Dr. GODDARD. The law does permit the distributor label, as Mr. Goodrich points out. Mr. DINGELL. Apropos of that question, Doctor, is it not really important so that you can make some objective judgments? Let us say drug X, manufactured by companies A, B, and C, is going to be exactly the same, but you might be able to make the projection that in the case of A and B, it is going to be the same in the case of its therapeutic effects or that A and B are going to be the same. So you can, not only to the distributor, but to the manufacturer, prescribe that it is going to have the same therapeutic equivalency; can you not? Dr. GODDARD. No, sir. Mr. DINGELL. You can on the tests Dr. GODDARD. The certification program, where the manufacturer submits samples, provides a reasonable measure of assurance that there is therapeutic equivalency. But that does not even provide complete assurance, Mr. Dingell. Mr. DINGELL. I would envision, and I sat on the committee that wrote the amendments that you have discussed, that therapeutic equivalency was one thing that was in the minds of the legislators at the time they put that piece of legislation together. Dr. GODDARD. No question, sir. Mr. DINGELL. The problem would really appear to be that scientific and technical capabilities at this time are not such that we can project that judgment absolutely. But you indicate that your agency is moving in that direction. Dr. GODDARD. Oh, yes. We have already started studies of therapeutic equivalency in the category of antibiotics. I think in a matter of months we can have the majority of these most frequently prescribed agents checked in the general sense, determining whether or not we have a problem. Mr. DINGELL. This will include, however, certain judgments with regard to sound manufacturing practices, too. Dr. GODDARD. Yes. Mr. DINGELL. And the same manufacturing practices and circumstances are involved in those same drugs in each instance which may require very nearly standard manufacturing practices? Dr. GODDARD. It may well. Mr. POTVIN. Doctor, I understood that counsel stated that the fact that it is distributed by United Research Laboratories may be revealed, but that you have no authority to require both. Dr. GODDARD. That is correct. Mr. POTVIN. Yet I find in your weekly recall report-I happen to have one for September 13 through September 19 in hand-there are three separate items: first, the label name, in this case Armour Pharmaceutical Co., a rather well-known manufacturer; secondly, the manufacturer's name, which surprisingly was not Armour in this instance it was Nysco; and thirdly, the name of the company responsible for handling recall, and designated as handling the packager, which is again, Armour. In this instance, you seem to have no difficulty in going both ways, the manufacturer and the distributor. Dr. GODDARD. I would have to ask you to look and see if that was a voluntary recall. It should indicate there. Mr. PorVIN. Yes, it was. Dr. GODDARD. You see, the firm itself provided us with the information, as we can and do require them to do in the course of our normal inspections. Mr. POTVIN. Well, do you feel that it would require legislation for you to be able to require information of this kind first on the label! Dr. GODDARD. Yes. Mr. POTVIN. How would you feel about also requiring it in the adverstisement? Particularly I am talking about advertisements to the trade, now. Dr. GODDARD. I do not really think that it gives anybody any greater assurance. These problems can and do occur with large companies as well as small. Mr. POTVIN. Now, you say that there is not precise therapeutic equivalency, from which I infer that if eight firms are making a given product, there would be some that were, in your view, suitable, and some that were not suitable. Dr. GODDARD. What I am really saying is we do not know that today. We have set about on a program of research that will answer that question for us. We have also set about revising and updating good manufacturing practices. Now, it may become necessary, as the chairman points out, to ultimately get down to standard manufacturing practices and then place the burden upon the manufacturer. Then if he wishes to deviate from the standard, he must show that he can produce a product that is therapeutically equivalent with the drug produced by a different manufacturing practice. Mr. POTVIN. Doctor, of course, one of the claims that the committee and, I would presume, your agency is confronted with is the claim by the larger firms in the industry that they have a sort of quality assurance or, if you will, a quality that is lacking in less known products. So do you not feel that the pharmacists and the physicians dispensing, say, the tetracycline in that ad, might be a bit more com fortable if they knew the dosage form fabricator was Squibb, Wyeth, or Merck, and so on? Dr. GODDARD. Saying so does not make it so. I have heard them say this and I have asked for proof that their drug is better than others, but they cannot produce such proof. I have heard them say it often enough, and maybe people will believe it. But I would have to have their proof. Then maybe people would agree that advertising the manufacturer's name would help the pharmacist. Mr. POTVIN. If it were to develop, sir, that the fabricator for some of the drugs at very low prices were from the big leagues of the industry, that would indicate some sort of dual distribution form, whereby the same pill made in the same plant is being marketed at a startling variety of prices. And we are not talking about Government procurement. Dr. GODDARD. I understand that. They do this today, though. Mr. DINGELL. The chair notes that it would be advisable to have counsel communicate with United Research Laboratories to find who the manufacturers of the several items listed in this advertisement referred to happen to be. Dr. GODDARD. We can find that for you, Mr. Chairman, and transmit it to you very easily through the Philadelphia district. They are required to maintain that for their record, you see. Mr. DINGELL. Well, if that would be your wish, Doctor, that would be very good. Dr. GODDARD. We will be happy to do so. STATEMENT OF THE FDA REGARDING MANUFACTURERS OF DRUGS ADVERTISED BY A limited inspection of United Research Labs was conducted by FDA's Philadelphia District Office to ascertain manufacturers of those drugs listed in an advertisement which appeared in the October 9, 1967 issue of Drug News Weekly. The following lists manufacturers of drugs on hand at United Research Labs at the time of inspection (October 27 and October 30, 1967): Tetracycline Hel: 100's-Pro-Ter, Milan, Italy. 1000's-Richlyn Laboratories, Philadelphia, Pa. Oxytetracycline Hel: 100's-Richlyn Laboratories, Philadelphia, Pa. 25 mg.: 1000's-Davis-Edwards Pharmacal Corp., New York, N.Y. Niacin 1000's-Bolar Pharmaceutical Co., Brooklyn, N.Y. 100 mg.: 1000's-Bolar Pharmaceutical Co., Brooklyn, N.Y. Digitoxin: 0.1 mg.: 1000's-Prestige Laboratories Co., Philadelphia, Pa. 0.2 mg.: 1000's-Davis-Edwards Pharmacal Corp., New York, N.Y. Pentobarbital Sodium, 11⁄2 gr.: 1000's-Nysco Laboratories, Long Island, N.Y. 5000's-Nysco Laboratories, Long Island, N.Y. Quinidine Sulfate, 3 gr.: 100's-Gyma Laboratories, Forest Hills, N.Y. 1000's-Milan Pharmaceuticals, Inc., Morgantown, W. Va. Conj. Estrongens Tabs : 0.625 mg.: 100's-Prestige Laboratories, Philadelphia, Pa. 1.25 mg.: 100's-Prestige Laboratories, Philadelphia, Pa. 2.50 mg.: 100's-Prestige Laboratories, Philadelphia, Pa. Chloramphenical: 100's-Nylos Trading Co., Inc., New York, N.Y., distributor. 500's-John D. Copanos & Co., Inc., Baltimore, Md. 1000's-John D. Copanos & Co., Inc., Baltimore, Md. Penicillin Buffered Tabs.: 400,000 units: 100's-Pure Laboratories, Parsippany, N.J. 500's-Milan Pharmaceuticals, Morgantown, W. Va. 100's-Milan Pharmaceuticals, Morgantown, W. Va. 1000's-Copanos & Co., Inc., Baltimore, Md. Mr. DINGELL. I Would like to discuss with you the theory of generics, if I could. This is something that has troubled me for some time. In theory, a chemical substance which achieves a certain degree of purity should give the same results in every circumstance, considering age, humidity, temperature, the person on whom it happens to operate, the physical condition, the solubility and other factors being constant. Am I correct? Dr. GODDARD. In theory. Mr. DINGELL. So assuming that you have achieved this chemical identity, generally the therapeutic effect should be substantially identical; should it not? Dr. GODDARD. If you are dealing with a pure chemical and it is not combined with inactive ingredients, binders, shellacs, sugar coating, and other agents which are used to produce the dosage from, then your assumption is indeed correct. Mr. DINGELL. Now, has Food and Drug taken any steps to assure the substantial identity of the additives and so forth used-the inert substances, the binders, the tableting agents, and so forth-to achieve the dosage form? Dr. GODDARD. Yes. We do require information on each of these. Mr. DINGELL. When we achieve substantial identity in a pill by including the different devices that are used to create a substantially identical dosage form, in theory, then, we should achieve therapeutic identity insofar as the effect of the particular drug in the body of the patient is concerned. Is that correct?* Dr. GODDARD. In theory; yes. Mr. DINGELL. How often, in fact, would this type of circumstances deviate from theory and practice? Dr. GODDARD. This is what is not known. We have had, perhaps, a dozen major episodes in the past 5 or 7 years, where so-called generics have been demonstrated to be therapeutically not equivalent, and in part, this has been related to, oh, a variety of factors. Mr. DINGELL. Have you been able to identify the reasons on this, Doctor? Dr. GODDARD. In every instance, I believe we have. Mr. DINGELL. Could you submit for the record a statement of those instances to which you allude? Dr. GODDARD. I would be happy to. Mr. DINGELL. I know your time is limited this morning, so rather than ask you to set them out, it would be better for you to give us this for the record. Dr. GODDARD. I would be happy to. (The statement follows:) STATEMENT OF THE FDA REGARDING REPORTING INSTANCES OF LACK OF THERAPEUTIC EQUIVALENCY The following are examples of lack of efficiency of generic formulations in cases where brand products of the same drug had been effective in the past and proved to be effective subsequent to failure of the generic products. All references were taken from an article entitled "Biopharmaceutics Therapeutic Implications," by Milo Gibaldi, Ph.D., in Hospital Formulary Management, 1 (1966) 23-29. 1. Amonium Chloride-Enteric coated tablets of this drug were reported to have little effect in a large number of patients. 2. Bishydroxycoumarin-A larger physical size of tablets of this drug was reported to alter therapeutic response due to the larger quantity of inert diluent. 3. Choramphenical Palmitate-A crystalline form of the drug used in place of an amorphous form renders the drug biologically inactive. 4. Penicillin-Differences in crystalin form utilized may produce therapeuti cally unequivalent results. 5. Novobiocin-Differences in crystalin form utilized may produce therapeuti cally unequivalent results. 6. Theophylline Differences in crystalin form utilized may produce therapeutically unequivalent results. 7. Tetracycline-Differences in crystalin form utilized may produce therapeutically unequivalent results. 8. Prednisone-Inactive tablets result from incomplete absorption of the drug. 9. Thyroid-Powder for this drug could be extracted from two sources under U.S.P. standards; however, it was found that the biologic activity was twice as great with one of the sources as compared to the other. 10. Tolbutamide-Changes in dosage form have been reported to produce unsatisfactory therapeutic response. 11. Vitamin preparations-Sugar coated tablets were reported to produce incomplete absorption. Mr. DINGELL. You have referred to some other matters, but I would like to follow up this problem of therapeutic identity. I am troubled very much by the fact that this is almost within the realm of scientific impossibility, and you indicate that it is within several years of scientific possibility. What other steps are you taking to assure that this scientific possibility is achieved in terms of generics? Dr. GODDARD. The major steps are, one, the letting of contracts to carry out studies on therapeutic equivalency; two, the upgrading and tightening up of good manufacturing practices; three, the conduct of seminars throughout the United States where manufacturers are brought together to discuss problems that we have encountered in quality control. These are the major steps. The inspections and the St. Louis activity, which is an end product determination of quality control. Mr. DINGELL. Do you look to the day when it will be possible for you to include therapeutic identity as one of the elements of the new drug application? Dr. GODDARD. Therapeutic equivalency? Mr. DINGELL. Therapeutic equivalency. Dr. GODDARD. It is required today, sir, in the new drugs that have come into the marketplace since 1962. We think we have relatively few problems with these. Mr. DINGELL. With regard to generic names, do you not generally require that, let us say, a drug manufactured for sale as a generic pass the same new drug application form that a drug manufactured for sale under a trade name or patent name passed? Dr. GODDARD. In general; yes. Mr. DINGELL. As a general rule. Dr. GODDARD. In general. But there was a period of time when some new drugs were declared old drugs by administrative fiat. Reserpine is one. Then anybody could make it without any Mr. DINGELL. You mean under the grandfather clause? Dr. GODDARD. No; the administrative procedure that was used by the agency was to declare a new drug no longer a new drug and thus, anybody could make it without a new drug application. So we have a number of those to contend with. Mr. DINGELL. Do you have the power to assure therapeutic equivalency in the case of those new drugs that have been declared old drugs? Dr. GODDARD. Well, we have been making efforts to recapture some of these. We have required the manufacturers of two specific compounds in a group of drugs, drugs used for coronary vasodilation, to come in with a new drug application form last year. We had 65 or 70 NDA's |