DRUG SAFETY (A short recess was taken.) 673 Mr. FOUNTAIN. Let the subcommittee come to order. Let the record show that a quorum is present. As this hearing draws to a close, I would like to make some comments and to insert relevant documents in the record. As you will recall, Mr. Larrick, you initially refused the subcommittee access to your agency's new drug files on Flexin, as well as the files on MER/29. By letter of May 2, 1962, I had requested that arrangements be made for the subcommittee staff to examine the files containing the new drug applications for these two drugs, which had been withdrawn from the market a short time before due to the discovery of dangerous side effects. You replied by letter of May 10, 1962, denying our request on the grounds that the Federal Food, Drug, and Cosmetic Act prevented you from complying. As a substitute for the subcommittee's examination of your files, you proposed the preparation of a summary of these new drug applications, which you stated "would contain all of the pertinent information." I would like to submit as exhibits at this point in the record, my letter to Commissioner Larrick of May 2, 1962, and his reply dated May 10, 1962. (The documents are as follows:) EXHIBIT 32A-LETTER FROM HON. L. H. FOUNTAIN, CHAIRMAN, INTERGOVERN MENTAL RELATIONS SUBCOMMITTEE, TO GEORGE P. LARRICK, MAY 2, 1962 Hon. GEORGE P. LARRICK, Commissioner, Food and Drug Administration, Department of Health, Education, and Welfare, Washington, D.C. DEAR MR. LARRICK: In connection with its responsibility for studying the activities of the Food and Drug Administration with respect to efficiency and economy of operation, the Intergovernmental Relations Subcommittee wishes to obtain information concerning two drugs which were recently withdrawn from the market due to the discovery of dangerous side effects. They are Mer-29, manufactured by Richardson-Merrill Co., and Flexin, manufactured by McNell Laboratories. Will you please arrange for Mr. Donald Gray of the subcommittee's staff to examine your files containing the new drug applications for these two drugs and any other information you may have concerning them? Your cooperation in this matter will be greatly appreciated. L. H. FOUNTAIN, EXHIBIT 32B-LETTER FROM GEORGE P. LARRICK, COMMISSIONER, FOOD and Drug ADMINISTRATION, TO HON. L. H. FOUNTAIN, MAY 10, 1962 DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE, Hon. L. H. FOUNTAIN, Chairman, Intergovernmental Relations Subcommittee, Committee on Government Operations, House of Representatives, Washington, D.C. DEAR MR. FOUNTAIN: We have your letter of May 2, 1962, requesting us to arrange for Mr. Donald Gray of the subcommittee staff to examine our files covering the new drug applications for Mer-29 and Flexin. We want to be as helpful as possible to your committee. However, the Federal Food, Drug, and Cosmetic Act imposes certain restrictions on us which we must respect. Under the law, we are forbidden to disclose any information submitted in connection with a new drug application that is entitled to protection as a trade secret. Our regulations further emphasize the fact that all information submitted in connection with new drug applications will be treated as confidential. The reason for these restrictions is to encourage manufacturers to make as full a disclosure as possible when they submit their new drug application, including information involving doctor-patient relationships. We have uniformly declined to make the files on new drugs available to anyone except employees of the Food and Drug Administration. We are confident, however, that we can prepare a summary of these new drug applications that will contain all pertinent information. We will undertake the preparation of these summaries promptly and they will be sent to you as soon as they are completed. After you have had an opportunity to review them, we will be glad to arrange for a meeting between Mr. Gray and our personnel who are familiar with these files to clarify any questions you may have. We should point out that even though these drugs have been removed from the market, we are actively investigating both of these eases to determine whether false statements were made in connection with the new applications or whether there was a failure to disclose material facts. We hope that our suggested handling of your request will be satisfactory. Again let me say that we want to furnish you with all information that we possibly can within the limitations imposed on us by the statutes. Sincerely yours, GEO. P LARRICK, Commissioner of Food and Drugs. Mr. FOUNTAIN. As we informed your agency at the time, Mr. Larrick, the subcommittee could not accept your interpretation of the law. Moreover you erroneosuly stated in your letter of May 10, that: We have uniformly declined to make the files on new drugs available to anyone except employees of the Food and Drug Administration. The fact is that our subcommittee staff had examined such files in the past and FDA had not previously, in our experience, claimed confidentiality for these records. It was only after considerable delay which necessitated my appearance before the House Commerce Committee for the purpose of proposing an additional amendment to the Drug Amendments Act of 1962 which would prevent the withholding of information from duly authorized committees of Congress that the subcommittee was given access to the records, which it must see if it is to meet its responsibilities. We will incorporate in the hearing record as an exhibit at this point the brief chronology of events on Flexin, which was prepared by the FDA in accordance with Mr. Larrick's proposal of May 10, 1962. I think the inadequacy of this document, as a primary source of information for a duly authorized committee of the Congress, is obvious. It can be further evaluated in the light of the facts brought out in this hearing record. (The document follows:) EXHIBIT 33-FDA CHRONOLOGY ON FLEXIN. FLEXIN (McNeil Laboratorier Inc., Fort Washington, Pa.) A chronology relating to the original New Drug Application for Flexin (Zoxazolamine) to the time of its withdrawal from the market, is given below: 1. New Drug Application under the name "Tablets Flexin (Zɔxazolamine, McNeil) 250 mg." was submitted by McNeil Laboratories, Inc., on November 14, 1955. 2. On January 13, 1956, Food and Drug Administration acknowledged receipt of the above application and additional material dated December 27, 1955, rela tive to toxicology. The application was made effective on January 13, 1956, with the understanding that certain label and brochure changes be made. These changes included: inclusion of both the generic and complete chemical name under the trade name; a change in the brochure statement 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 3 gm. (12 tablets)."; that the warning statement in the brochure be italicized; that a new section be added to include: "Convulsive Disorders-Flexin is not recommended for administration to patients with convulsive disorders such as grand mal epilepsy." 3. On February 21, 1956, Food and Drug Administration acknowledged receipt of additional control data and revised labels and labeling. 4. On April 11, 1956, a supplement of March 14, 1956, providing for a change in the formulation and a revised chemical test was made effective by Food and Drug Administration. 5. On November 29, 1956, Food and Drug Administration acknowledged receipt on November 1 of a supplemental application concerning printed labeling for Tablets Flexin, Engestic Coated. 6. On January 24, 1957, Food and Drug Administration commented on proper labeling for the drug. Namely, that there was no precedence between generic and chemical names and the prescription legend. But, there was precedence between mandatory labeling and other statements not required under the Food, Drug, and Cosmetic Act. The words "Flexin is the McNeil brand" were not necessary, nor was it necessary for the name of the drug and the name of the company to appear in such relatively large type. 7. On July 24, 1958, Food and Drug Administration acknowledged the receipt on June 11, 1958, of a supplemental new drug application providing for including the use of "Flexin" as a uricosuric agent in gout. (Uricosuric agents cause increased elimination of uric acid in the urine.) 8. On July 30, 1958, Food and Drug Administration acknowledged the receipt on July 25, 1958, of a supplemental new drug application providing for revision in a proposed brochure along with further clinical data on the use of "Flexin" in gout. 9. On December 2, 1958, Food and Drug Administration acknowledged the receipt of labeling pursuant to a conditionally effective supplemental new drug application of July 30, 1958. This amounted to a change in the brochure to include a section on chronic gout and gouty arthritis. This application was made effective on December 2, 1958. 10. On November 20, 1959, Food and Drug Administration acknowledged the receipt on September 29, 1959, of a supplemental new drug application providing for a revised label, brochure, and index card. For the first time the firm reported that it had knowledge of 32 reports suggesting that the administration of the drug may have been associated with the development of hepatitis with jaundice. The revised label, brochure, and index card included a recommendation that dosage for Flexin as a uricosuric agent be reduced from 250 mg. or less three or four times a day to 125 mg. three or four times a day. 11. On May 2, 1961, Food and Drug Administration acknowledged receipt on April 19, 1961, of a communication pertaining to transfer of manufacturing facilities and the use of a new seal for the packaged drug. 12. On July 13, 1961, in an interview the firm informed Food and Drug Administration of 54 cases of hepatitis associated with the use of "Flexin." 13. On July 17, 1961, Food and Drug Administration phoned the firm and advised that a special "flagged" letter be sent to physicians calling attention to the information on the occurrence of hepatitis. 14. On August 23, 1931, in a telephone conversation, Food and Drug Administration asked the firm for all data it had on hepatitis from Flexin. 15. On August 23, 1961, Food and Drug Administration acknowledged receipt of a supplemental new drug application dated July 26, 1961, for "Tablets 'Flexin' Zoxazolamine, 250 mg.." "Tablets 'Flexin' Zoxazolamine Enteric Coated. 250 mg.," "Tablets 'Flexilon'," "Tablets 'Flexilon-HC'," and "Tablets "Triurate'." The supplemental applications provided for revised labeling together with new labeling in the form of a letter to physicians discussing hepatitis occurring in patients receiving zoxazolamine. Food and Drug Administration requested complete reports of all evidence of injury from preparations containing Flexin. Such as, copies of all the clinical records, correspondence with physicians and others who had contributed to such information; any expert opinions received from consultants; and anything else pertinent to the subject. Food and Drug Administration considered these supplemental new drug applications unacceptable and incomplete and that the proposed labeling was inadequate to warn of the danger of hepatitis. Accordingly, FDA did not permit the filing of these supplemental new drug applications. 16. On September 14, 1961, Food and Drug Administration called the firm and asked when FDA could expect the material requested on August 23, 1961. Food and Drug Administration emphasized the importance of the problem and the urgency of determining how it was to be solved. The firm promised the data in possibly a week. 17. On October 2, 1961, Food and Drug Administration called the firm to again request the data on the toxicity of Flexin. 18. On October 3, 1961, the firm submitted the data requested in Food and Drug Administration's letter of August 23, 1961. At this time, FDA recommended that all drugs containing Flexin be removed from the market and that the firm voluntarily request suspension of the respective applications. 19. On October 8, 1961, representatives of the firm met with Food and Drug Administration. At this time, FDA again informed the firm that in its opinion Flexin could not be considered safe. The firm agreed that in spite of the usefulness of the drug, its hazards outweighed its value and it should not be used and it should be removed from the market. 20. On October 12, 1961, Food and Drug Administration acknowledged the firm's letter of October 6 requesting withdrawal of the new drug applications pertaining to Flexin, Flexin Enteric Coated, Flexilon, Flexilon-HC, and Tablets Triurate (Drug containing Flexin). 21. On October 13, 1901, a formal order signed by the Commissioner of Food and Drugs was entered suspending the New Drug Application for Flexin. This order was based on a finding that clinical experience showed that the drug may be unsafe under the conditions of use set forth in the New Drug Application. Mr. FOUNTAIN. Mr. Larrick, I want to thank you and your col leagues for making yourselves available to the subcommittee. We will probably be seeing you again soon. Mr. LARRICK. Thank you very much indeed. And let me say that you and the subcommittee and the staff have been very pleasant people to work with. Mr. FOUNTAIN. Thank you very much. The subcommittee will stand in recess until the call of the Chair. (Whereupon, at 12:50 p.m., the subcommittee was adjourned, subject to call of the Chair.) DRUG SAFETY (Part 2) WEDNESDAY, JUNE 17, 1964 HOUSE OF REPRESENTATIVES, INTERGOVERNMENTAL RELATIONS SUBCOMMITTEE OF THE COMMITTEE ON GOVERNMENT OPERATIONS, Washington, D.C. The subcommittee met, pursuant to call of the Chair, at 10 a.m., in room 1310, Longworth Office Building, Hon. L. H. Fountain (chairman of the subcommittee) presiding. Present: Representatives L. H. Fountain, Torbert H. Macdonald, J. Edward Roush, John E. Moss, Florence P. Dwyer, and Bill Stinson. Professional staff present: Dr. D. C. Goldberg and W. Donald Gray, Intergovernmental Relations Subcommittee; and Raymond T. Collins, minority professional staff, Committee on Government Oper ations. Mr. FOUNTAIN. Let the subcommittee come to order and the record show that a quorum is present. The subcommittee this morning is resuming its hearings on drug safety to take testimony from Assistant Commissioner Winton B. Rankin and other representatives of the Food and Drug Administration in connection with the drug known as Orabilex, which was removed from the market earlier this year because of dangerous side effects. This is one of the several such drug withdrawals which are being intensively reviewed as a part of the subcommittee's overall drug safety study. By carefully examining the process by which Orabilex and other problem drugs were approved by the Food and Drug Administration for commercial sale, we are endeavoring to discover what went wrong and at what stage, so as to require each drug's subsequent withdrawal In so doing, we are seeking to distinguish between those regulatory problems which may have been corrected by the Drug Amendments Act of 1962 and those which are primarily attributable to weaknesses in FDA's internal operations. While the subcommittee's inquiry will focus on the decisions and the actions of FDA with respect to these problem drugs, it will also be necessary, of course, to examine to some extent the actions of the drug manufacturers, in order to place the agency's performance in proper perspective. Mr. Rankin, we are delighted to have you and your colleagues with us, in Mr. Larrick's absence. I understand that Mr. Larrick is in the hospital. I hope he is rapidly recuperating. Mr. RANKIN. He is, Mr. Chairman. Thank you. Mr. FOUNTAIN. Would you kindly identify your colleagues before proceeding with your prepared statement. 677 |