Mr. FOUNTAIN. The Chair, and I am sure the members of the subcommittee, appreciate that, and I am sure we agree with you that this procedure is necessary. But it is quite likely that all of the members of the subcommittee have not seen the documents. For that reason, if as you go along, we can get enough copies so that the members can see them, I think it would be extremely helpful and maybe expedite our consideration. Mr. LARRICK. I just don't have the number that would be required. I would be happy to read the entire exhibit, sir. Mr. FOUNTAIN. This one is not exceptionally long. Some of the others may be long, and if so, I would not want them read, particularly if in your statement you give the substance of what the exhibits contain. Mr. LARRICK. I have sought to do that throughout the testimony. (Exhibit 1 follows:) EXHIBIT 1-MEMORANDUM FROM ROBERT L. MCNEIL, JR., VICE PRESIDENT, MCNEIL LABORATORIES, INC., TO FOOD AND DRUG ADMINISTRATION, NOVEMBER 14, 1955, AND EXCERPT FROM FLEXIN NEW DRUG APPLICATION MCNEIL LABORATORIES, INC., Philadelphia, Pa., November 14, 1955. Re Tablets Flexin (Zoxazolamine, McNeil) 250 mg. FOOD AND DRUG ADMINISTRATION, Department of Health, Education, and Welfare, (Attention: Ralph G. Smith, M.D., Chief, New Drug Section, Division of Medicine). GENTLEMEN: We are submitting herewith an application in accordance with section 505(b) of the Federal Food, Drug, and Cosmetic Act. In view of the fact that Flexin is an entirely new drug, we would like to have an opportunity to discuss the application with you in a preliminary fashion as soon as convenient. Would you therefore be good enough to telephone us collect so that we may make an appointment to go over the application with you. Very truly yours, Enclosure: New drug application (2). ROBERT L. MCNEIL, Jr., I. INTRODUCTION AND BACKGROUND Vice President. Since the original demonstration by Goodman in the early 1940's that it was possible to diminish or even abolish voluntary muscle tone by selective depression of subcortical and spinal polysynaptic transmission by the administration of benzimidazole, numerous other chemical compounds have been found to have this primary pharmacological action. In spite of the extensive investigation of 3-(0-toloxy)-1,2-propanediol (Mephenesin, Myanesin) and its many analogs and derivatives, various benzazoles, and other pharmacologically related, but chemically divergent, agents, Goodman and Gilman have recently stated that no agent has been found among these groups that is useful clinically. The available compounds are said to be relatively ineffective orally, have only a transient duration of effect, or possess unpleasant, or even hazardous, secondary activity; for these reasons their use as adjuncts in the treatment of patients with skeletal muscular hypertonicity (rigidity, spasticity, etc.) and hyperreflexia is impractical. For some time the pharmacology department at McNeil Laboratories has conducted a program designed to discover compounds which will selectively depress spinal polysynaptic transmission. Hundreds of compounds prepared by the organic chemistry department have been tested for this activity. Of this group, Flexin was chosen as the compound most likely to have clinical usefulness. No pharmacological data concerning Flexin were available prior to this study although the precursor, 2-aminobenzoxazole, as well as the even simply benzoxa zole and the related benzoxazolinone, were included in the pharmacological survey carried out by Domino, et al. Benzoxazolinone has been investigated by Lespagnol for hynotic activity, and certain N-substituted derivatives of this compound were described by Close, Tiffany, and Spielman and were tested for analgetic activity. In a study of the excretion of various aminophenols and derivatives, Bray, Clowes and Thorpe mentioned that 1-gram doses of benzoxazolinone produced depression in the rabbits that received it. No other references to the activity of even closely related compounds have been found in the available literature; those references to 2-amino-5-chlorobenzoxazole that are currently available are the result of studies conducted with material supplied by McNeil Laboratories. Mr. LARRICK. The clinical and pharmacological data submitted were given careful consideration by FDA medical officers, chemists, and pharmacologists and, in evaluating the benefit to be derived from use of the drug versus the risk to the user, it was FDA's institutional decision that this data showed the drug to be safe for use with the proposed labeling. The application was made effective on January 13, 1956. The drug was then marketed for over 8 months and no adverse reports appeared in medical literature or were reported to FDA by the firm or by any physicians. We later learned that McNeil Laboratories had a report of fatal hepatitis in a patient on this drug even before we allowed the application to become effective, but that report was not relayed to us until 1961. I have here, if you care to receive it, exhibit No. 2, which is a report of a telephone call from Dr. Bernard J. Alpers to McNeil Laboratories, on December 2, 1955, and following letter from the pathologist, Dr. Delaney, of January 6, 1956, submitted to FDA by McNeil Laboratories, in 1961. Mr. FOUNTAIN. Exhibit No. 2, if there is no objection, will become a part of the record of the hearings. (Exhibit 2 follows:) EXHIBIT 2-COMMUNICATIONS FROM DR. B. ALPERS, JEFFERSON MEDICAL COLLEGE, DIVISION OF CLINICAL INVESTIGATION, Subject: Telephone conversation with Dr. B. Alpers, Jefferson Medical College, re clinical trials with Flexin. Doctor Alpers called to let us know about a patient who had been receiving Flexin and who had developed an acute fulminating hepatitis. This patient was a female in the 30- to 40-year age group who had been receiving Flexin three to four times a day for several weeks. The clinical picture could not be distinguished from acute infectious hepatitis. The clinical course was progressively downhill and the patient died about 10 days after the onset of jaundice. Doctor Alpers stated that this was probably a case of acute infectious hepatitis, but since a drug was being administered the possibility of a toxic or chemical hepatitis had to be considered. Additional details in regard to this case are to be sent to us and Doctor Alpers suggested that we contact Dr. W. E. Delaney who had carried out the post mortem examination. JAMES M. SHAFFER, M.D. JEFFERSON MEDICAL COLLEGE OF PHILADELPHIA, January 5, 1956. Dr. JAMES M. SHAFFER, Director, Division of Clinical Investigation, DEAR DR. SHAFFER: In accordance with our conversation of December 23, I am sending you the complete protocol and brief clinical summary of Isabelle Reeves. The conclusion that the hepatic changes may be due to drug therapy and in addition cannot be differentiated from fulminating viral hepatitis is concurred by my chief, Dr. Peter A. Herbut. If I can be of further help, please do not hesitate to call me. Very truly yours, WILLIAM E. DELANEY, Mr. LARRICK. On August 14, 1956, the firm submitted a supplemental NDA for Flexin to FDA to provide for a new dosage form of the drug. As required by regulation, the application was accompanied by five copies of the proposed brochure to be distributed to physicians. These ostensibly reflected the proposed changes in labeling. On two of these five copies the section on adverse reactions caused by the drug were identical with those submitted with the original application. They read in part, "anemia, leukopenia, agranulocytosis, jaundice, or kidney damage has not been reported in any patient receiving Flexin." However, in three copies of the brochure the words "jaundice" and "kidney damage" were deleted, and the statement was changed to read "Flexin has been administered to patients daily for periods of over 6 months with no reports of anemia, leukopenia, or agranulocytosis.' We did not detect the change in these three copies, and the firm was not called upon to explain the significance of the change. By this time the firm had been informed by physician users of six cases of liver damage in patients also taking Flexin, including one death. Exhibits 3A and 3B deal with the two different submissions to which I have just testified. Mr. FOUNTAIN. Exhibits 3A and 3B are both dated in August 1956. Mr. LARRICK. Yes. Mr. GRAY. It might be helpful, Mr. Larrick, since it does say at the top of the brochure, "revised January 12, 1956," to point out that this is actually a copy of the proposed labeling submitted with the original new drug application of November 1955, and then submitted again with slight changes for this supplemental application in August 1956. Mr. LARRICK. That is quite right, that is entirely correct, Mr. Gray. Mr. GRAY. That is exhibit 3A. Exhibit 3-B is the markup of the final printed labeling that was submitted with the original new drug application. Mr. LARRICK. That is right. Mr. FOUNTAIN. Is there any objection to inclusion of these exhibits in the record? (No response.) If not, they will become a part of the record of the hearings. (Exhibits 3A and 3B follow :) EXHIBIT 3A-EXCERPT FROM DRAFT OF PROPOSED FLEXIN BROCHURE, WITHOUT CHANGE RE JAUNDICE FLEXIN1 (ZOXAZOLAMINE, 2-AMINO-5-CHLOROBENZOXAZOLE, MONEIL) A COMPLETELY NEW LISSIVE AGENT FOR THE RELIEF OF MUSCLE SPASM IN SUCH CONDITIONS AS MUSCULO-SKELETAL DISORDERS AND NEUROLOGICAL DISEASES Prepared by the Division of Clinical Investigation, McNeil Laboratories, Inc., Philadelphia, Pa. SIDE EFFECTS, TOXICITY, AND PRECAUTIONS Flexin has produced no irreversible toxic reactions when administered to patients daily for periods of over 6 months. Individuals receiving Flexin for prolonged periods have been carefully checked with blood counts, urinalyses, and liver function tests. Anemia, leukopenia, agranulocytosis, jaundice, or kidney damage has not been reported in any patient receiving Flexin. Flexin may produce certain bothersome side effects. The type and approximate incidence of side effects that may be expected with the use of Flexin are listed in table 1. This information is based on clinical reports involving 385 patients who received Flexin for periods of as long as 6 months. EXHIBIT 3B-EXCERPT FROM DRAFT OF PROPOSED FLEXIN BROCHURE CONTAINING CHANGE RE JAUNDICE FLEXIN, A COMPLETELY NEW LISSIVE AGENT FOR THE RELIEF OF MUSCLE SPASM IN SUCH CONDITIONS AS MUSCULOSKELETAL DISORDERS AND NEUROLOGICAL DISEASES SIDE EFFECTS, TOXICITY, AND PRECAUTIONS Flexin has been administered to patients daily for periods of over 6 months with no reports of anemia, leukopenia, or agranulocytosis. Flexin may produce certain bothersome side effects. The type and approximate incidence of side effects that may be expected with the use of Flexin are listed in table 1. This information is based on clinical reports involving 385 patients who received Flexin for periods of as long as 6 months. Mr. STINSON. Mr. Chairman, I am not quite clear as to the difference between these exhibits. Is one the actual copy of the label that was to be used on the container of the drug? Mr. LARRICK. Not the label, Mr. Stinson; all five purportedly identical documents were proposed copies of the brochure the literature that goes in the package, to acquaint the physician in detail with what the drug is for, what the contraindications are, how you use it. The original submission was made and then later, as is customary, they wanted to make some changes. Mr. STINSON. Were these in printed form? Mr. LARRICK. Originally the brochure was submitted in mimeographed form and before we acted on it finally, after we had discussed it, changes were made on copies of these. When agreement was reached on its wording, it was finally printed. Mr. STINSON. When it was submitted to you, you received one version in typed form? Mr. LARRICK. We received one version in mimeographed form with handwritten changes in ink. Mr. STINSON. And in printed form in the other version? Is that the way it was? Mr. LARRICK. Our practice is to require the submission of material for review in five copies, so that one copy can go to the doctor, one copy can go to the pharmacologist, one can go to the chemist and so on, and they can be reviewed simultaneously. Well, of the five, three were mimeographed, and the other two were printed. 1 Trademark. Mr. STINSON. Typed or printed? Mr. LARRICK. Printed, with changes typed on pieces of paper and scotch-taped over the sections to be changed. The corrections, however, were only made in two of the five copies. And the copy reviewed by our medical officer apparently was one that did not have the changes that were significant in the light of the new facts that had come to light with respect to the drug. Mr. STINSON. But actually they were in a different form, one was a mimeographed form and the other in a typed form? Mr. LARRICK. One form was mimeographed and the other was printed. Mr. FOUNTAIN. I think some of these things will be clarified later on. Mr. LARRICK. It won't bother me at all; I am quite happy to be interrupted at any minute. Mr. FOUNTAIN. Go right ahead, if there are no further questions at this point. Mr. LARRICK. Following this submission, the drug continued to be marketed for another 22 months with still no reports being received by FDA from either the firm or the medical community that use of the drug was associated with increasing numbers of severe and fatal cases of liver damage. On June 11, 1958, the firm submitted to FDA a supplemental NDA to provide for use of Flexin as a uricosuric agent-for the treatment of gout. Most of the additional material submitted was concerned with the clinical use of the drug in gout, and all these reports of clinical use stressed the safety of the product. The investigators who participated in the studies on the uricosuric action of Flexin included wellqualified members of medical schools, hospitals, and research institutions. Under the heading "Adverse or Side Effects," the statement was made that: The reports received on patients with gout treated with Flexin indicate that there have been no adverse effects or undesirable side reactions caused by the drug. This absence of side effects may be related to the relatively small doses of Flexin required to produce the uricosuric effect. Extensive clinical experience during the past 3 years with the use of Flexin as a skeletal muscle relaxant has indicated that this drug is well tolerated in doses of 250 milligrams, three or four times a day. Exhibit 4 is a page on the adverse reactions from the supplemental new drug application of June 11, 1958. And this relates to the statement that I have just inserted in the record. Mr. FOUNTAIN. What you have just said is the substance of what is contained in exhibit 4? Mr. LARRICK. Precisely. And that is true throughout my testimony. Mr. FOUNTAIN. After the staff and the subcommittee have had an opportunity to examine the exhibits more carefully, they can ask questions about them. If there is no objection, exhibit 4 submitted by Mr. Larrick will become a part of the record of hearings at this point. EXHIBIT 4-PAGE ON ADVERSE REACTIONS, FROM SUPPLEMENTAL NEW DRUG APPLICATION FOR FLEXIN, JUNE 11, 1958 VI, ADVERSE OR SIDE EFFECTS The reports received on patients with gout treated with Flexin indicate that there have been no adverse effects or undesirable side reactions caused by the drug. This absence of side effects may be related to the relatively small doses of Flexin required to produce the uricosuric effect. Extensive clinical experience during the past 3 years with the use of Flexin as a skeletal muscle relaxant |