United States. This included the new prescribing information for the Parke, Davis chloramphenicol succinate for intravenous administration. On December 30, 1968, the Bureau of Medicine sent a memorandum to the Office of the Commissioner referring to the Rachelle complaint about the Parke, Davis outstanding stocks. On January 14, 1969, I ordered a thorough investigation of outstanding stocks, not only in the Parke, Davis plant in Detroit, but also in its branch warehouses and at its Puerto Rico plant. This investigation, which was completed in early February 1969, indicated that the firm did have a substantial quantity of chloramphenicol capsules, as well as chloramphenicol succinate, on the market and in their warehouses bearing the old labeling. On February 4, 1969, we sent a telegram to Parke, Davis expressing concern about the continued availability of chloramphenicol products with old labeling. We requested the firm to notify us as to the amounts of such chloramphenicol on hand at all Parke, Davis warehouses and to advise us of their intended disposition of this material. We also told the firm that, henceforth, no certified chloramphenicol products, including products for export, were to be distributed unless the labeling met the new requirements. On February 6, 1969, a representative of Parke, Davis met with FDA. Parke, Davis agreed to supply all the information that had been requested in our telegram of February 4, 1969. As of that date, the firm stopped shipments from all its warehouses of chloramphenicol which did not bear the latest revised labeling. They assured us there would be no more export shipments of certified chloramphenicol products which did not bear the approved labeling or the authorized equivalent in a foreign language. In March, Parke, Davis had underway the return of the old merchandise to its Detroit plant. On April 4, 1969, Detroit district inspectors checked the Parke, Davis plant and determined that the merchandise was being properly handled. After revising the labeling as ordered in September 1968, Parke, Davis under, took two efficacy studies of chloramphenicol succinate. This was first suggested to them by FDA representatives at a meeting on June 19, 1968, when it had become apparent that the blood levels of the product administered intramuscularly were much lower than those achieved by the capsules. On September 19, 1968, Parke, Davis submitted a protocol for a Rocky Mountain spotted fever study, and on October 31, 1968, a similar protocol for a typhoid fever study. In both instances, volunteer subjects were to be given the disease, and then treated with intramuscularly administered chloramphenicol succinate. Both blood levels and clinical response would be recorded. The Rocky Mountain spotted fever study began on September 19, 1968. Nine subjects developed the disease. All were treated with chloramphenicol succinate by the intramuscular route. In five patients, the treatment was effective; in the remaining four, there were relapses. The typhoid study began on November 7, 1968. Four subjects were treated with chloramphenicol succinate by the intramuscular route, and four with oral chloramphenicol. The study showed, in the words of the Parke, Davis director of clinical investigation: "Intramuscular Chloromycetin Succinate was ineffective in producing cure of the disease in four of four patients studied." The results of both studies were not submitted to FDA until March 5, 1969. They were received in the division of Anti-Infective Drugs on March 12, 1969. An evaluation was prepared by March 19, 1969, and presented to our Medical Advisory Board on March 28, 1969. The evaluation and the results of the Medical Advisory Board review were submitted to me on April 7, 1969. On the basis of these studies, I concluded that chloramphenicol sodium succinate is ineffective when administered intramuscularly. Although we have no clinical data, I would expect even less therapeutic effect when the drug is given by the subcutaneous route. On April 7, 1969, I notified Parke, Davis and Rachelle Laboratories as follows: 1. All further certification under the approved labeling of September 1968 is being suspended as of April 7, 1969. 2. All manufacturers are to revise labeling by April 14, 1969, using the following text in bold type: "Chloramphenicol Sodium Succinate is intended for intravenous use only. It has been demonstrated to be ineffective when given intramuscularly." 3. After the labeling has been approved, manufacturers will start by May 15, 1969, to replace all outstanding stocks on the market down to the user level bearing the September 1968 labeling. This replacement is to be completed by June 30, 1969. 4. All promotional material, including ads and/or written and oral instructions to the detail men, are to be submitted to FDA for approval no later than April 30, 1969. In the meantime, no promotional materials, including ads, are to be used until FDA approval had been received. All ads currently in process are to be canceled until such time. In addition, Parke, Davis was told to do the following: 1. Institute an immediate total recall of chloramphenicol succinate bearing any labeling in use prior to that approved in September 1968. 2. Issue a "Dear Doctor" letter by April 21, 1969. The text is to be submitted for approval by FDA no later than April 14, 1969. (A draft letter was submitted and discussed with FDA on April 11, 1969, and a revised draft approved by FDA on the same date.) This letter is to include the following: (a) A statement concerning the pre-1968 labeling which recommended intramuscular use. (b) A statement concerning the labeling changes initiated by FDA in 1968 limiting indications for the product to intravenous use and discouraging the intramuscular and subcutaneous uses. (c) A statement giving the results of the current study that Parke, Davis performed on Rocky Mountain spotted fever and typhoid fever which showed that the product, by the intramuscular route, is not effective. (d) The following statement from the new labeling: "Chloramphenicol sodium succinate is intended for intravenous use only. It has been demonstrated to be ineffective when given intramuscularly." (e) The letter shall commence with the prominent statement that chloramphenicol succinate is not effective by the intramuscular route. (f) A statement that chloramphenicol is not the drug of choice for any of the indicated conditions. Mr. Chairman, this brings us up to date on the actions that have been taken in regard to this drug, particularly the chloramphenicol succinate. I assure you that we will follow through to insure full compliance with the steps we have ordered to be carried out over the next several weeks. My staff and I will be happy to answer any questions you may have. Dr. LEY. I wish to direct my remarks chiefly to the problems of chloramphenicol succinate which I believe is your principal concern. Rachelle filed an IND to establish the safety and effectiveness of its chloramphenicol succinate for intravenous administration. Early in 1968 blood level data were submitted comparing Rachelle's and Parke, Davis' chloramphenicol succinate administered intravenously. Initially, it appeared that these data were adequate to justify certification. However, having experienced the variability of blood levels achieved with the use of capsules of different manufacturers, we reviewed information in our files and in the published literature to determine what was known about blood levels produced by parenteral forms of the drug when given by intramuscular, subcutaneous, or intravenous routes. On March 15, 1968, one of our medical officers summarized the results of this review. He reported that there were no significant blood level data on subcutaneously administered chloramphenicol succinate, and that the blood level data on intramuscular use showed results significantly lower than those achieved by the intravenous route. This led to a more critical review of the certification files on Parke, Davis' chloramphenicol succinate to determine what blood level and clinical data these contained to support the safety and effectiveness of the parenteral dosage forms. There was little meaningful clinical data in the files. We then concluded that parenteral forms of chloramphenicol, in order to be regarded as effective, would have to show blood levels. comparable to those achieved by oral administration. oramphenicol succinate pending resolution of the mat One. y 1968, Parke, Davis submitted two volumes of material, ely from the literature, to substantiate the efficacy of y and intravenously administered chloramphenicol suchave already noted, the blood level data from the literahelpful, and the clinical data incorporated in that file e. Thus, the future status of parenteral chloramphenicol o turn on either new blood level studies or the impendthe National Academy of Science-National Research group. 1968, representatives of Rachelle Laboratories met with of our Bureau of Medicine and Office of Certification cuss their firm's application for chloramphenicol sucere advised of the recent developments in our evaluaoduct and of our conclusion that there had to be conchloramphenicol succinate, without regard to who was the drug. -presentatives contended that FDA should either imfy their chloramphenicol succinate for intravenous use ts Parke, Davis had marketed prior to the suspension 's position, however, that we should not certify addiof chloramphenicol succinate for any manufacturer ving information on parenteral administration. But want to simply sweep chloramphenicol succinate off le these questions were being resolved. Chloramphenicol use only in extremely serious conditions, as you have ted this morning, Mr. Chairman. Critically ill patients, ildren, cannot always take a drug orally. This is when ust have an injectable form. o parenteral forms of chloramphenicol available. One, lution of chloramphenicol base, has the disadvantage amuscular injection or the risk of damaging veins on . The labeling for this product carries the statement, ded for pediatric use." The second parenteral form, l succinate, is much better tolerated and is the product. d in pediatric practice. obvious need to move as quickly as possible to resolve ved. On July 22, 1968, Dr. Minchew summarized the e, pointing out the need to expedite the report of the parenteral chloramphenicol. We asked that the report lit was. 1968, we received the NAS-NRC report on chloramvill arrange to submit copies for the record. (The inforI to appears on pp. 114-120.) The panel endorsed the ngs that we had required in May, emphasized the ise of this antibiotic, and recommended the use of less light of th review par obtained by istration. I phenicol as levels. On panel's find succinate v release on t use and caut New labe tember 3, 19 publication ing for the Particula is the fact name chlora cations were stated that recommende ment E of t mid-Novem Both Par the new labe chloramphen September 1 less accompa marketed ch amphenicol the discontin In your 1 explain why market of t distributed b On July 2 month suppl 13-month sup then that 6 w to prepare th tion to wareh Therefore. for intravend stood that a supply of ins consider a re the existing would move 37-327-7 hazardous agents where they could be expected to accomplish the desired therapeutic effect. We reexamined the labeling that had been developed in May for the various chloramphenicol preparations and concluded that the labeling for the parenteral forms required further revision in the light of the blood level data that were known to us. The Academy review panel had noted the higher and preferable blood levels obtained by intravenous use as compared with intramuscular administration. It recommended that the patient be shifted to oral chloramphenicol as soon as possible since these preparations gave better blood levels. On August 15, 1968, FDA publicly reported the Academy panel's findings and announced that certification of chloramphenicol succinate would be resumed after labeling was revised. The news release on this decision emphasized that this drug was for intravenous use and cautioned against intramuscular use. New labeling reflecting these recommendations was approved September 3, 1968, and subsequently was the subject of a Federal Register publication (October 19, 1968). I submit a copy of the revised labeling for the record. (See footnote on p. 7.) Particularly noteworthy here, as we indicated in the news release, is the fact that the product was designated by its official title or name chloramphenicol succinate for intravenous injection. The indications were to use the product for intravenous injection. The labeling stated that while intramuscular injection had been used, it was not recommended. This distinction was also incorporated into supplement E of the 1968 Physicians Desk Reference which was issued in mid-November 1968. Both Parke, Davis and Rachelle were notified in September that the new labeling had ben approved and that the FDA would certify chloramphenicol succinate on the basis of the revised labeling. Since September 1968, no chloramphenicol succinate has been certified unless accompanied by the new labeling. Rachelle had not previously marketed chloramphenicol in this form. Parke, Davis did have chloramphenicol succinate in distribution which had been certified prior to the discontinuance of certification on June 4, 1968. In your letter of April 4, Mr. Chairman, you asked FDA to explain why no action had been taken to assure the removal from the market of these lots of chloramphenicol succinate which had been distributed by Parke, Davis with the old labeling. On July 26, 1968, we had been advised that the company had a 4month supply of single-dose vials of chloramphenicol succinate and a 13-month supply of multiple-pack vials for hospital use. We were told then that 6 weeks would be needed, after the approval of new labeling, to prepare the new insert, package the product, and make the distribution to warehouses. Therefore, when the revised labeling for chloramphenicol succinate for intravenous injection was approved in September 1968, we understood that a small supply of single-dose vials, and a somewhat larger supply of institutional packages, remained in distribution. We did not consider a recall of this material essential because we anticipated that the existing stocks would be exhausted and that the new production would move out promptly with the revised prescribing information. 37-327-70-pt. 1-2 cases, ndications for intramuscular use still present in the minds harmacies. noted that at about this same time, in mid-November, ns Desk Reference mailed supplement E of its 1968 edihysicians in the United States. This included the new nformation for the Parke, Davis chloramphenicol succivenous administration. ber 30, 1968, the Bureau of Medicine sent a memorandum tigation, which was completed in early February 1969, ry 6, 1969, a representative of Parke, Davis met with Parke, Davis had underway the return of the old to its Detroit plant. On April 4, 1969, Detroit district ecked the Parke, Davis plant and determined that the was being properly handled. ing the labeling as ordered in September 1968, Parkeook two efficacy studies of chloramphenicol succinate. suggested to them by FDA representatives at a meet19, 1968, when it had become apparent that the blood product administered intramuscularly were much lower hieved by the capsules. ber 19, 1968, Parke, Davis submitted a protocol for a ain spotted fever study, and on October 31, 1968, a simior a typhoid fever study. amphenico treated wi and four v of the Par The res 1969, and we will fo have order I would be further bro are availab Mr. Fou Mr. Bro suggested t to he could text in the might be b he deleted transcript If there provide th questioning at a time, a will yield same sectio Mr. BRO Mr. For prepared s "The Febr must not be ment is ac |