(The documents referred to follow :)

From: FDA/DET-DO Thomas W. Brown, Director.

To: FDA/CC-100/Washington, D.C. Attention: R. C. Brandenburg.

I spoke by phone with Dr. Lueck of Parke, Davis on Monday, April 7, who stated firm was taking immediate steps to comply with points 2 and 5 of Commissioner's TWX same date.

Proposed letter to salesmen was obtained April 9, 1969. Letter read in part, "The Food and Drug Administration wishes to recall. .." The letter did not indicate reason for recall other than it was to remove from the market product bearing labeling prior to September 1968 showing intramuscular administration. Letter instructed salesmen to inventory customer's stock and authorize return of product with the "old" labeling.

We objected to their letter as not being forthright and informative and to their proposed procedure as not being effective. If the Parke, Davis proposal was followed, dealers would not know why product was being recalled and the burden of returning stock would be placed upon them with little assurance it would be handled promptly. Parke, Davis states they have over 1,000 representatives who would be able to contact all accounts in about 3 weeks. Parke, Davis at first stated that their representatives had other work to do and could not pick up product as we suggested. We did not buy this and gave them the alternative of either sending recall letter to all accounts or having Parke, Davis representative pick up product. They agreed to latter which we believe will be as effective. This, of course, is in addition to the dear doctor letter.

We recommended letter to Parke, Davis representative be flagged, “urgent recall," and revised to specify the reason for the recall, instruct salesmen to inform customers of the reason, and instruct detail men to pick up products bearing "old" labeling.

On April 10, 1969, firm was revisited and the amended letter to salesmen reviewed. Letter was flagged, "urgent recall," and read, "The Food and Drug Administration has requested . . . their intent is to assure that Chloromycetin sodium succinate will not be used intramuscularly on the basis of their contention that it is ineffective by this route of administration." Firm would not agree to following wording indicating concurrence with FDA's evaluation: "Clinical data now shows the product is not effective in the treatment of typhoid and rocky mountain spotted fever when given intramuscularly."

Letter did not instruct salesmen to inform customers of reason for recall. Management finally agreed to add statement, "This explanation should be given to the customer at time of contact."

We expect Parke, Davis to notify defense medical supply, Philadelphia, Pa., of recall by letter and include copy of Commissioner's TWX and letter to firm's salesmen. Domestic military installation covered in firm's letter to salesmen.

There has been international distribution from Detroit under labeling bearing instructions for I-M administration. Parke, Davis states this labeling is satisfactory to countries where shipped. Limited amounts went to Hong Kong, Beirut, Bahamas, Belgium, Jordan, Iraq, Iran, and Kenya. Major quantity went to firm's Panama branch warehouse for distribution in Latin and Central America. According to information provided, there are about 3,800 250 mg. vials and 245,000 1 gm. vials of this product which have been returned to Detroit or is in route from branch warehouses and an estimated 50,000 vials of product (both 250 mg. and 1 gm. vials) beyond that point.

PARKE, DAVIS & CO., Detroit, Mich., April 21, 1969.

DEAR DOCTOR: At the direction of the Food and Drug Administration, Parke, Davis & Co. is informing you of an important change in the labeling of Chloromycetin (chloramphenicol) sodium succinate based on results of two studies which the Food and Drug Administration believes demonstrate that Chloromycetin sodium succinate is not effective by the intramuscular route.

In one study Chloromycetin sodium succinate was given intramuscularly to nine male subjects with induced (experimental) Rocky Mountain Spotted Fever; 1 gram was administered every 8 hours for 7 days with a single dose on the eighth day. The treatment was effective in five patients. The remaining four patients had a variable response but subsequently relapsed. All four relapses responded to treatment with another antibiotic orally.

Eight volunteers were infested orally with the Quailes strain of Salmonella typhosa. Four volunteers were treated with Chloromycetin sodium succinate

given intramuscularly, 1 gram every 8 hours and four were treated with oral Chloromycetin Kapseals, 1 gram every 8 hours. Therapy was carried out for 7 days, interrupted for 7 days, and reinstituted for a final 5 days. The patients treated with oral Chloromycetin Kapseals showed a prompt response to treatment which in three of the four patients resulted in a clinical cure. The fourth patient required a second course of treatment with oral Chloromycetin which produced a cure. This is in keeping with a known relapse rate of this disease under adequate treatment. The four patients receiving Chloromycetin sodium succinate given intramuscularly showed an initial satisfactory response but all four subsequently relapsed with a recurrence of signs and symptoms of typhoid fever 16 to 32 days following the end of treatment. All four then showed clinical response to oral Chloromycetin.

In light of the results obtained in these studies, the FDA has directed that the package insert be amended to include the following statement:

"Chloramphenicol sodium succinate is intended for intravenous use only. It has been demonstrated to be ineffective when given intramuscularly."

Product containing the revised labeling will soon be available and stocks of product with current labeling will be replaced.

The earlier labeling for Chloromycetin sodium succinate permitted intramuscular, intravenous or subcutaneous use. In September 1968, the package insert was changed to limit chloramphenical sodium succinate to intravenous use. The use of the product by the intramuscular route in emergency situations was referred to, but this route was not recommended because lower blood levels were obtained and there was a lack of evidence of efficacy when given by this route. It further stated that patients started on intravenous drug should be changed to the oral form as soon as practicable.

We have also been directed to remind you that chloramphenicol is not the drug of choice in any indication. It must be used in strict accordance with the warnings and indications of the package insert.

PARKE, DAVIS & Co.,

L. M. LUECK, Ph. D., Vice President, Quality Control, and Government Regulations.

Mr. GRAY. Just one question. It is jumping ahead somewhat, but because you said the warning letter should go out on the 21st, which will be Monday, before we get together again, I was just wondering how you are proposing this letter be sent?

Dr. LEY. We are proposing this letter be sent by first class mail with, as I recall it, the red-drug warning label.

Mr. GRAY. I was wondering in view of all of the past history and so on, and the urgency of the matter, if you had given any consideration to perhaps sending it by certified mail.

Dr. LEY. As the automobile manufacturers are doing these days? This is the technique they use, I understand.

Mr. GRAY. Have you given consideration to that possibility? Dr. LEY. This has not been given consideration in terms of requesting the firm to do this. We have discussed this on several occasions in the past with regard to letters which we mail.

Mr. GRAY. The reason I bring it up, referring again to that Yarrow decision, which Mr. Goodrich and I discussed, I believe there is an interesting section in the decision of the appellate court in which finds that the manufacturer had not made all reasonable efforts because they could have at least sent the warning letters certified mail so they would be sure they were received. You might want to consider that. Mr. GOODRICH. We are developing a policy to implement the Yarrow decision.

Mr. FOUNTAIN. Any other questions today?

(No response.)

Mr. FOUNTAIN. Thank you very much. The committee stands recessed until 10 o'clock Tuesday morning.

(Whereupon, at 11:25 a.m., the hearing was adjourned to reconvene at 10 a.m. Tuesday morning, April 22, 1969.)

DRUG EFFICACY

(Part 1)

TUESDAY, APRIL 22, 1969

HOUSE OF REPRESENTATIVES,

INTERGOVERNMENTAL RELATIONS SUBCOMMITTEE

OF THE COMMITTEE ON GOVERNMENT OPERATIONS,

Washington, D.C. The subcommittee met, pursuant to recess, at 10:12 a.m., in room 2203, Rayburn House Office Building, the Honorable L. H. Fountain (chairman of the subcommittee) presiding.

Present: Representatives L. H. Fountain and Guy Vander Jagt. Professional staff present: Delphis C. Goldberg, W. Donald Gray, and Robert S. McCleery, Intergovernmental Relations Subcommittee, and William P. Russell, assistant minority counsel, Committee on Government Operations.

Mr. FOUNTAIN. Let the subcommittee come to order and the record show that quorum is present for the purpose of taking testimony. FURTHER TESTIMONY OF DR. HERBERT L. LEY, JR., COMMISSIONER OF FOOD AND DRUGS, CONSUMER PROTECTION AND ENVIRONMENTAL HEALTH SERVICE, PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE; ACCOMPANIED BY WILLIAM W. GOODRICH, ASSISTANT GENERAL COUNSEL, HEW; J. KENNETH KIRK, ASSOCIATE COMMISSIONER FOR COMPLIANCE; B. HARVEY MINCHEW, M.D., ACTING DIRECTOR, BUREAU OF MEDICINE; JOHN JENNINGS, M.D., ACTING DEPUTY DIRECTOR, BUREAU OF MEDICINE; JEAN LOCKHART, M.D.; EDWIN M. ORTIZ, M.D.; ROBERT C. BRANDENBURG; AND MORTON M. SCHNEIDER, ALL OF FDA

Mr. FOUNTAIN. Dr. Ley, getting back to your statement last week before the subcommittee, on page 11 you note that Rachelle Labs complained in November 1968 that Parke, Davis was continuing the claim that their product could be used by more than one injectable route of administration while pointing out that Rachelle's product was for intravenous use only.

And on page 12 you again referred to the Rachelle complaint in connection with a December 30 memorandum from the Bureau of Medicine.

Our review of the files reveals that, in fact, there was a series of complaints from Rachelle during this period, and it may be that you

were not trying to cover all of them. I believe it would be instructive, however, to read into the record at this point some relevant excerpts from Rachelle complaints and the FDA inspection reports following up on these complaints.

Mr. Gray, will you read those excerpts?

Mr. GRAY. First is a letter from Rachelle Labs to Dr. John Jennings, Acting Director, Bureau of Medicine, dated November 27:

DEAR DR. JENNINGS:

... we are running into problems in the sale of our sterile chloramphenical sodium succinate U.S.P. i.v. in that we are trying to compete with chloromycetin sodium succinate U.S.P. sterile vials that are labeled for i.v., i.m., and subcutaneous use. We are receiving an increasing number of complaints from our sales representatives stating that doctors in their hospitals are insisting on chloromycetin sodium succinate as opposed to our iv. use only product because the Parke, Davis vial can be used i.v., i.m., and subcutaneously.

As we are dealing with chloramphenicol, we feel it is dangerous to permit this product to be sold for these three routes and that the FDA should take action to recall all Parke, Davis chloromycetin so labeled and replace with chloromycetin for i.v. administration only. There are enough problems with the use of choramphenicol without adding the inherent dangers of having two routes of administration which the FDA has rejected.

The next is a memorandum from Inspector Clifford Broker, Baltimore district, dated December 3, 1968, subject: "Complaint on Parke, Davis' chloramphenicol."

On November 29, 1968, Mr. Armond Welch of the Office of New Drugs called to request that we obtain information relative to the use of Parke, Davis' chloramphenicol by the Washington Sanitarium, Takoma Park, Md.

On November 29, 1968, I talked to Mr. Wilford A. N. Wilson at the Washington Sanitarium. According to him, Washington Sanitarium had ordered and received 200 vials of chloramphenicol from Rachelle Labs, Long Beach, Calif. When these were distributed to the wards, the nurses complained because the physicians had ordered the drug given i.m. and Rachelle's label indicated only i.v. The nurses had been used to Parke, Davis' chloramphenicol, the labels of which indicated that same can be used i.v., i.m., and subcutaneously.

Another letter from Rachelle Labs, December 19, 1968, again to Dr. John Jennings:

Confirming our telephone discussion of this date, we greatly appreciate your decision to have a representative of the FDA contact the administrator of pharmaceutical services of the Union Hospital in the Bronx, N.Y., regarding sterile chloramphenicol sodium succinate U.S.P. i.v. He is a Mr. Daniel Fruchter...

Mr. Fruchter refuses to consider our chloramphenicol sodium succinate i.v. (MYCHEL-S) as he claims that the Parke-Davis product, chloromycetin sodium succinate U.S.P. is labeled for i.v., i.m., and subcutaneous use.

Your comment that you expect to have a definitive solution in the near future is greatly appreciated. Anything that can be done in this can only have the effect of benefiting the public in view of the FDA decision in August as to the proper labeling for this product. It will also eliminate an unfair situation in which Rachelle Laboratories, Inc., is encountering many difficulties in the competitive sale of sterile chloramphenicol sodium succinate i.v. because of Rachelle's proper and FDA approved labeling as opposed to the mislabeled Parke, Davis product. This is an FDA inspector's report, from Carlos Perez, chief, Brooklyn section, dated January 7, 1969:

On January 6, 1969 *** I visited Union Hospital *** Bronx, N.Y. ***

Mr. H. Kaplan, hospital pharmacist... stated that he purchases drugs from both Rachelle Labs and Parke, Davis, Inc. However, he stated that the chloramphenicol presently is purchased from Parke, Davis because of the fact that the