Dr. SMITH. That would have been done before in the actual handling of the supplement, by the medical officer. Mr. GRAY. Has it always been the practice to do this automatically? Dr. SMITH. I would say that it has always been done. Mr. GRAY. Then how do you account for the fact that it was not done in the cases we are discussing? Dr. SMITH. Well, that is something I can't account for. Mr. GOODRICH. The comparison was made. Three of them were the same. The fact that you didn't catch the dropping of these words on two copies is what happened here. But there is no indication. that comparison was not made. Mr. GRAY. I am not just referring to the one supplemental application where there were three of one kind and two of another. There were several other supplemental applications where changes were made in the labeling, including the giving of positive statements about the occurrence of hepatitis, which was a definite and significant change in the labeling, but which were not detected. In these cases there was no question of the five copies being dissimilar; they were all alike. Mr. GOODRICH. And all of them were submitted in settings of supplements that had other emphasis in them. Mr. GRAY. All I am asking is whether you compare what is submitted with what is in effect? Mr. Moss. Will you yield here? I think Mr. Larrick has agreed to check this matter, to make certain they have policies now in effect which would insure against five different reviews that must be made on the five copies submitted, that there could be no possibility of a dissimilar copy being run in and evaluated by one person without the other having knowledge of the dissimilarity. And he is to submit to the committee details as to whether or not procedures guard against this. Mr. LARRICK. That is correct. Mr. GRAY. I understand that, Mr. Moss. That was not my question. My question was whether, at the time a supplemental comes in, there is in existence some approved labeling for this product, against which the proposed labeling in the supplemental application is automatically compared? In some of the cases we examined this morning there was no question that all five copies of the proposed labeling were the same. But apparently these were not read and compared with the existing labeling. I am trying to determine whether there is any system whereby FDA sees, not only that the five copies are identical, but also what changes are made in the proposed labeling as opposed to that which is currently approved. Apparently you gentlemen cannot say this was done with certainty in some of these cases. Mr. FOUNTAIN. Mr. Larrick, in response to my earlier question as to whether or not you had requested additional medical officers in the period 1956 through 1959, I believe you responded with the figures on your overall request including persons other than doctors. Do I understand that you will get this information and clarify it for the record? Mr. LARRICK. If it is available, Mr. Fountain. I don't know whether the breakdown is available in the form in which Dr. Goldberg asked for it. If it is agreeable to you, I will give you whatever there is. Mr. FOUNTAIN. All right. Mr. LARRICK. Mr. Brandenburg has a statement. Mr. BRANDENBURG. We attempted to obtain the breakdown in the fashion you are seeking and we have been unable to come up with those figures as of yet. Mr. FOUNTAIN. What I am primarily interested in is what you went before the Appropriations Committee and requested and what you got. (The information referred to follows:) The following table shows the numbers of medical officers and veterinarians requested in the President's budget for the years 1955 through 1959. Each request was granted by the Congress. Mr. LARRICK. I can tell you the Appropriations Committee in general gives us what we ask for. Way back, just before I took over, they cut us back and cut us back hard, just before all of this stuff happened. We went through a period when we antagonized some people on the Appropriations Committee and by virtue of that, they cut our appropriation and cut it drastically and as a result of that, my predecessor had to fire a lot of his scientists. Then that caught us at a time when we had great responsibilities put upon us and we had a double handicap: One, we had been cut back, and two, we had the reputation in the scientific community of being a place that was bad to take a job in, because you might get riffed. But since 1954 our appropriations have gone steadily upward and we have been treated-well, not as well as I would have liked to be treated, but rather well. Mr. FOUNTAIN. I note that in January 1956, in hearings before the House Appropriations Committee, you requested one additional medical officer, a GS-14, in the Medical Division. According to page 65 of the hearing record you were asked: "On the basis of what you know at the present time, what do you think you need in that [New Drug] Division?" And you responded by saying, "I think we may need one additional officer and in the succeeding years we would plan to request more." Is that correct? Mr. LARRICK. I don't remember, but I was speaking as an officer of the Department, if I go before the Budget Bureau, I speak for the Department. Mr. FOUNTAIN. Incidentally, in connection with your testimony here, all of us realize that although you are head of the agency, you don't personally do all of these things, and of necessity may have to call upon your colleagues to respond to some of these questions. Mr. LARRICK. Thank you very much indeed, but I still have to take the responsibilities for it. Mr. FOUNTAIN. We understand that. And we will probably treat you in that way. But I do think the record ought to indicate you can't make every individual decision. I understand that we must be out of this room by 1 o'clock, so we have to operate fast. I have one more question. While the supplemental application for Flexin was being considered by the Food and Drug Administration, a field office inquiry concerning a suspected case of liver damage due to Flexin, was referred to the New Drug Branch by the Bureau of Field Administration. In responding to this inquiry one medical officer made this statement, and I quote: "I am not aware of Flexin causing a toxic hepatitis." And two other medical officers indicated that they agreed with his remarks. I ask that the FDA memorandum concerning this inquiry be made a part of the record. You are familiar with this? Mr. LARRICK. I am not, but I take your word for it. Mr. FOUNTAIN. I refer to it primarily for the purpose of asking: What is your explanation for the fact that three of your medical officers were not aware, in October 1959, of the company's statements in the supplemental new drug applications of June 1958 and September 1959, specifically calling attention to reports of hepatitis in association with the administration of Flexin? Mr. LARRICK. What is the date, may I ask? I think you will find the date on the top. I believe it is October 6, 1959. Mr. FOUNTAIN. I am referring to the new drug applications of June 1958 and September 1959. Mr. LARRICK. May I ask, "Did this document come from our new drug file or our factory file?" Mr. GRAY. I believe it came from the factory file. Mr. LARRICK. Mr. Chairman, I am not prepared to answer this question. If I may, I would like to study the document and see who the medical officers were and see whether or not we can prepare an answer for you. Mr. FOUNTAIN. We would be happy to give you an opportunity to examine the document and respond to that question. (The document is as follows:) EXHIBIT 22--INTRA-AGENCY MEMORANDUM REGARDING SUSPECTED CASE OF LIVER DAMAGE DUE TO FLEXIN To: Dr. SMITH (N.D.). For comment on this suspected case of liver damage due to Flexin of McNeil Labs. B.F.A./Cribbett. (Response:) October 7, 1959: I am not aware of Flexin causing a toxic hepatitis although more and more drugs are becoming implicated and for that reason this possibility cannot be ruled out. The clinical history does not favor a toxic hepatitis which is often rather acute in onset, progression of symptoms, etc. Her history goes well with infectious hepatitis-virus A type-and although she denies venepuncture, injections, etc., it might still be virus B in Etiology. The liver function tests do not permit a differential diagnosis between extrahepatic or intrahepatic obstructive (cholangiolytic) jaundice and I do not agree with the reservations placed on the interpretation of the alk phosphatase. This patient could still have a resolving viral hepatitis and by no means have they excluded extrahepatic obstruction. The clinical course of the pt. will have to be further followed to clarify the diagnostic problem and, of course, liver biopsy might give further diagnostic information. To D.D.B. & R.R.B. for comment. I.S./N.D.B. Agree with Dr. Siegel's remarks. I agree with the above. J.W.N./R.R.B. Intra-Administrative Referral. Issuance date: December 14, 1959. To: Bureau of Field Administration. The latest report on the liver case goes along well with my "armchair diagnosis" remarks of October 7, 1959 in that this probably was not due to Flexin. The IV cholangiagrams & G.B. series go along with extrahepatic obstructive jaundice and not drug hepatitis. I do not feel further follow up is worth while or indicated on this case. I.S./N.B.D. Mr. FOUNTAIN. Are there any further questions? If not, the committee stands in recess until tomorrow morning at 10 a.m. (Whereupon, at 12:55 p.m., the subcommittee was recessed, to reconvene at 10 a.m., Wednesday, April 29, 1964.) DRUG SAFETY (Part 2) WEDNESDAY, APRIL 29, 1964 HOUSE OF REPRESENTATIVES, INTERGOVERNMENTAL RELATIONS SUBCOMMITTEE OF THE COMMITTEE ON GOVERNMENT OPERATIONS, Washington, D.C. The subcommittee met at 10 a.m., pursuant to recess, in the caucus room, Cannon Office Building, Hon. L. H. Fountain (chairman of the subcommittee) presiding. Present: Representatives L. H. Fountain, J. Edward Roush, 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 Operations. Mr. FOUNTAIN. Let the subcommittee come to order and the record show that a quorum is present. Mr. Larrick, just before we recessed yesterday I asked you a question which you said you would respond to this morning. For the benefit of those who may not recall the question, I will ask it again. While the September 1959 supplemental application for Flexin was being considered by FDA, a field office inquiry concerning a suspected case of liver damage, due to Flexin, was referred to the New Drug Branch by the Bureau of Field Administration and in responding to this inquiry, one medical officer made the statement: "I am not aware of Flexin causing a toxic hepatitis." And two other medical officers, I believe, indicated that they agreed with this remark. The FDA memo concerning this inquiry was placed in the record yesterday. My question was this: How do you account for the fact that three of your medical officers were not aware in October 1959 of the company's statements in the supplemental new drug applications of June 1958 and September 1959, specifically calling attention to reports of hepatitis in association with the administration of Flexin? STATEMENT OF GEORGE P. LARRICK, COMMISSIONER, FOOD AND DRUGS; ACCOMPANIED BY WINTON RANKIN, ASSISTANT COMMISSIONER; R. C. BRANDENBURG, STAFF OFFICER; DR. RALPH G. SMITH, DIRECTOR, DIVISION OF NEW DRUGS; DR. BERT J. VOS, DIRECTOR, DIVISION OF TOXICOLOGICAL EVALUATION; AND WILLIAM W. GOODRICH, ASSISTANT GENERAL COUNSEL Mr. LARRICK. As you have pointed out, Mr. Chairman, at the close of the meeting yesterday you introduced into the record two exhibits 621 |