brandenburg has been into our files with respect to that and I will ask him to make a statement.

Mr. FOUNTAIN. Mr. Brandenburg.

Mr. BRANDENBURG. The cover letter and the supplemental new drug application submitted on September 28, 1959, were received by the Bureau of Medicine on September 29, 1959. Dr. DeFelice, who was the reviewing medical officer on this supplemental new drug application for Flexilon, which was a Flexin-containing drug, made his final decision on this drug on October 28, 1959. That is the sequence of events. The supplemental new drug application was not for Flexin, it was for Flexilon.

Mr. FOUNTAIN. Mr. Gray?

Mr. GRAY. Flexin is contained in Flexilon, is it not?

Mr. BRANDENBURG. Yes.

Mr. GRAY. And there is specific information in that application pertaining to Flexin as one of the ingredients of Flexilon?

Mr. BRANDENBURG. Yes, there is.

Mr. GRAY. There was also a supplemental application in June 1958, handled by Dr. Siegal, in which the company stated that there had been occasional reports of hepatitis and jaundice in association with Flexin. Now, in view of the fact that, more than a year before, Dr. Siegal had reviewed an application containing this statement, how could he state over a year later that he was not aware of toxic hepatitis in association with Flexin?

Mr. BRANDENBURG. As you will recall Commissioner Larrick's testimony yesterday, in referring to Dr. Siegal's review of the 1958 supplemental new drug application he said we can only guess at what occurred. The application was mainly concerned with the new use

37-272-64-pt. 2--18

of Flexin as a uricosuric agent, and if you recall he also stated it could very well have been that Dr. Siegal confined his review of that application only to those portions dealing with safety of the drug for use in gout. We can't tell, naturally.

Mr. LARRICK. Dr. Siegal is here in town and would be available. Mr. FOUNTAIN. You haven't contacted him, have you ?

Mr. LARRICK. No, sir. I think it should be emphasized that in all of these submissions, the hepatitis was characterized in the submissions as viral hepatitis.

Mr. GRAY. I don't think it was concluded that it was viral hepatitis. I think the statement was that it was possibly viral hepatitis.

Mr. LARRICK. I think it is much stronger than that, Mr. Gray. I think if you reverse that and say occasionally a statement was made that some of them might possibly be drug induced.

Mr. FOUNTAIN. That is coming from the company ?

Mr. LARRICK. Coming from the company.

Mr. GRAY. I think I perhaps have that statement.

Mr. LARRICK. That was true clear through to the end, even the final ones, when we did not accept, when we took the drug off the market. Mr. GRAY. I believe I have here the direct quote from that application which states that:

During the 3 years that Flexin has been in use clinically, there have been occasional reports of patients who have developed jaundice while receiving Flexin. After careful inquiry into these cases, it has usually been concluded that the possibility of a viral hepatitis as the cause rather than a drug induced hepatitis, could not be excluded. The possibility exists that Flexin in rare cases may produce hepatitis and jaundice.

Mr. LARRICK. The latter statement is what I rely on to say that that means to me that in rare cases it might be drug induced, but in general it was not drug induced, but was viral hepatitis.

Mr. GRAY. That is not what it says, is it ?

Mr. LARRICK. That is what it says to me.

Mr. GRAY. It says the possibility cannot be excluded.

Mr. FOUNTAIN. I guess that is the language these people use. I have heard lawyers use that too sometimes but it seems to me a lot of this is very indefinite information, either indicating that people know and don't want to tell, or they are putting it in language that protects them both ways.

Mr. GRAY. But the statement does say the possibility exists that Flexin may in rare cases cause hepatitis. Yet a year later the statement is made by the man who reviewed this labeling that he is not aware of Flexin having caused a toxic hepatitis.

Mr. LARRICK. If you feel strongly on this, I would strongly recommend you call the gentleman who would be in a position to answer the question.

Mr. FOUNTAIN. Mr. Larrick, isn't it extremely important to a doctor, and wouldn't it normally arouse concern, because of the great difficulty in distinguishing whether or not it was drug induced or viral hepatitis?

Mr. LARRICK. I think it would.

Mr. FOUNTAIN. So it would cause concern and prompt inquiries? Mr. LARRICK. I think it would.

Mrs. DWYER. Mr. Chairman, why don't we call the doctor involved in this?

Mr. FOUNTAIN. We will at the appropriate time, if it appears necessary and material. I think the testimony thus far and from here on out will probably give us the answers to the questions we are seeking concerning the way in which these things were handled. It may be that the witness in question can give us a little bit more specific information and, if so, it might be well to call him.

Are there any questions by other members of the committee before I go into some questioning concerning some of the other supplemental applications?

Mrs. DWYER. No.

Mr. LARRICK. Mr. Chairman, I offered some exhibits which you haven't ruled on.

Mr. FOUNTAIN. If there is no objection, Mr. Larrick's exhibit will be made a part of the record.

(The letter follows:)

EXHIBIT 23-LETTER FROM Barbara MOULTON, M.D., MEDICAL OFFICER, NEW DRUG BRANCH, DIVISION OF MEDICINE, TO MCNEIL LABORATORIES, INC., MAKING EFFECTIVE THE NEW DRUG APPLICATION FOR FLEXIN

MCNEIL LABORATORIES, INC.,

Philadelphia, Pa.

(Attention: Mr. Robert L. McNeil, Jr.).

JANUARY 13, 1956.

GENTLEMEN: This will acknowledge your new drug application dated November 14, 1955, submitted pursuant to section 505 of the Federal Food, Drug, and Cosmetic Act for your product "Tablets Flexin (Zoxazolamine, McNeil) 250 mg." Also acknowledged is the additional material dated December 27, 1955, relative to toxicology. The application was filed on January 12, 1956.

It is our understanding, as discussed by telephone on January 12, 1956, with Mr. McNeil and Mr. Shaw that: (1) The raw materials milk sugar, starch, calcium phosphate dibasic, gelatin and stearic acid are purchased under guarantee as meeting the requirements of the United States Pharmacopeia, and are independently tested in your laboratories. A description of these tests will be submitted. (2) You will continue your stability studies with Flexin Tablets and forward the resulting data as it becomes available. (3) The calculations in estimating the benzoxazolone content of raw material Flexin will be clarified, and (4) You will submit a description of the reference sample used to derive the constant, 0.400, in the equation given under the assay of Flexin.

It is understood as discussed with Mr. McNeil by telephone on January 10, 1956, that the labels and brochure will be changed to include both the generic name and the complete chemical name in parenthesis under the trade name; that the paragraph on the label beginning "Flexin (Zoxazolamine, McNeil) will be deleted; that the fourth paragraph on page 5 of the brochure will be changed to read "In patients with severe spasticity individual adjustment of the dosage is necessary in order to achieve maximum benefit. It is recommended that the total dose of Flexin should not exceed 3Gm. (12 tablets),"; that the warning statement on page 8 of the brochure will be italicized; that a new section will be added on page 11 as follows: "Convulsive Disorders-Flexin is not recommended for administration to patients with convulsive disorders such as grand mal epilepsy"; that the words "U.S. Patent Pending" will be added to the label; that the second paragraph on page 11 will be deleted; and that the word "Experimental" in the heading on page 12 will be changed to "Other potential"; and that the last paragraph on page 12 will be deleted. It is understood, as discussed with Mr. McNeil by telephone on January 12, 1956, that the first two paragraphs on page 12 will be deleted. Our affirmative action in allowing the application to become effective is based on these understandings.

We have completed our study of this application and in accordance with the provisions of the regulation under section 505(c) of the act it has become effective.

Please submit five copies of the final printed label and labeling and three finished market packages of the drug when available.

Sincerely yours,

BARBARA MOULTON, M.D., Medical Officer, New Drug Branch, Division of Medicine.

Mr. FOUNTAIN. Mr. Larrick, I would like to ask whether the decision on the application for Triurate, which I understand is a combination of Flexin, Colchicine and Tylenol, submitted on January 6, 1960, was an institutional or an individual decision?

Mr. LARRICK. Dr. Smith, I believe, can answer that.

Mr. FOUNTAIN. The question is, whether the decision on this particular application was an institutional or an individual decision? Dr. SMITH. I am sorry, I don't know the answer to that.

Mr. LARRICK. We would have to see the documents involved and review the file to know who handled it and how.

Mr. FOUNTAIN. Do you know who handled it?

Mr. LARRICK. I don't.

Mr. FOUNTAIN. Mr. Gray, do you know?

Mr. GRAY. I believe this was handled by Dr. DeFelice.

Mr. LARRICK. I am afraid we just don't have the answer to your question. We can get it.

Mr. GRAY. I have some documents here that we will introduce which should enable you to answer that question.

Mr. FOUNTAIN. In your files it appears you do have a memorandum of January 29, 1960, regarding this application, from Dr. J. M. Taylor of the Division of Pharmacology, to Dr. DeFelice of the New Drug Branch, bearing the initials EIG, which may be those of Dr. E. Ï. Goldenthal, also of the Pharmacology Division.

This memo, a copy of which-if there is no objection-we shall include in the record, contains the following statements:

No animal studies on the safety of this combination are presented.

And:

Further clinical studies should be made with this combination for an evaluation of its safety.

However, there is another memorandum in the files bearing the initials P.D.F., which I believe are those of Dr. DeFelice, which reads: "No objection in view of the fact that all of these drugs are presently being used and apparently without damage. I do not feel that any additional data is needed."

I think at this time we ought to include a copy of this memorandum for the record, if there is no objection, and submit it to Mr. Larrick and his colleagues also.

Mr. FOUNTAIN. I also submit a copy of the letter of March 7, 1960, from Dr. DeFelice to the McNeil company, making this application conditionally effective pending the receipt of final printed labeling. (The memorandums and letter follow :)

EXHIBIT 24-INTRA-AGENCY MEMORANDUMS REGARDING TRIURATE NEW DRUG APPLICATION AND LETTER MAKING THE APPLICATION EFFECTIVE

OFFICE MEMORANDUM, U.S. GOVERNMENT

To: New Drug Branch. Attu. Dr. DeFelice.
From: Division of Pharmacology.

Subject: Tablets Triurate (McNeil Laboratories, Inc.).

JANUARY 29, 1960.

Application is made for the use of Tablets Triurate in the treatment of gout and gouty arthritis. Tablets Triurate is a combination-each tablet contains Flexin Zoxazolamine (2-amino-5-chlorobenzoxazole)-100 mg., colchicine-0.5 mg.,