in the absence
form of chlora

The Bureau of the drug must be are found to be la in the act. On thi succinate be susp previously approv nels. If we believ would demand re could be resolved. experience with th with apparent effi chloramphenicol, t blood level criteria courses of action made to define the And the three

No. 1. To take no tion apparently due No. 2. Recall or rently in commerci No. 3. Interim r knowledge and lack And then you which I don't bel (The entire tex

Mr. GRAY. Would you think it was in that early June period or later than that?

Dr. JENNINGS. I think it was probably later than that.

Mr. GRAY. It is a briefing memorandum to the Commissioner of Food and Drugs from MED-that is the abbreviation for the Bureau of Medicine "Subject: Status of chloramphenicol sodium succinate in the absence of the usual sort of evidence of efficacy for this parenteral form of chloramphenicol for intramuscular and subcutaenous use.

The Bureau of Medicine feels that the criteria used in judging oral forms of the drug must be applied. When this is done, all dosage forms of the succinate are found to be lacking in substantial evidence of efficacy as required and defined in the act. On this basis, the Bureau has recommended that certification for the succinate be suspended. This action has raised the question of the status of previously approved batches of chloramphenicol currently in commercial channels. If we believe a serious question of efficacy of the succinate exists, logic would demand recall or some form of embargo of the drug until the question could be resolved. Such an action, however, would be made in the face of long experience with this form of the drug by many doctors for a variety of conditions with apparent efficacy. To complete the picture, there is a parenteral form of chloramphenicol, the base, certified for intravenous use only, which satisfies the blood level criteria applied to the oral dosage forms. It would appear that three courses of action are open to the agency. These will be listed with an attempt made to define the pros and cons of each.

And the three courses of action listed, I won't read except the title: No. 1. To take no further action pending receipt of the NAS-NRC recommendation apparently due in about one week.

No. 2. Recall or embargo on all previously approved batches of succinate currently in commercial channels.

No. 3. Interim relabeling of previously certified succinate to reflect current knowledge and lack of knowledge regarding efficacy.

And then you list the pros and cons of these three courses of action, which I don't believe we have to read into the record, Mr. Chairman. (The entire text of the document follows:)

STATUS OF CHLORAMPHENICOL SODIUM SUCCINATE

In the absence of the usual sort of evidence of efficacy for this parenteral form of chloramphenicol for intramuscular and subcutaneous use, the Bureau of Medicine feels that the criteria used in judging oral forms of the drug must be applied. When this is done, all dosage forms of the succinate are found to be lacking in substantial evidence of efficacy as required and defined in the act. On this basis, the Bureau has recommended that certification for the succinate be suspended.

This action has raised the question of the status of previously approved batches of chloramphenicol currently in commercial channels. If we believe a serious question of efficacy of the succinate exists, logic would demand recall or some form of embargo of the drug until the question could be resolved.

Such an action, however, would be made in the face of long experience with this form of the drug by many doctors for a variety of conditions with apparent efficacy.

To complete the picture, there is parenteral form of chloramphenicol, the base, certified for intravenous use only, which satisfies the blood level criteria applied to the oral dosage forms.

It would appear that three courses of action are open to the agency. These will be listed with an attempt made to define the pro and cons of each.

POSSIBLE COURSES OF ACTION

1. Take no further action pending receipt of NAS/NRC recommendations apparently due in about 1 week.

2. Recall or embargo of all previously approved batches of succinate currently in commercial channels.

3. Interim relabeling of previously certified succinate to reflect current knowledge and lack of knowledge regarding efficacy.

Discussion of possible courses of action.

1. Defer action pending receipt of NAS/NRC recommendations.

Pro-NAS/NRC findings provide acceptable basis for action. Findings by NAS/NRC of "effective" could be accepted to resolve problem without further difficulty. Finding of "ineffective" could provide firm basis for withdrawal of NDA.

Con-We may not be allowed to wait-matter has already received publicity and aroused congressional interest.

Waiting cannot be defended on logical, medical or legal grounds.

2. Recall or embargo.

Pro-In keeping with what we know; in keeping with our usual reaction to such a situation; medically defensible; legally defensible.

Con-Removal of succinate leaves no parenteral preparation available (under current labeling) for "children."

NAS/NRC recommendations may be contrary to this action.
Medical opinion may be against us in view of long experience.

3. Relabeling of previously certified succinate.

Pro-In keeping with what we know involves medical community in question; keeps a possibly effective drug on market for serious condition; further restricts already restrictive labeling; directs attention alternate drugs; might decrease overall use of chloramphenicol; leaves a parenteral form available for "children." Con-Contrary to our usual reaction to such a situation; may be contrary to act; keeps on market a drug not proved to be effective; may be confusing to medical practitioners; labeling acceptable to manufacturers difficult to write.

Selection of action 2 or 3 would require appropriate notification to medical community and public.

DEAR DOCTOR: The FDA has requested the manufacturer(s) of chloramphenicol sodium succinate to recall (embargo) all supplies of the various dosage forms of this parenteral form of the drug. This action was taken because recent review of the data submitted to the FDA in accordance with the provisions of the FD&C Act revealed no substantial evidence of efficacy of this parenteral form of the drug as required and defined by the act.

Recognizing that a perenteral form of chloramphenicol might at times be desirable and perhaps lifesaving, the FDA directs your attention to the intravenous form, available as the base. Recently revised labeling for this form of chloramphenicol is enclosed. Your particular attention is invited to the dosage schedule and the notation that the drug is not recommended for children under 6 (or 12, or 3) years of age. If an antibiotic encompassing a spectrum similar to that of chloramphenicol is needed for a patient in the age range mentioned, consideration should be given to the following drugs: amphicillin, etc., etc.

The FDA is interested in reports of adverse reactions to all drugs. A facsimile of the standard reporting form (1639) is reproduced on the last page of this letter. Additional copies may be obtained by writing Bureau of Medicine, FDA, Washington, D.C. ZIP.

Mr. FOUNTAIN. I might say it is not your handwriting, Doctor, that is causing us trouble. This is a mimeographed copy of what appears to be a very good hand. It would appear from this memorandum that the course of action that you favored was that of recalling the outstanding stocks of drugs, is that correct?

Dr. JENNINGS. Yes, sir. I want to emphasize again that this is a rough draft of a document which was never finalized, and, in essence, represents my personal summary of what I felt was available to us, and the course of action that I personally advocated, but that it was never formalized into a recommendation to the Commissioner.

Mr. FOUNTAIN. What did you do with the memorandum and why did you not put it into a formal recommendation?

Dr. JENNINGS. All I can tell you is in the course of discussions it became apparent that we were going to the Bureau, the Agencywe were going to relv rather heavily on the recommendations of the NAS-NRC who were reviewing this product for efficacy in all of its

dosage forms. Therefore, it seemed without purpose to prevail in advocating a course of action that was not going to be undertaken.

Mr. FOUNTAIN. But you still thought that was the course of action that should be taken?

Dr. JENNINGS. Yes, that was my personal opinion.

Dr. LEY. Mr. Fountain, there is one additional fact that I think has to be included in the evaluation of this briefing memo. I learned to my surprise that this fact is not at present incorporated in the labeling for the aqueous chloramphenicol solution. I happen to be aware of the fact, because I was involved in some of the early exploratory work with this same product in treating tropical diseases. The aqueous solution on intramuscular injection is essentially intolerable. It is exceedingly painful. The aqueous solution furthermore has a very strong tendency to obliterate veins when it is given intravenously. This is not, as I say, in the present labeling for the product. The wording that is in the present labeling is it is not recommended for pediatric use. I think this is an understatement as well. Any product with these characteristics would not be acceptable in pediatric use. So, what we have here essentially is a situation in which as far as parenteral nonoral forms of chloramphenicol are concerned for treatment of acute illness, the succinate is, particularly for the pediatric use, the only product that is tolerated at all well by the patient. In the adult, the aqueous form can be administered intravenously if you are willing to lose the veins and keep going for other veins. But it is not a useful product in children. So, this fact I think should have been included among the pros and cons and the discussion in the briefing memo. Mr. GRAY. I don't know what the basis is for the statements you are now making, but in the course of reviewing your files on this aqueous injectable product, which goes back a long time, we came across a number of studies that I think bear on this point. The first is by Dr. Harry B. O'Rear, Medical College of Georgia, letter transmitted January 17, 1952. The number of patients in the study was 42, age 1 month to 12 years. He talks about intramuscular injection, and he says: "The induration and redness around the injection site was no more severe than that noted with repeated injections of procaine penicillin. No sterile abscesses developed and the induration subsided after discontinuance of the drug. Many of these children have subsequently been followed in the pediatric clinic and no atrophic or fibrotic changes have been found."

Then he concludes: "Parenteral chloramphenicol 25 percent and 50 percent acetyl dimethylamine has been administered to 42 children by the subcutaneous, intravenous, and intramuscular routes. Preparation has been found to be safe and effective."

Dr. LEY. That is an intermediate product that I do not believe is on the market.1

Mr. GRAY. It is the same product using a different base, is it not? But there are some others.

Dr. LEY. Go ahead.

Mr. GRAY. There is one from Children's Hospital, Buffalo, Dr. Erwin Neter. The covering letter says: "Enclosed please find another summary table of 21 additional cases treated with Chloromycetin in

1 Subsequently. Dr. Ley acknowledged that the drug referred to in these studies is the same as the chloramphenicol aqueous solution currently on the market. (See p. 93.)

tramuscularly. I think the most remarkable fact is that none of these patients had any side effects. The drug was well tolerated even by a 3-day-old infant. Second, four cases of meningitis improved following the use of this drug. From our own experience it is evident that this preparation is well tolerated in infants and children and is of real clinical value."

There is another study from Drs. Moseley and Barcody of Charleston, S.C.: "A report on the safety and therapeutic effectiveness of parenterally administered chloramphenicol by the intramuscular and intravenous routes." It gives the dosage, which is "prepared in ampoule form in a concentration of 0.5 gram per 2 cc. of solvent. For intravenous use this preparation may then be added to solutions of 5 percent glucose in physiological saline solution, or to solutions of glucose and distilled water, in proportion of 0.5 gram to 1 gram of Chloromycetin, per 2 to 4 cc. of acetyl dimethylamine per 250 to 500 cc. of glucose or saline solution, and at this dilution strength it may be given intravenously very safely. To date, we have employed chloromycetin intravenously in 11 patients and have observed no ill effects."

Mr. FOUNTAIN. We have got to cut off somewhere. Is this a good point?

Mr. GRAY. There is more of the same sort of thing.

There is one reference on the other side which says that 45-this is a different study by Drs. Burnell and Kirby of Washington. Mr. FOUNTAIN. If there is no objection, all of these will go in the record.

(The documents referred to follow :)

MEDICAL COLLEGE OF GEORGIA,
Augusta, Ga., January 17, 1952.

Dr. CHARLES N. LEWIS,

Federal Security Agency,

Food and Drug Administration,

Washington, D.C.

DEAR DR. LEWIS: Due to unexplainable circumstances, the enclosed report on our use of parenteral Chloromycetin which was compiled last fall was never sent to you.

You will note that the majority of our patients received the product intramuscularly.

Sincerely yours,

HARRY B. O'REAR, M.D.

THE USE OF PARENTERAL CHLOROMYCETIN IN INFANTS AND CHILDREN This report of our investigation of a parenteral form of Chloromycetin was undertaken with the cooperation of Parke, Davis. The period of investigation being reported was from December 1950, through July 1951.

The form of drug used was 25 percent crystalline Chloromycetin in 50 percent Acetyl dimethyl amine. This solvent was necessary because Chloromycetin possesses neither acidic nor basic groups capable of forming salts soluble in aqueous?

ROUTE OF ADMINISTRATION

1. Intravenously as a 0.25 to 5 percent solution in saline or saline and glucose mixtures. To mix the Chloromycetin-acetyl-dimethylamine solution with an aqueous media requires some care. The Chloromycetin must be withdrawn into a dry syringe and then injected into the saline or saline-glucose mixtures beneath the surface to prevent crystallization.

2. Subcutaneously as a 0.25 percent solution with or without hyaluronidase. 3. Intramusuclarly as the undiluted ampoule material. Administration at our clinic has been given in alternate gluteal muscles.